amphotericin-b and Mycoses

During the catastrophic wave of Coronavirus disease 2019, health agencies started to report an infrequent but lethal mucormycosis or black fungal infection. Primarily, it causes sinusitis by affecting nasal, oral, lung, brain, ocular, and other body tissues. It becomes more fatal, especially in diabetic, cancer, and immune-compromised patients. Before 2020, the prevalence of mucormycosis was very rare but it has rapidly emerged globally from late 2020 to mid-2021. Recently, the mucormycosis got worse and epidemic with more than 30,000 cases reported across India. The etiology of infection can be diagnosed by molecular, serological, microscopic, and clinical methods. However, early diagnosis of this ailment is still a challenging task due to no standalone diagnostic tool available along with clinical manifestations of the ailment resembling other fungal diseases. The treatment of mucormycosis is also challenging and frequently requires long-term treatment. Amphotericin B was found to be an effective antifungal for preventing mucormycosis but it failed if infection disseminated to necrotizing tissues or adjacent organs. Removal of infected tissue/organ by surgery is an alternative treatment to control mucormycosis. In addition, reversal of underlying predisposing conditions based on therapy is also in practice for its prevention. This review highlights different aspects of mucormycosis such as pathogenesis, diagnosis, treatment, and their challenges and so on. We also emphasized the epidemiological shift during the recent outbreak and its influence on the different regions of India.

Topics: Amphotericin B; Antifungal Agents; COVID-19; Humans; Mucormycosis; Mycoses

Invasive fungal infections in humans are common in people with compromised immune systems and are difficult to treat, resulting in high mortality. Amphotericin B (AmB) is one of the main antifungal drugs available to treat these infections. AmB binds with plasma membrane ergosterol, causing leakage of cellular ions and promoting cell death. The increasing use of available antifungal drugs to combat pathogenic fungal infections has led to the development of drug resistance. AmB resistance is not very common and is usually caused by changes in the amount or type of ergosterol or changes in the cell wall. Intrinsic AmB resistance occurs in the absence of AmB exposure, whereas acquired AmB resistance can develop during treatment. However, clinical resistance arises due to treatment failure with AmB and depends on multiple factors such as the pharmacokinetics of AmB, infectious fungal species, and host immune status.

Topics: Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Candida albicans; Drug Resistance, Fungal; Ergosterol; Humans; Invasive Fungal Infections; Microbial Sensitivity Tests; Mycoses; Sphingolipids

The outbreak of a fatal black fungus infection after the resurgence of the cadaverous COVID-19 has exhorted scientists worldwide to develop a nutshell by repurposing or designing new formulations to address the crisis. Patients expressing COVID-19 are more susceptible to Mucormycosis (MCR) and thus fall easy prey to decease accounting for this global threat. Their mortality rates range around 32-70% depending on the organs affected and grow even higher despite the treatment. The many contemporary recommendations strongly advise using liposomal amphotericin B and surgery as first-line therapy whenever practicable. MCR is a dangerous infection that requires an antifungal drug administration on appropriate prescription, typically one of the following: Amphotericin B, Posaconazole, or Isavuconazole since the fungi that cause MCR are resistant to other medications like fluconazole, voriconazole, and echinocandins. Amphotericin B and Posaconazole are administered through veins (intravenously), and isavuconazole by mouth (orally). From last several years so many compounds are developed against invasive fungal disease but only few of them are able to induce effective treatment against the micorals. Adjuvant medicines, more particularly, are difficult to assess without prospective randomized controlled investigations, which are challenging to conduct given the lower incidence and higher mortality from Mucormycosis. The present analysis provides insight into pathogenesis, epidemiology, clinical manifestations, underlying fungal virulence, and growth mechanisms. In addition, current therapy for MCR in Post Covid-19 individuals includes conventional and novel nano-based advanced management systems for procuring against deadly fungal infection. The study urges involving nanomedicine to prevent fungal growth at the commencement of infection, delay the progression, and mitigate fatality risk.

Topics: Amphotericin B; COVID-19; Humans; Mucormycosis; Mycoses; Virulence

Fungi are a small but important part of the human microbiota and several fungi are familiar to the immune system, yet certain can cause infections in immunocompromised hosts and referred as opportunistic pathogens. The fungal coinfections in COVID-19 hosts with predisposing conditions and immunosuppressive medications are posing higher severity and death. The immunological counteraction (innate/adaptive immunity) is triggered when the PRRs on the host cells recognize the fungal PAMPs. However, in simultaneous infections (COVID-19 and fungal coinfection), the synergism of TLR and NLR may hyperactivate the immune cells which dramatically increase the cytokine level and generate cytokine storm. Fungal colonization in the human gut assists the development of microbiome assembly, ecology, and shaping immune response. However, SARS-CoV-2 infection represented unstable mycobiomes and long-term dysbiosis in a large proportion in COVID-19 patients. Normally, amphotericin B is considered as first-line treatment for invasive fungal infection. So, amphotericin B therapy is recommended in COVID-19 hosts with serious fungal infections. Still, the long-term corticosteroid supplementation prescribed in case of severe pneumonia and lower oxygen levels may result in systemic fungal infection in COVID-19 patients, eventually limiting the lifesaving benefits of available medications. Also, due to the evolution of fungal resistance to available antibiotics, the current treatments are becoming ineffective. Therefore, this review summarizes the concerns, needed to deal with the impending crises.

Topics: Amphotericin B; COVID-19; Humans; Immunity; Mycoses; Pandemics; SARS-CoV-2

Over the last 50 years, the number of patients with mycotic infections has gradually increased. Amphotericin-B is a gold-standard drug used in serious systemic fungal infections. However, limited solubility and permeability are challenging issues associated with Amphotericin-B. Chemical modification is one of the ways to get its broader applicability and improved physicochemical properties. The review article provides a comprehensive overview of the chemical modification approach for investigating the mechanism of action, biological activity, bioavailability, and toxicity of Amphotericin B. Further, several drug delivery approaches have also been utilized to provide better therapeutic outcomes. This gives an overview of chemical approaches for exploring various factors associated with Amphotericin B and information on its drug delivery approaches for improved biopharmaceutical outcomes.

Topics: Amphotericin B; Antifungal Agents; Biological Products; Drug Delivery Systems; Humans; Mycoses

Blastoschizomyces capitatus infection is a rare fungal infection; mainly occurring in immunodeficient patients, which can cause multiple organ involvement. At present, there is no clear designated treatment regimen. This case was a rare example of Blastoschizomyces capitatus lung infection in patient with normal immune function, which was effectively controlled by combined antifungal therapy.. We report a 67-year-old male smoker, who, after cleaning a small bungalow for a long period, without any protective measures, developed cough with expectoration, fever and dyspnea. Pre-admission anti-infective medication (amoxicillin and roxithromycin) had little effect, and the patient's condition worsened. He had a past history of pulmonary tuberculosis with pleurisy 6 years before. Chest computed tomography (CT) showed evidence of old tuberculosis in the right upper lobe and inflammation in both lower lobes. White blood cell count was 14.51×109/L, neutrophils was 13.39×109/L and C-reactive protein (CRP) was 170 mg/L. Broad-spectrum antibiotics piperacillin sodium 4.0 g and tazobactam sodium 0.5 g q8h were administered empirically for 5 days. Blastoschizomyces capitatus infection was confirmed by next generation of macro genome sequencing (NGS) of bronchoalveolar lavage fluid and mass spectrum analysis of sputum. He was then switched to voriconazole antifungal therapy combined with aerosol inhalation of amphotericin B. His temperature normalized, expectoration and dyspnea were relieved. Total white cell count fell to 8.10×109/L, neutrophils to 5.81×109/L, and CRP to 76.8 mg/L.. This case demonstrates that Blastoschizomyces capitatus infection can occur in patients with normal immune function. Mass spectrometry and metagenomic NGS methods may have an advantage over traditional methods in identifying this fungal infection. In addition, the combination of voriconazole and nebulized amphotericin B can be employed as a novel regimen for treating Blastoschizomyces capitatus infection. For pulmonary infection with a history of environmental exposure, early pathogen identification and culture, and appropriate antibiotic treatment are key to optimizing outcome.

Topics: Aged; Amphotericin B; Antifungal Agents; Dyspnea; Humans; Lung; Male; Mycoses; Pneumonia; Voriconazole

Pseudozyma spp. are described as environmental yeasts but have also been identified as rare human pathogens found in immunocompromised patients. This systematic review details the clinical manifestations, diagnostic methodology, and empirical anti-fungal therapy for this rare yeast. PubMed, LILACS, Scielo, and Web of Science databases were searched for articles about Pseudozyma spp. infections from inception to June 2019. Inclusion criteria were any published studies that included patients with Pseudozyma spp. infection. Infections were identified using criteria set forth by the European Organization for Research and Treatment of Cancer, and were further classified according to clinical, laboratory, or radiologic findings, microbiologic confirmation, and response to therapy. Eleven articles were included with 15 patients. Oncological and/or hematological disorders were the most reported risk factors. Nontraditional microbiological methods correctly identified Pseudozyma spp., whereas traditional methods failed to identify fungal genus. Species were identified by sequencing, and most demonstrated a higher minimal inhibitory concentration (MIC) for fluconazole and echinocandins. MICs for itraconazole, voriconazole, and posaconazole varied by species. All isolates were susceptible to amphotericin B, which was the most used treatment. Pseudozyma spp. infections usually present with fever and are diagnosed by blood culture. Most species studied appeared to be resistant to fluconazole and echinocandin. Voriconazole, posaconazole, and amphotericin were effective in treating P. aphidis. However, more studies are needed to evaluate voriconazole and posaconazole in species other than P. aphidis.

Topics: Amphotericin B; Antifungal Agents; Echinocandins; Fluconazole; Humans; Itraconazole; Mycoses; Voriconazole; Yeasts

There are no standard choices on antifungal drugs for talaromycosis due to various factors, and related studies are also limited. This study summarizes and analyzes efficacy of different antifungal drugs for patients with talaromycosis, which can provide more reference evidence for drugs' choices in practice. We conducted a meta-analysis on prognostic impacts of different antifungal drugs against talaromycosis, and primary outcome was all-cause mortality. A total of 975 patients from 8 studies were included. One of the 8 studies was a randomized controlled trial and the others were retrospective studies. Among these patients, 582 cases were initiated with amphotericin B, 31 cases died (9.28%). The other 393 cases were initiated with itraconazole, and 54 cases died (14.00%). The initial use of amphotericin B for talaromycosis significantly reduced mortality compared with itraconazole (risk ratio (RR): 0.61; 95% confidence interval (CI): 0.41-0.90; P=0.01; I

Topics: Amphotericin B; Antifungal Agents; Fluconazole; Humans; Itraconazole; Mycoses; Pharmaceutical Preparations; Randomized Controlled Trials as Topic; Retrospective Studies

Pulmonary mycoses are associated with high morbidity and mortality. The current standard treatment by systemic administration is limited by inadequate local bioavailability and systemic toxic effects. Aerosolisation of antifungals is an attractive approach to overcome these problems, but no inhaled antifungal formulation is currently available for the treatment of pulmonary mycoses. Hence, the development of respirable antifungals formulations is of interest and in high demand. In this review, the recent advances in the development of antifungal formulations for pulmonary delivery are discussed, including both nebulised and dry powder formulations. Although the clinical practices of nebulised parenteral amphotericin B and voriconazole formulations (off-label use) are reported to show promising therapeutic effects with few adverse effects, there is no consensus about the dosage regimen (e.g. the dose, frequency, and whether they are used as single or combination therapy). To maximise the benefits of nebulised antifungal therapy, it is important to establish standardised protocol that clearly defines the dose and specifies the device and the administration conditions. Dry powder formulations of antifungal agents such as itraconazole and voriconazole with favourable physicochemical and aerosol properties are developed using various powder engineering technologies, but it is important to consider their suitability for use in patients with compromised lung functions. In addition, more biological studies on the therapeutic efficacy and pharmacokinetic profile are needed to demonstrate their clinical potential.

Topics: Amphotericin B; Antifungal Agents; Humans; Itraconazole; Mycoses; Voriconazole

The genus Blastobotrys consists of at least 20 species. Disease in humans has been reported with B adeninivorans, B raffinosifermentans, B proliferans and B serpentis, mostly in immunocompromised patients and those with cystic fibrosis.. We report a lung infection secondary to B raffinosifermentans in a cystic fibrosis patient successfully treated with isavuconazole and review the literature of invasive infections caused this genus. We also evaluated clinical isolates in our laboratory for species identification and antifungal susceptibility.. Phylogenetic analysis was performed on a collection of 22 Blastobotrys isolates in our reference laboratory, and antifungal susceptibility patterns were determined for nine clinically available antifungals against 19 of these isolates.. By phylogenetic analysis, 21 of the 22 isolates in our collection were identified as B raffinosifermentans and only 1 as B adeninivorans. Most were cultured from the respiratory tract, although others were recovered from other sources, including CSF and blood. Isavuconazole, caspofungin and micafungin demonstrated the most potent in vitro activity, followed by amphotericin B. In contrast, fluconazole demonstrated poor activity. The patient in this case responded to isavuconazole treatment for breakthrough infection due to B raffinosifermentans that was cultured from pleural fluid while on posaconazole prophylaxis post-bilateral lung transplantation for cystic fibrosis.. Blastobotrys species are rare causes of infections in humans and primarily occur in immunocompromised hosts. In our collection, the majority of isolates were identified as B raffinosifermentans. To our knowledge, this is the first report of successful treatment of such an infection with isavuconazole.

Topics: Adult; Amphotericin B; Antifungal Agents; Cystic Fibrosis; Female; Fluconazole; Genes, Fungal; Humans; Immunosuppression Therapy; Microbial Sensitivity Tests; Mycoses; Nitriles; Phylogeny; Pneumonia; Pyridines; Saccharomycetales; Triazoles

In the recent past, prevalence of life threatening fungal diseases have increased rapidly in immune-compromised cases such as acquired immunodeficiency syndrome (AIDS), cancer, organ transplant etc. Side by side, the appearance of drug resistance to the presently available antifungal therapeutics is on a rapid rise. It has become a top priority for the academia and pharmaceutical industries to develop new antifungal agents able to combat this resistance, and at the same time, possess potential broad spectrum of activity and minimum toxicity. An understanding of the pharmacological interactions between antifungal agents and their targets offers opportunities for design of new therapeutics. This review discusses the various methodology of drug design, structure activity relationships (SARs), and mode of action of variety of new antifungal agents.

Topics: Antifungal Agents; Drug Design; Fungi; Humans; Molecular Structure; Mycoses; Structure-Activity Relationship

Due to the limit of available treatments and the emergence of drug resistance in the clinic, invasive fungal infections are an intractable problem with high morbidity and mortality. The cell wall, as a fungi-specific structure, is an appealing target for the discovery and development of novel and low-toxic antifungal agents. In an attempt to accelerate the discovery of novel cell wall targeted drugs, this Perspective will provide a comprehensive review of the progress made to date on the development of fungal cell wall inhibitors. Specifically, this review will focus on the targets, discovery process, chemical structures, antifungal activities, and structure-activity relationships. Although two types of cell wall antifungal agents are clinically available or in clinical trials, it is still a long way for the other cell wall targeted inhibitors to be translated into clinical applications. Future efforts should be focused on the identification of inhibitors against novel conserved cell wall targets.

Topics: Antifungal Agents; Cell Wall; Drug Discovery; Fungi; GPI-Linked Proteins; Humans; Mannans; Mycoses; Triterpenes

We report here a case of disseminated Emergomyces pasteurianus infection from India in a patient with AIDS. The patient presented with weight loss, dyspnoea and multiple non-tender skin lesions over face, neck and chest over 3 months. The case was diagnosed by microscopy, histopathology of sample and isolation of fungus from skin lesion, breast nodule, bone marrow and sputum. The identification of the isolates was confirmed by sequencing internal transcribed spacer region of rDNA, beta-tubulin, actin and intein PRP8. The patient responded well to intravenous amphotericin B deoxycholate followed by itraconazole therapy.

Topics: Acquired Immunodeficiency Syndrome; Actins; Adult; Amphotericin B; Antifungal Agents; Deoxycholic Acid; DNA, Intergenic; DNA, Ribosomal; Drug Combinations; Female; Humans; India; Inteins; Itraconazole; Mycoses; Onygenales; Tubulin

Sinusitis is a serious infectious complication of allogeneic hematopoietic stem cell transplantation. Schizophyllum commune (S commune) is a common basidiomycete fungus that is rarely involved in human disease. We report herein a case of S commune sinusitis after allogeneic bone marrow transplantation. A 66-year-old man with myelodysplastic syndrome underwent allogeneic bone marrow transplantation and developed maxillary and ethmoid sinusitis. The sinusitis did not improve with liposomal amphotericin B after neutrophil engraftment, so we considered that surgical intervention was needed for the recovery of sinusitis. Endoscopic sinus surgery was performed. In the debridement tissue of paranasal mucosa, filamentous fungal elements were observed. Moreover, genetic analysis of the tissue revealed the presence of S commune. Schizophyllum commune should be recognized as a fungal pathogen that causes sinusitis after allogeneic hematopoietic stem cell transplantation. This case suggests the effectiveness of prompt surgical intervention with liposomal amphotericin B treatment for S commune sinusitis and the usefulness of genetic diagnosis for cases under antifungal treatment. (160 words).

Topics: Aged; Amphotericin B; Antifungal Agents; Bone Marrow Transplantation; Endoscopy; Hematopoietic Stem Cell Transplantation; Humans; Male; Mycoses; Myelodysplastic Syndromes; Schizophyllum; Sinusitis

To determine the cost-effectiveness of amphotericin B supplementation, we analyzed both current costs to treat postendothelial keratoplasty (EK) fungal infections and potential costs associated with amphotericin B supplementation.. We collected 19 US cases of post-EK fungal eye infections from the published literature and assessed the associated costs from the literature. A survey of surgeons was also conducted with questions regarding their experiences in managing these infections.. We estimated that the costs to diagnose, manage, and treat post-EK fungal keratitis and post-EK fungal endophthalmitis are USD $21,113 and $34,850, respectively. The largest portion of the costs can be attributed to the need for additional surgical management, which is required in 79% of the cases. We estimated the total cost of amphotericin B supplementation to be $44.39 per graft with use of conventional amphotericin B and conservative assumptions regarding supplementation processes. Cost-effectiveness analysis demonstrated that amphotericin B supplementation is cost-effective at $100,000 per quality-adjusted life-year level only if amphotericin B supplementation can prevent more than 69.62% of post-EK fungal infections, assuming the incidence of post-EK fungal infection remains at the level it was between 2012 and 2017.. We found that amphotericin B supplementation can be cost-effective under conservative assumptions if it is moderately effective in preventing post-EK fungal infections.

Topics: Administration, Oral; Amphotericin B; Antifungal Agents; Corneal Transplantation; Cost-Benefit Analysis; Endothelium, Corneal; Eye Infections, Fungal; Humans; Mycoses; Organ Preservation

Empirical antifungal therapy is recommended in high-risk patients who have persistent febrile neutropenia (FN) despite broad-spectrum antibiotic therapy. Based on high-quality evidence, most guidelines recommend caspofungin. The aim of this study was to clarify whether echinocandins, including micafungin, are associated with improved clinical outcomes in patients with persistent FN. We conducted a meta-analysis of randomized controlled trials (RCTs) of empirical therapy with echinocandins and non-echinocandins for FN in patients with hematological disease. The primary outcome was all-cause mortality within 7 days after completion of therapy. Secondary outcomes included treatment success, and discontinuation of therapy because of adverse events. For subgroup analysis, we compared RCTs of echinocandins with liposomal amphotericin B. Six RCTs (four that evaluated caspofungin and two that evaluated micafungin) were included in the meta-analysis. Mortality and adverse events in echinocandin-treated patients were significantly lower than in those treated with non-echinocandins [risk ratio (RR) 0.70, 95% confidence interval (CI) 0.49-0.99; RR 0.48, 95% CI 0.33-0.71, respectively]. There was no significant difference in treatment success (RR 1.09, 95% CI 0.87-1.36). Mortality and adverse events in echinocandin-treated patients were significantly lower than in those treated with liposomal amphotericin B (RR 0.68, 95% CI 0.46-0.99; RR 0.53, 95% CI 0.37-0.74, respectively). In conclusion, patients with persistent FN treated with echinocandins had decreased risk of death and adverse events. Both caspofungin and micafungin may be recommended as first-line empirical antifungal therapy in these patients. However, the small number of enrolled patients and the lack of RCTs involving pediatric patients should be considered when using micafungin.

Topics: Amphotericin B; Antifungal Agents; Echinocandins; Febrile Neutropenia; Humans; Mycoses; Randomized Controlled Trials as Topic; Treatment Outcome; Voriconazole

Talaromyces marneffei infection is an important opportunistic infection associated with acquired immune deficiency syndrome (AIDS). However, it is unusual in patients with non-AIDS and other non-immunosuppressed conditions. We report a case of delayed diagnosis of disseminated T. marneffei infection in non-AIDS, non-immunosuppressive and non-endemic conditions.. Early diagnosis in HIV-negative patients who are otherwise not immunosuppressed and endemic poses a serious challenge. T. marneffei infection is an FDG-avid nonmalignant condition that may lead to false-positive FDG PET/CT scans. Nevertheless, integrated FDG PET/CT is necessary in patients with fever of unknown origin in the early period to perform earlier biopsy for histopathology and culture in highly avid sites and to avoid delays in diagnosis and treatment.

Topics: AIDS-Related Opportunistic Infections; Amphotericin B; Antifungal Agents; China; Delayed Diagnosis; Diagnosis, Differential; Fatal Outcome; Fever; High-Throughput Nucleotide Sequencing; HIV; Humans; Liver Failure, Acute; Lymphoma; Male; Mycoses; Positron Emission Tomography Computed Tomography; Talaromyces; Tomography, X-Ray Computed; Young Adult

Fungi, which can cause serious infections, results in more than 1.35 million deaths annually throughout the world. Azole antifungal drugs which could inhibit the enzyme lanosterol 14α-demethylase, occupy an important position in the treatment of fungal infections. Tetrazoles, practically non-metabolized bioisosteric analog of carboxylic acid and cis-amide, possess a variety of chemotherapeutic properties, including antifungal activities. Hybridization represents a promising strategy to develop novel drugs, and hybridization of tetrazole with other antifungal pharmacophores has the potential to increase the activity and overcome the drug resistance. Various tetrazole hybrids have been designed, synthesized and screened for their antifungal activities, and some of them showed promising activity against both drug-susceptible and drug-resistant fungi. In this review, we present tetrazole hybrids for fighting against fungi. The structure-activity relationship (SAR) is also discussed to provide an insight for rational designs of more effective candidates.

Topics: Animals; Antifungal Agents; Azoles; Fungi; Humans; Mycoses; Pyridines; Pyrimidines; Quinolines; Structure-Activity Relationship; Tetrazoles

The resistance of pathogenic fungi and failure of drug therapy increased dramatically. Numerous studies have reported the individual or synergistic antifungal potency of natural and synthesized flavonoids, especially against drug-resistant fungi. This brief review summarizes the structure and individual or synergistic antifungal activity of natural and synthesized flavonoids (literatures mainly cover the past 10 years 2009-2019), with a special focus on the antifungal spectra, structure-activity relationship and mechanisms of actions. These may contribute to a better understanding of flavonoids as multi-target agents in the treatment of mycoses and provide some ideas on the development of novel flavonoids-based antifungals.

Topics: Antifungal Agents; Biological Products; Flavonoids; Fungi; Humans; Mycoses

Cerebral abscesses caused by dark-pigmented Fonsecaea fungi are rare, especially in otherwise healthy individuals. In this case report, we present a 61-year-old man from Moldova, living in the Czech Republic, who had worked as a locksmith on oil platforms in Turkmenistan, Kazakhstan, Sudan, and Iraq since 1999, and was admitted to a neurology ward for a sudden motion disorder of the right leg, dysarthria, and hypomimia. Imaging revealed presence of expansive focus around the left lateral ventricle of the brain and a pronounced peripheral edema. The intracranial infectious focus was excised under intraoperative SonoWand guidance. Tissue samples were histologically positive for dark-pigmented hyphae, suggesting dematiaceous fungi. Therefore, liposomal amphotericin B therapy was initiated immediately. Fonsecaea monophora was provisionally identified using ITS rDNA region sequencing directly from brain tissue. The identification was subsequently confirmed by cultivation and DNA sequencing from culture. The strain exhibited in vitro sensitive to voriconazole (MIC = 0.016 μg/mL) and resistance to amphotericin B (MIC = 4 μg/mL); therefore, the amphotericin B was replaced with voriconazole. Postoperatively, a significant clinical improvement was observed and no additional surgery was required. Based on the literature review, this is the third documented case of cerebral infection due to this pathogen in patients without underlying conditions and the first such case in Europe.

Topics: Amphotericin B; Antifungal Agents; Ascomycota; Brain Abscess; Czech Republic; DNA, Ribosomal; Humans; Immunocompetence; Male; Middle Aged; Mycoses; Treatment Outcome

Colletotrichum species are known as important pathogens of plants with an impact on crop production. Some of these species are also known as a cause of rare ophthalmic infections in humans. A case of keratitis caused by Colletotrichum dematium after corneal trauma in a 56-year-old woman is presented. Infection was diagnosed based on positive microscopy and culture. The fungal isolate was identified by morphological characteristics and DNA sequencing of the ITS rDNA region, β-tubulin (tub2) and glyceraldehyde-3-phosphate dehydrogenase (gapdh) genes. The patient responded well to topical therapy with amphotericin B combined with intravenous amphotericin B but improvement was associated with the corneal collagen cross-linking. The review of the literature revealed another 13 cases of C. dematium keratitis, all but one patient having at least one keratitis risk factor in their history. Almost all patients (n = 12) were treated with topical polyene antibiotics (natamycin or amphotericin B), improvement and cure were achieved in eight of them.

Topics: Administration, Topical; Adolescent; Adult; Amphotericin B; Antifungal Agents; Colletotrichum; DNA, Ribosomal Spacer; Eye Injuries; Female; Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); Humans; Keratitis; Male; Microbiological Techniques; Middle Aged; Molecular Diagnostic Techniques; Mycoses; Sequence Analysis, DNA; Treatment Outcome; Tubulin; Young Adult

Invasive fungal diseases carry high morbidity and mortality in patients undergoing chemotherapy for hematological malignancies or allogeneic hematopoietic stem cell transplantation. In order to prevent these life-threatening infections, antifungal chemoprophylaxis plays an important role in daily clinical practice. Broad-spectrum antifungal triazoles are widely used but exhibit disadvantages such as relevant drug-drug interactions. Therefore, amphotericin B products or echinocandins can be an alternative in selected patient populations. As these compounds are available as intravenous formulations only, there is growing interest in extended dosing regimens. Although not approved for these agents, this strategy is a rational option, as these compounds have properties suitable for this strategy, including dose-proportional pharmacokinetics, prolonged elimination half-life, and a large therapeutic window. As the use of extended dosing regimens in antifungal prophylaxis is expanding in clinical practice, we reviewed the pharmacokinetic and pharmacodynamic rationale for this strategy, animal model data, dose escalation studies, and clinical trials supporting this concept.

Topics: Amphotericin B; Antibiotic Prophylaxis; Antifungal Agents; Echinocandins; Hematologic Neoplasms; Humans; Mycoses; Transplant Recipients; Transplantation, Homologous

Invasive fungal disease is a serious infectious complication of allogeneic hematopoietic stem cell transplantation (HSCT). Exserohilum rostratum is a species causing phaeohyphomycosis, which rarely causes invasive disease in humans. We treated a case of sinusitis caused by E. rostratum after cord blood transplantation (CBT). A 60-year-old man with myelodysplastic syndrome, who had a medical history of an operation to correct deviation of the nasal septum, developed sinusitis caused by E. rostratum under prolonged profound neutropenia after a second CBT because of the graft rejection of the first transplantation. Liposomal amphotericin B improved the sinusitis. A literature review revealed nine reported cases of sinusitis caused by E. rostratum, including our case. Although five cases had severe neutropenia at onset (HSCT recipients, n = 2; aplastic anemia, n = 3), the remaining four had no preexisting immunosuppressive conditions. However, three of the four patients had preexisting nasal diseases with or without a history of surgery, as in our case. Excluding our case, the outcome was fatal in five neutropenic patients, whereas the four patients without neutropenia recovered. Although sinusitis caused by E. rostratum is rare, E. rostratum should be recognized as a possible pathogen causing sinusitis in highly immunosuppressed patients such as HSCT recipients. Preexisting nasal disease and/or nasal surgery could be risks for this infection.

Topics: Adolescent; Amphotericin B; Anemia, Aplastic; Antifungal Agents; Ascomycota; Bone Marrow Transplantation; Child; Child, Preschool; Female; Fetal Blood; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Male; Middle Aged; Mycoses; Myelodysplastic Syndromes; Neutropenia; Sinusitis; Young Adult

To assess the efficacy and safety of bladder irrigation with amphotericin B for treatment of fungal infection in the urinary tract.. All the available randomized controlled trials (published before March, 2018) examining bladder irrigation with amphotericin B for treatment of urinary tract fungal infection were searched in the Cochrane Central Register of Controlled Trials (Issue 12, 2017), PubMed, EMBase, Web of Knowledge Database, CNKI, CBM, Wanfang DATA and VIP information. Data were extracted from the selected trials for meta-analysis using RevMan 5.3 software.. A total of 96 studies were retrieved from the databases, and 9 trials involving 853 patients were included in the analysis. Meta-analysis results showed that compared with oral administration of fluconazole, bladder irrigation with amphotericin B was more effective in the treatment of fungal infection in the urinary tract (OR=1.66, 95%CI: 1.2-2.3, P=0.002) and was associated with less adverse reactions.. Bladder irrigation with amphotericin B can improve the curative effect of fungal infection in the urinary tract, but due to the small sample size of the included studies, this conclusion needs to be further validated by high-quality studies.

Topics: Amphotericin B; Antifungal Agents; Fluconazole; Humans; Mycoses; Randomized Controlled Trials as Topic; Therapeutic Irrigation; Urinary Bladder; Urinary Tract Infections

Invasive fungal infections often occur in immunocompromised patients. Here, we report an infection case caused by Geotrichum capitatum in a severe aplastic anemia patient.. Identification of the pathogenic bacteria was done by sequencing and mass spectrometric analysis.. The fungal infection was isolated from blood cultures. The pathogenic bacteria were identified as Geotrichum capitatum. The infection was primarily cured by voriconazole and caspofungin monotherapy. However, the effect was not obvious. Then a combination of liposomal amphotericin B and caspofungin was used. Body temperature of the patient decreased, and clinical symptoms improved.. Sequencing and mass spectrometric analysis could have a role for Geotrichum capitatum diagnosis. Curative effect of using a single antifungal drug was unsatisfactory. Using liposome amphotericin B combined with caspofungin might obtain certain curative effect. Early diagnosis and appropriate combined therapy were necessary to improve the outcome of patients with Geotrichum capitatum infection.

Topics: Adolescent; Amphotericin B; Anemia, Aplastic; Antifungal Agents; Caspofungin; Drug Therapy, Combination; Female; Geotrichum; Humans; Mycoses; Severity of Illness Index; Voriconazole

It is not yet established the advantages between amphotericin B lipid complex (ABLC) and liposomal (L-AmB) in patients with invasive fungal infections refractory to usual doses of conventional AmB (d-AmB), previous renal impairment, or unacceptable d-AmB renal toxicity. This systematic review aims to compare ABLC and L-AmB effectiveness and safety outcomes in these subgroups of patients.. The search was performed on Medline, Cochrane Library, EMBASE, and LILACS databases.. treatment comparing L-AmB with ABLC; patients who had (i) refractory infection after being treated with d-AmB, (ii) previous renal impairment, or (iii) unacceptable d-AmB toxicity. Two investigators independently screened the search results, assessed trial quality, and extracted data. A total of 1,054 articles were identified in the literature. Among those, eleven were selected for full-text reading and five met the inclusion criteria.. The five articles included reported on four separate observational studies. Overall, no significant difference was found in clinical relevant outcomes as new-onset dialysis, length of hospital stay, or mortality when comparing both lipid formulations. The studies reported a trend toward lower nephrotoxicity in patients treated with L-AmB. However, the results were imprecise and heterogeneous and the studies presented important methodological biases.. The studies included in this systematic review pointed toward less nephrotoxicity events in the L-AmB group. However, due to low quality of evidence and no statistically significant differences in other clinical relevant outcomes, there is no definitive evidence of overall superiority in effectiveness or safety outcomes regarding one lipid formulation or another in this population subgroup.

Topics: Amphotericin B; Antifungal Agents; Humans; Length of Stay; Mycoses; Observational Studies as Topic; Renal Dialysis; Renal Insufficiency

Recently an increase in both the prevalence and incidence of invasive fungal infections have been reported. The number of fungal species that can cause systemic mycoses are higher and current antifungal therapies are still far from ideal. The emergence of antifungal resistances has a major clinical impact when using azoles and echinocandins leading to possible treatment failure and ultimately putting the patient's life at risk. Amphotericin B can play a key role in treating severe invasive mycoses as the incidence of antifungal resistance is very low combined with a high efficacy against a wide range of fungi. However, the use of this drug is limited due to its high toxicity and the infusion-related side effects often necessitating patient hospitalisation. New medicines based on lipid-based systems have been commercialised in the last decade, these treatments are able to reduce the toxicity of the drug but intravenous administration is still required. An oral or topically self-administered amphotericin B formulation can overcome these challenges, however such a product is not yet available. Several drug delivery systems such as cochleates, nanoparticulate and self-emulsifying systems are under development in order to enhance the solubility of the drug in aqueous media and promote oral absorption and cutaneous permeation across the skin. In this review, the type of drug delivery system and the effect of particle size on efficacy, toxicity and biodistribution will be discussed.

Topics: Amphotericin B; Antifungal Agents; Drug Delivery Systems; Humans; Mycoses; Tissue Distribution

By selecting a unique combination of lipids and amphotericin B, the liposome composition for AmBisome® (L-AmBis) has been optimized resulting in a formulation that is minimally toxic, targets to fungal cell walls, and distributes into and remains for days to weeks in various host tissues at drug levels above the MIC for many fungi. Procedures have been standardized to ensure that large scale production of the drug retains the drug's low toxicity profile, favorable pharmacokinetics and antifungal efficacy. Tissue accumulation and clearance with single or multiple intravenous administration is similar in uninfected and infected animal species, with tissue accumulation being dose-dependent and the liver and spleen retaining the most drug. The efficacy in animals appears to be correlated with drug tissue levels although the amount needed in a given organ varies depending upon the type of infection. The long-term tissue retention of bioactive L-AmBis in different organs suggests that for some indications, prophylactic and intermittent drug dosing would be efficacious reducing the cost and possible toxic side-effects. In addition, preliminary preclinical studies using non-intravenous routes of delivery, such as aerosolized L-AmBis, catheter lock therapy, and intravitreal administration, suggest that alternative routes could possibly provide additional therapeutic applications for this antifungal drug.

Topics: Amphotericin B; Animals; Antifungal Agents; Chemistry, Pharmaceutical; Dose-Response Relationship, Drug; Drug Liberation; Humans; Liposomes; Liver; Mycoses; Spleen; Tissue Distribution

Liposomal amphotericin B (AmBisome

Topics: Amphotericin B; Antifungal Agents; Cell Membrane; Cell Wall; Drug Liberation; Drug Resistance, Fungal; Humans; Liposomes; Mycoses

Amphotericin B (AmB) is the drug of choice in the treatment of invasive fungal infections and visceral leishmaniasis. Although AmB has a higher selectivity for ergosterol (present in fungi and Leishmania spp. membrane) than for cholesterol, mammalian cells are affected by AmB, mainly in its oligomeric aggregated form, resulting in side effects, especially nephrotoxicity. The development of nanotechnology-based drug delivery systems for AmB is a promising avenue since nanoparticles have the ability to target drugs to the infected cells, and their prolonged drug release profile permits longer contact between the drug and the fungi/parasite. In this review, we made an overview about nanoparticles as colloidal carriers for AmB, including polymeric-based nanoparticles, protein-based nanoparticles and solid lipid-based nanoparticles with respect to their application for the treatment of invasive fungal infections and leishmaniasis.

Topics: Amphotericin B; Animals; Colloids; Drug Carriers; Drug Delivery Systems; Humans; Leishmaniasis; Mycoses; Nanoparticles; Nanotechnology

Objective To know the patterns and consumption trends (2008-2013) of antifungal agents for systemic use in 52 acute care hospitals affiliated to VINCat Program in Catalonia (Spain). Methods Consumption was calculated in defined daily doses (DDD)/100 patient-days and analyzed according to hospital size and complexity and clinical departments. Results Antifungal consumption was higher in intensive care units (ICU) (14.79) than in medical (3.08) and surgical departments (1.19). Fluconazole was the most consumed agent in all type of hospitals and departments. Overall antifungal consumption increased by 20.5%during the study period (p = 0.066); a significant upward trend was observed in the consumption of both azoles and echinocandins. In ICUs, antifungal consumption increased by 12.4% (p = 0.019). Conclusions The study showed a sustained increase in the overall consumption of systemic antifungals in a large number of acute care hospitals of different characteristics in Catalonia. In ICUs there was a trend towards the substitution of older agents by the new ones.

Topics: Amphotericin B; Antifungal Agents; Azoles; Bone Marrow Transplantation; Drug Utilization; Echinocandins; Fungi; Humans; Intensive Care Units; Mycoses; Organ Transplantation; Retrospective Studies; Spain; Surgery Department, Hospital

Trichoderma species are saprophytic filamentous fungi producing localized and invasive infections that are cause of morbidity and mortality, especially in immunocompromised patients, causing up to 53% mortality. Non-immunocompromised patients, undergoing continuous ambulatory peritoneal dialysis, are other targets of this fungus. Current molecular diagnostic tools, based on the barcode marker ITS, fail to discriminate these fungi at the species level, further increasing the difficulty associated with these infections and their generally poor prognosis.. We report on the first case of endocarditis infection caused by Trichoderma longibrachiatum in a 30-year-old man. This patient underwent the implantation of an implantable cardioverter defibrillator in 2006, replaced in 2012. Two years later, the patient developed fever, treated successfully with amoxicillin followed by ciprofloxacin, but an echocardiogram showed large vegetation onto the ventricular lead. After CIED extraction, the patient had high-grade fever. The culturing of the catheter tip was positive only in samples deriving from sonication according to the 2014 ESCMID guidelines, whereas the simple washing failed to remove the biofilm cells from the plastic surface. Subsequent molecular (ITS sequencing) and microbiological (macromorphology) analyses showed that the vegetation was due to T. longibrachiatum.. This report showed that T. longibrachiatum is an effective threat and that sonication is necessary for the culturing of vegetations from plastic surfaces. Limitations of the current barcode marker ITS, and the long procedures required by a multistep approach, call for the development of rapid monophasic tests.

Topics: Adult; Amphotericin B; Antifungal Agents; Base Sequence; Biofilms; Defibrillators, Implantable; DNA, Intergenic; Endocarditis; Heart; Humans; Male; Mycoses; Sequence Analysis, DNA; Trichoderma; Voriconazole

Obesity is a worldwide epidemic associated with multiple comorbidities that increase the risk of hospitalization. Very little pharmacokinetic data are available for antifungal agents in obesity, as this population is often excluded from drug development studies and these agents are less commonly used than other antimicrobials. Systemic antifungal therapy for invasive candidiasis continues to have a high failure rate, and dose optimization in obesity provides an opportunity for improvement. Based on currently available data, some antifungals should be dosed based on total body weight (i.e. fluconazole), while others should not be adjusted for increased body weight (i.e. posaconazole). More studies are needed to determine if and when dosing changes are needed for many of the antifungal agents. Therefore, drug therapy regimens should be individually evaluated for dose optimization due to body weight.

Topics: Amphotericin B; Antifungal Agents; Candidiasis, Invasive; Caspofungin; Echinocandins; Fluconazole; Humans; Lipopeptides; Micafungin; Mycoses; Nitriles; Obesity; Pyridines; Triazoles

We report here the first case of disseminated Emmonsia pasteuriana infection in a patient with AIDS in India. The patient presented with weight loss, dyspnoea, left-sided chest pain and multiple non-tender skin lesions over face and body for 3 months. Disseminated emmonsiosis was diagnosed on microscopic examination and fungal culture of skin biopsy and needle aspirate of lung consolidation. It was confirmed by sequencing internal transcribed spacer region of rDNA, beta tubulin, actin, and intein PRP8. The patient responded to amphotericin B and itraconazole therapy.

Topics: Adult; AIDS-Related Opportunistic Infections; Amphotericin B; Antifungal Agents; Biopsy, Needle; Chest Pain; Chrysosporium; Diagnostic Errors; DNA, Fungal; DNA, Ribosomal; Dyspnea; Female; Humans; India; Itraconazole; Mycoses; Phylogeny; Weight Loss

Amphotericin B (AmB)-deoxycholate micellar formulation, Fungizone®, is the drug of choice for the treatment of unidentified mycotic infections. However, it usage has been marred by long therapeutic regimes and severe side effects. The less toxic lipid associated AmB formulations have been limited by their high expense, with some loss in activity. The quest for decreasing AmB cytotoxicity as well as production cost has resulted in the development of AmB super-aggregate as an alternative to its existing lipid formulations. AmB super-aggregate is spectroscopically distinct from the aggregate present in Fungizone, displaying enhanced thermodynamic stability. The poly-aggregated form of AmB exhibits reduced toxicity in mammalian cells in vitro and to mice in vivo, while maintaining its 'gold standard' antifungal activity. Poly-aggregated AmB interacts predominantly with serum albumin and also attenuates its ability to induce potentially harmful cytokines. Bio-distribution studies have demonstrated that the self-associated AmB shows greater accumulation in reticulo-endothelial organs while sparing kidney, one of the principal organs where its toxic effects are seen. The super-aggregated AmB can thus be used to improve the therapeutic index of AmB against a plethora of fungal infections including candidiasis and cryptococcosis, thus providing a fitting solution to growing demand of an active, less toxic substitute of AmB.

Topics: Amphotericin B; Animals; Antifungal Agents; Cytokines; Deoxycholic Acid; Drug Combinations; Humans; Mice; Mycoses; Serum Albumin; Tissue Distribution

Invasive fungal infections are important causes of morbidity and mortality among critically ill patients. Early institution of antifungal therapy is pivotal for mortality reduction. Starting a targeted antifungal therapy after culture positivity and fungi identification requires a long time. Therefore, alternative strategies (globally defined as 'untargeted antifungal treatments') for antifungal therapy institution in patients without proven microbiological evidence of fungal infections have been discussed by international guidelines. This review was originally published in 2006 and updated in 2016. This updated review provides additional evidence for the clinician dealing with suspicion of fungal infection in critically ill, non-neutropenic patients, taking into account recent findings in this field.. To assess the effects of untargeted treatment with any antifungal drug (either systemic or nonabsorbable) compared to placebo or no antifungal or any other antifungal drug (either systemic or nonabsorbable) in non-neutropenic, critically ill adults and children. We assessed effectiveness in terms of total (all-cause) mortality and incidence of proven invasive fungal infections as primary outcomes.. We searched the following databases to February 2015: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (OVID), and EMBASE (OVID). We also searched reference lists of identified studies and major reviews, abstracts of conference proceedings, scientific meetings and clinical trials registries. We contacted experts in the field, study authors and pharmaceutical companies as part of the search strategy.. We included randomized controlled trials (RCTs) (irrespective of language or publication status) comparing the use of untargeted treatment with any antifungal drug (either systemic or nonabsorbable) to placebo, no antifungal, or another antifungal agent in non-neutropenic critically ill participants.. Three authors independently applied selection criteria, extracted data and assessed the risk of bias. We resolved any discrepancies by discussion. We synthesized data using the random-effects model and expressed the results as risk ratios (RR) with 95% confidence intervals. We assessed overall evidence quality using the GRADE approach.. We included 22 studies (total of 2761 participants). Of those 22 studies, 12 were included in the original published review and 10 were newly identified. Eleven trials compared the use of fluconazole to placebo or no antifungal treatment. Three trials compared ketoconazole versus placebo. One trial compared anidulafungin with placebo. One trial compared caspofungin to placebo. Two trials compared micafungin to placebo. One trial compared amphotericin B to placebo. Two trials compared nystatin to placebo and one trial compared the effect of clotrimazole, ketoconazole, nystatin and no treatment. We found two new ongoing studies and four new studies awaiting classification. The RCTs included participants of both genders with wide age range, severity of critical illness and clinical characteristics. Funding sources from pharmaceutical companies were reported in 11 trials and one trial reported funding from a government agency. Most of the studies had an overall unclear risk of bias for key domains of this review (random sequence generation, allocation concealment, incomplete outcome data). Two studies had a high risk of bias for key domains. Regarding the other domains (blinding of participants and personnel, outcome assessment, selective reporting, other bias), most of the studies had a low or unclear risk but four studies had a high risk of bias.There was moderate grade evidence that untargeted antifungal treatment did not significantly reduce or increase total (all-cause) mortality (RR 0.93, 95% CI 0.79 to 1.09, P value = 0.36; participants = 2374; studies = 19). With regard to the outcome of proven invasive fungal infection, there was low grade evidence that untargeted antifungal treatment significantly reduced the risk (RR 0.57, 95% CI 0.39 to 0.83, P value = 0.0001; participants = 2024; studies = 17). The risk of fungal colonization was significantly reduced (RR 0.71, 95% CI 0.52 to 0.97, P value = 0.03; participants = 1030; studies = 12) but the quality of evidence was low. There was no difference in the risk of developing superficial fungal infection (RR 0.69, 95% CI 0.37 to 1.29, P value = 0.24; participants = 662; studies = 5; low grade of evidence) or in adverse events requiring cessation of treatment between the untargeted treatment group and the other group (RR 0.89, 95% CI 0.62 to 1.27, P value = 0.51; participants = 1691; studies = 11; low quality of evidence). The quality of evidence for the outcome of total (all-cause) mortality was moderate. There is moderate quality evidence that the use of untargeted antifungal treatment is not associated with a significant reduction in total (all-cause) mortality among critically ill, non-neutropenic adults and children compared to no antifungal treatment or placebo. The untargeted antifungal treatment may be associated with a reduction of invasive fungal infections but the quality of evidence is low, and both the heterogeneity and risk of publication bias is high.Further high-quality RCTs are needed to improve the strength of the evidence, especially for more recent and less studied drugs (e.g. echinocandins). Future trials should adopt standardized definitions for microbiological outcomes (e.g. invasive fungal infection, colonization) to reduce heterogeneity. Emergence of resistance to antifungal drugs should be considered as outcome in studies investigating the effects of untargeted antifungal treatment to balance risks and benefit.

Topics: Adult; Amphotericin B; Antifungal Agents; Critical Illness; Fluconazole; Humans; Immunocompromised Host; Mycoses; Randomized Controlled Trials as Topic

The treatment of fungal infections in severely ill patients is a clinical and economic challenge worldwide. Liposomal amphotericin B and caspofungin are highly effective antifungal drugs; however, they are very expensive and health systems must select the drug that results in the best clinical outcomes and is economically feasible.. A systematic search was conducted in PubMed, Scopus, Web of Science, Cochrane Library, Health Economic Evaluation Database, and Centre for Review and Dissemination to find complete economic evaluations that directly compared the two treatment strategies. Expert commentary: Because of the high cost, patients in developing countries experience difficulty accessing highly effective treatments. These data can subsidize a decision for an effective antifungal treatment with reduced costs from all perspectives.

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Cost-Benefit Analysis; Drug Costs; Echinocandins; Humans; Lipopeptides; Mycoses; Severity of Illness Index; Treatment Outcome

Invasive mycoses are a major problem for immunocompromised individuals and patients in intensive care units. Morbidity and mortality rates of these infections are high because of late diagnosis and delayed treatment. Moreover, the number of available antifungal agents is low, and there are problems with toxicity and resistance. Alternatives for treating invasive fungal infections are necessary. Nanostructured systems could be excellent carriers for antifungal drugs, reducing toxicity and targeting their action. The use of nanostructured systems for antifungal therapy began in the 1990s, with the appearance of lipid formulations of amphotericin B. This review encompasses different antifungal drug delivery systems, such as liposomes, carriers based on solid lipids and nanostructure lipids, polymeric nanoparticles, dendrimers, and others. All these delivery systems have advantages and disadvantages. Main advantages are the improvement in the antifungal properties, such as bioavailability, reduction in toxicity, and target tissue, which facilitates innovative therapeutic techniques. Conversely, a major disadvantage is the high cost of production. In the near future, the use of nanosystems for drug delivery strategies can be used for delivering peptides, including mucoadhesive systems for the treatment of oral and vaginal candidiasis.

Topics: Amphotericin B; Antifungal Agents; Dendrimers; Drug Delivery Systems; Humans; Lipids; Liposomes; Mycoses; Nanostructures

Invasive fungal sinusitis (IFS) represents an often fatal condition within the pediatric population. In an effort to characterize demographics, treatment modalities, and prognostic factors, we performed a systematic review.. We systematically reviewed EMBASE, Medline, TRIPdatabase, SCOPUS and the Cochrane database for invasive fungal nasal and sinus infections limited to individuals <18 years of age. Case series including 3 or more patients were included. Demographics, treatment and outcomes were analyzed using R Gui statistical software.. Twelve studies met inclusion criteria (103 patients). There was male preponderance of 48.5% with median age of 11 years old. Majority of patients had underlying leukemia (44.6%). Aspergillus was the predominant organism (47%). Isolated nasal findings occurred in 14% of patients and nasal findings occurred in 49% overall. Absolute neutrophil count (ANC) of immunocompromised patients was below 600 in most patients (99%). Average and median length of neutropenia was 2 weeks. All patients were prescribed amphoterocin with 50% as single medicinal therapy. Surgery occurred in 82.8% of cases. The mortality rate was 46%. Univariate analysis identified presenting with facial pain as a negative predictor of overall mortality (OR 0.296, 95% CI: 0.104-0.843, p < 0.05).. Mortality remains high in pediatric patients with IFS. An ANC of <600 occurred in the majority of immunocompromised patients at a duration of 2 weeks. Presenting with facial pain was a negative predictor of mortality. Many studies label this condition as invasive fungal sinusitis; however, approximately one seventh presented with only nasal findings and half overall had nasal involvement.

Topics: Amphotericin B; Anemia, Aplastic; Antifungal Agents; Aspergillosis; Burkitt Lymphoma; Candidiasis, Invasive; Child; Facial Pain; Female; Fusariosis; Humans; Immunocompromised Host; Leukemia; Male; Mucormycosis; Mycoses; Neutropenia; Otorhinolaryngologic Surgical Procedures; Prognosis; Retrospective Studies; Sinusitis

Antifungal prescription remains a challenge in pregnant women because of uncertainties regarding fetal toxicity and altered maternal pharmacokinetic parameters that may affect efficacy or increase maternal and fetal toxicity. We present updated data reviewing the available knowledge and current recommendations regarding antifungal prescription in pregnancy. Amphotericin B remains the first-choice parenteral drug in spite of its well-established toxicity. Topical drugs are used throughout pregnancy because of limited absorption. Recent data have clarified the teratogenic effect of high-dose fluconazole during the first trimester and provided reassuring cumulative data regarding its use at a single low dose in this key period. Recent data have also provided additional safety data on itraconazole and lipidic derivatives of amphotericin B. Regarding newer antifungal drugs, including posaconazole and echinocandins, clinical data are critically needed before considering prescription in pregnancy.

Topics: Administration, Intravenous; Administration, Topical; Amphotericin B; Anti-Infective Agents, Local; Antifungal Agents; Female; Fluconazole; Humans; Itraconazole; Mycoses; Pregnancy; Pregnancy Complications, Infectious; Teratogens

Invasive fungal infections (IFIs) in neonatal and pediatric patients are still associated with high morbidity and mortality, increased length of hospital stay and high healthcare cost. Two key components are prerequisite to combat pediatric IFIs; first, definition of the 'at-risk' populations that could benefit the most from prophylactic treatment and second, prompt initiation of effective antifungal therapy.. In this article, updated prevention and targeted therapeutic approaches for IFIs in neonates and immunocompromised children are reviewed. Furthermore, European and American guidelines concerning IFI treatment in neonates and children are compared.. IFIs in neonates and children present substantial differences from adults in respect to their epidemiology, pharmacokinetics of antifungal agents and dosing as well as absence of interventional Phase III and IV clinical trials for guidance of evidence-based decisions. In the therapeutic armamentarium of these age groups, although amphotericin B formulations remain widely indicated, azoles with broader spectrum activity as well as echinocandins have been added in the updated antifungal treatment algorithm. Recent European guidelines (ESCMID and ECIL) contain specific recommendations for pediatric patients with IFIs. In both age groups, definitive updated guidance for prophylaxis and more importantly targeted treatment need to be further evaluated by large, multicenter, randomized controlled trials.

Topics: Amphotericin B; Antifungal Agents; Azoles; Child; Echinocandins; Humans; Immunocompromised Host; Infant, Newborn; Mycoses

Neonatal fungal and viral infections are associated with mortality and neurologic impairment among survivors. Advances in pharmacokinetics (PK) and pharmacodynamics (PD) of antimicrobial medications have led to improved dosing guidance for neonates. This article discusses the basic PK/PD properties and dosing of the most common antifungal and antiviral medications used in neonates.

Topics: Acyclovir; Amphotericin B; Antifungal Agents; Antiviral Agents; Candidiasis, Invasive; Cytomegalovirus Infections; Deoxycholic Acid; Drug Combinations; Fluconazole; Ganciclovir; Herpes Simplex; Humans; Infant; Infant, Newborn; Mycoses; Practice Guidelines as Topic; Pregnancy Complications, Infectious; Valganciclovir; Virus Diseases

Granulomatous diseases are caused by multiple infectious and noninfectious causes. Deep fungal infections can present in the skin or extracutaneously, most commonly with lung manifestations. An Azole or amphotericin B is the universal treatment. Blastomycosis-like pyoderma is a clinically similar condition, which is caused by a combination of hypersensitivity and immunosuppression. Successful treatment has been reported with antibiotics and, more recently, the vitamin A analog, acitretin. Granuloma inguinale and lymphogranuloma venereum cause ulcerative genital lesions with a granulomatous appearance on histology. The Centers for Disease Control and Prevention recommens treatment of these genital infections with doxycycline.

Topics: Acitretin; Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Azoles; Blastomycosis; Coccidioidomycosis; Cryptococcosis; Dermatomycoses; Doxycycline; Granuloma Inguinale; Histoplasmosis; Humans; Keratolytic Agents; Lymphogranuloma Venereum; Mycoses; Pyoderma; Sexually Transmitted Diseases; Sporotrichosis

This article presents an overview of the characteristics of liposomes as drug carriers, particularly in relation to liposomal formulations of amphotericin B. General features regarding structure, liposome-cell interactions, stability, encapsulation of active substances and elimination of liposomes are described. Up to the present time extensive efforts to produce similar or bioequivalent products of amphotericin B formulations, in particular in the case of liposomal amphotericin B, have been unsuccessful in spite of having a very similar composition and even an apparently identical manufacturing process. Guidelines for the development of generic liposomal formulations developed by the FDA and EMA are also summarized. Based on the available evidence of the composition of liposomes, any differences in the manufacturing process even if the same lipid composition is used may result in different final products. Therefore, it seems unreasonable to infer that all amphotericin B liposomal formulations are equal in efficacy and safety.

Topics: Amphotericin B; Animals; Antifungal Agents; Chemistry, Pharmaceutical; Clinical Trials as Topic; Drug Carriers; Drug Compounding; Drug Evaluation, Preclinical; Humans; Liposomes; Mycoses; Phospholipids; Unilamellar Liposomes

A restricted number of antifungal agents are available for the therapy of fungal diseases. With the introduction of epidemiological cut-off values for each agent in important fungal pathogens based on the distribution of minimal inhibitory concentration (MIC), the distinction between wild type and drug-resistant populations has been facilitated. Antifungal resistance has been described for all currently available antifungal agents in several pathogens and most of the associated resistance mechanisms have been deciphered at the molecular level. Clinical breakpoints for some agents have been proposed and can have predictive value for the success or failure of therapy. Tolerance to antifungals has been a much more ignored area. By definition, tolerance operates at antifungal concentrations above individual intrinsic inhibitory values. Important is that tolerance to antifungal agents favours the emergence of persister cells, which are able to survive antifungal therapy and can cause relapses. Here we will review the current knowledge on antifungal tolerance, its potential mechanisms and also evaluate the role of antifungal tolerance in the efficacy of drug treatments.

Topics: Amphotericin B; Antifungal Agents; Dose-Response Relationship, Drug; Drug Resistance, Fungal; Drug Tolerance; Echinocandins; Flucytosine; Fungi; Host-Pathogen Interactions; Humans; Microbial Sensitivity Tests; Mycoses; Triazoles

The management of neonatal sepsis is challenging owing to complex developmental and environmental factors that contribute to inter-individual variability in the pharmacokinetics and pharmacodynamics of many antimicrobial agents. In this review, we describe (i) the changing epidemiology of early- and late-onset neonatal sepsis; (ii) the pharmacologic considerations that influence the safety and efficacy of antibacterials, antifungals, and immunomodulatory adjuvants; and (iii) the recommended dosing regimens for pharmacologic agents commonly used in the treatment and prevention of neonatal sepsis. Neonatal sepsis is marked by high morbidity and mortality, such that prompt initiation of antimicrobial therapy is essential following culture collection. Before culture results are available, combination therapy with ampicillin and an aminoglycoside is recommended. When meningitis is suspected, ampicillin and cefotaxime may be considered. Following identification of the causative organism and in vitro susceptibility testing, antimicrobial therapy may be narrowed to provide targeted coverage. Therapeutic drug monitoring should be considered for neonates receiving vancomycin or aminoglycoside therapies. For neonates with invasive fungal infections, the development of new antifungal agents has significantly improved therapeutic outcomes in recent years. Liposomal amphotericin B has been found to be safe and efficacious in patients with renal impairment or toxicity caused by conventional amphotericin B. Antifungal prophylaxis with fluconazole has also been reported to dramatically reduce rates of neonatal invasive fungal infections and to improve long-term neurodevelopmental outcomes among treated children. Additionally, several large multicenter studies are currently investigating the safety and efficacy of oral lactoferrin as an immunoprophylactic agent for the prevention of neonatal sepsis.

Topics: Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Bacteremia; Bacterial Infections; Drug Monitoring; Fungemia; Humans; Infant; Infant, Newborn; Mycoses

The phenotypic methods for identification of antifungal resistance are reliable procedures, and MIC determination by reference techniques is the gold standard to detect resistant clinical isolates. In recent years, progress has been made towards the description of resistance mechanisms at molecular level. There are methods of detection that can be useful for clinical laboratories, but lack of standardization precludes their full and effective integration in the routine daily practice. The molecular detection of Candida resistance to azoles and to echinocandins and of Aspergillus resistance to triazoles can be clinically relevant and could help to design more efficient prevention and control strategies. This text reviews the present state of the detection of mechanisms of resistance at the molecular level in Candida spp. and Aspergillus spp. and its relevance to clinical practice.

Topics: Amphotericin B; Antifungal Agents; Azoles; Drug Resistance, Fungal; Echinocandins; Fungi; Humans; Microbial Sensitivity Tests; Mycoses

Nowadays, there are published trials in regards to the comparison of caspofungin with liposomal amphotericin B (L-AmB). However, these studies have a modest sample size and convey inconclusive results. The aim of this study was to review the efficacy and safety of caspofungin for the treatment of invasive fungal infections (IFIs), compared with L-AmB.. Electronic databases (up to July 31, 2013) PubMed and Embase databases, the Cochrane Library, and Google Scholar were searched to identify relevant trials of caspofungin and L-AmB. Analyses of efficacy and adverse outcomes were performed by relative risks (RRs) and 95% confidence intervals (CIs). Heterogeneity was assessed by χ(2)-test and the I(2)-statistic.. Three trials were included in this meta-analysis with 1249 modified intention-to-treat (MITT) patients. The results showed that caspofungin produced equal efficacy in favorable overall response (RR = 1.02, 95% CI 0.88-1.18; P = 0.81) and mortality rate (RR = 1.53, 95% CI 0.38-6.27, P = 0.55), safer in clinical adverse events (RR = 0.20, 95% CI 0.08-0.54; P = 0.001), laboratory adverse events (RR = 0.69, 95% CI 0. 57-0.84; P = 0.0002), and discontinuation rate (RR = 0.26, 95% CI 0.08-0.83, P = 0.02), compared with L-AmB in the treatment of patients with IFIs.. Based on the results of this meta-analysis, it would appear that caspofungin was measured to have equal efficacy in clinical outcomes and safer in terms of adverse events.

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Echinocandins; Febrile Neutropenia; Humans; Lipopeptides; Mycoses

Opportunistic fungal infections are a major cause of morbidity and mortality in neutropenic cancer patients and antifungal therapy is used both empirically and therapeutically in these patients.. To compare the benefits and harms of voriconazole with those of amphotericin B and fluconazole when used for prevention or treatment of invasive fungal infections in cancer patients with neutropenia.. Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2014, Issue 1 2014), MEDLINE (to January 2014). Letters, abstracts and unpublished trials were accepted. Contact was made with trial authors and industry.. Randomised clinical trials comparing voriconazole with amphotericin B or fluconazole.. Data on mortality, invasive fungal infection, colonisation, use of additional (escape) antifungal therapy and adverse effects leading to discontinuation of therapy were extracted independently by two review authors.. Three trials were included. One trial compared voriconazole to liposomal amphotericin B as empirical treatment of fever of unknown origin (suspected fungal infection) in neutropenic cancer patients (849 patients, 58 deaths). The second trial compared voriconazole to amphotericin B deoxycholate in the treatment of confirmed and presumed invasive Aspergillus infections (391 patients, 98 deaths). The third trial compared fluconazole to voriconazole for prophylaxis of fungal infections in patients receiving allogeneic stem cell transplantation (600 patients, number of deaths not stated). In the first trial, voriconazole was significantly inferior to liposomal amphotericin B according to the trial authors' prespecified criteria. More patients died in the voriconazole group and a claimed significant reduction in the number of breakthrough fungal infections disappeared when patients arbitrarily excluded from the analysis by the trial authors were included. In the second trial, the deoxycholate preparation of amphotericin B was used without any indication of the use of premedication to counter side effects and replacement of electrolytes or use of salt water. This choice of comparator resulted in a marked difference in the duration of treatment on the trial drugs (77 days with voriconazole versus 10 days with amphotericin B) and precluded meaningful comparisons of the benefits and harms of the two drugs. The third trial failed to find a difference in fungal free survival or invasive fungal infections at 180 days when voriconazole was compared to fluconazole.. Liposomal amphotericin B is significantly more effective than voriconazole for empirical therapy of fungal infections in neutropenic cancer patients and should be preferred. For treatment of aspergillosis, there are no trials that have compared voriconazole with amphotericin B given under optimal conditions. For prophylactic fungal treatment in patients receiving allogeneic stem cell transplantation, there was no difference between voriconazole and fluconazole regarding fungal free survival or invasive fungal infections.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Fluconazole; Humans; Liposomes; Mycoses; Neoplasms; Neutropenia; Opportunistic Infections; Pyrimidines; Randomized Controlled Trials as Topic; Triazoles; Voriconazole

Since the introduction of amphotericin B as an antifungal agent, the morbidity and mortality of pediatric patients with mycotic infections have increased, primarily because of the increased immunocompromised patients. Despite the fact that deoxycholate amphotericin B was once the primary drug used for mycotic infections, its administration to children older than neonates is currently controversial because of its nephrotoxic effects. Three lipid-associated formulations have been developed and have reportedly shown similar efficacy and fewer nephrotoxic effects in adults than conventional amphotericin B, but the conclusions from comparative studies in children evaluating the nephrotoxicity risks of the 4 agents are controversial. Nevertheless, guidelines favor liposomal or lipid complex amphotericin B when polyene antifungal therapy is recommended in this age group. However, high acquisition costs often preclude their prescription in economically poor regions. Thus, physicians must consider all of these factors when determining the most cost-effective polyene antifungal treatment for their pediatric patients. This is particularly pertinent in developing countries where resources are scarce. Adjuvant sodium supplementation has been reported to be effective in protecting kidney function in extremely low birth weight infants prescribed deoxycholate amphotericin B. Further pharmacokinetic and pharmacodynamic studies of the drug in children could also provide information for rational dosing regimens designed to decrease nephrotoxicity. Conventional amphotericin B, with appropriate kidney protective measures, still plays a role in the treatment of empiric invasive mycotic infections in most pediatric patients. Liposomal and lipid complex amphotericin B should be reserved for those receiving long-term nephrotoxic agents or with altered renal function or disease. Antifungal susceptibility, renal compromise and the clinical status of the patient should determine treatment for culture-proven infections. Under the current cost limitations, undertaking and evaluating low-cost, kidney-sparing, deoxycholate amphotericin B treatments for children should be a primary concern.

Topics: Adolescent; Amphotericin B; Antifungal Agents; Child; Child, Preschool; Deoxycholic Acid; Drug Combinations; Humans; Infant; Infant, Newborn; Kidney Diseases; Mycoses

Nystatin is sometimes used prophylactically in patients with severe immunodeficiency or in the treatment of fungal infection in such patients, although its effect seems to be equivocal.. To study whether nystatin decreases morbidity and mortality when given prophylactically or therapeutically to patients with severe immunodeficiency.. We searched PubMed from 1966 to 7 July 2014 and the reference lists of identified articles.. Randomised clinical trials comparing nystatin with placebo, an untreated control group, fluconazole or amphotericin B.. Data on mortality, invasive fungal infection and colonisation were independently extracted by both authors. A random-effects model was used unless the P value was greater than 0.10 for the test of heterogeneity.. We included 14 trials (1569 patients). The drugs were given prophylactically in 12 trials and as treatment in two. Eleven trials were in acute leukaemia, solid cancer, or bone marrow recipients; one in liver transplant patients; one in critically ill surgical and trauma patients; and one in AIDS patients. Nystatin was compared with placebo in three trials, with fluconazole in 10, and amphotericin B in one; the dose varied from 0.8 MIE to 72 MIE daily and was 2 mg/kg/d in a liposomal formulation. The effect of nystatin was similar to that of placebo on fungal colonisation (relative risk (RR) 0.85, 95% confidence interval (CI) 0.65 to 1.13). There was no statistically significant difference between fluconazole and nystatin on mortality (RR 0.75, 95% CI 0.54 to 1.03) whereas fluconazole was more effective in preventing invasive fungal infection (RR 0.40, 95% CI 0.17 to 0.93) and colonisation (RR 0.50, 95% CI 0.36 to 0.68). There were no proven fungal infections in a small trial that compared amphotericin B with liposomal nystatin. The results were very similar if the three studies that were not performed in cancer patients were excluded. For the 2011 and 2014 updates no additional trials were identified for inclusion.. Nystatin cannot be recommended for prophylaxis or the treatment of Candida infections in immunodepressed patients.

Topics: Amphotericin B; Antibiotic Prophylaxis; Antifungal Agents; Candidiasis; Fluconazole; Humans; Immunocompromised Host; Liposomes; Mycoses; Nystatin; Opportunistic Infections; Randomized Controlled Trials as Topic

Systemic fungal infection is considered to be an important cause of morbidity and mortality in cancer patients, particularly those with neutropenia. Antifungal drugs are often given prophylactically, or empirically to patients with persistent fever.. To compare the effect of fluconazole and amphotericin B on morbidity and mortality in patients with cancer complicated by neutropenia.. We searched PubMed from 1966 to 7 July 2014 and the reference lists of identified articles.. Randomised clinical trials comparing fluconazole with amphotericin B.. The two review authors independently assessed trial eligibility and risk of bias, and abstracted data.. Seventeen trials (3798 patients, 381 deaths) were included. In two large three-armed trials, results for amphotericin B were combined with results for nystatin in a 'polyene' group. Because nystatin is an ineffective drug in these circumstances, this approach creates a bias in favour of fluconazole. Furthermore, most patients were randomised to oral amphotericin B, which is poorly absorbed and poorly documented. There was overlap among the 'polyene' trials but we were unable to obtain any information from the trial authors or from Pfizer, the manufacturer of fluconazole, to clarify these issues. There were no significant differences in effect between fluconazole and amphotericin B, but the confidence intervals were wide. More patients dropped out of the study when they received amphotericin B, but as none of the trials were blinded decisions on premature interruption of therapy could have been biased. Furthermore, amphotericin B was not given under optimal circumstances, with premedication to reduce infusion-related toxicity, slow infusion, and with fluid, potassium and magnesium supplements to prevent nephrotoxicity. The major harms were hepatic impairment and gastrointestinal adverse effects with fluconazole and infusion-related toxicity, renal impairment and gastrointestinal adverse effects with amphotericin B. For the 2011 and 2014 updates no additional trials were identified for inclusion.. Amphotericin B has been disfavoured in several of the trials through their design or analysis, or both. Since intravenous amphotericin B is the only antifungal agent for which an effect on mortality has been shown, and since it is considerably cheaper than fluconazole, it should be the preferred agent.

Topics: Administration, Oral; Amphotericin B; Antifungal Agents; Confidence Intervals; Fluconazole; Humans; Injections, Intravenous; Mycoses; Neoplasms; Neutropenia; Nystatin; Odds Ratio; Randomized Controlled Trials as Topic

To summarize the clinical features, imaging characteristics, diagnosis and treatment of a case with central nervous system infection caused by Exophiala dermatitidis, as well as to review the related literature.. Associated literature and clinical data of an 8-year-old boy who was diagnosed as central nervous system infection caused by Exophiala dermatitidis in Beijing Children's Hospital Affiliated to Capital Medical University and hospitalized twice from 2012 to 2014 were analyzed retrospectively.. The boy was 8 years old with the chief complaint of dizziness for 2 months, intermittent fever for 1 month accompanied with spasm twice. He was diagnosed as bile ducts space-occupying lesions 2 years ago, when the pathological diagnosis was fungal infection. The boy was treated with irregular anti-fungal therapy. Then the boy developed nervous symptoms, impaired consciousness and abnormal physical activity that developed gradually. After hospitalization the cerebral MRI of the boy showed space-occupying lesions accompanied with edema of surrounding area. Filamentous fungi was found by brain biopsy, which was culture positive for Exophiala dermatitidis. After diagnosis the boy was treated with amphotericin B (AMB), voriconazole and 5-Fu, as well as symptomatic treatment. The state of the boy was improved gradually. Two months later, the boy could communicate with others normally and move personally. The lesions and edema seen on the MRI was decreased moderately. Accordingly, the boy was treated with oral voriconazole maintenance treatment for about 1 year and 4 months after discharge. During this period, the state of him was stable without symptoms. The lesions shown by MRI did not disappear but decreased on regular examination. However, recently the disease of the boy progressed again, with dizziness, neck pain, headache and progressive nervous symptoms (intermittent spasm, inability to cough, and impaired consciousness). The boy died at last, even with the active treatment at the second hospitalization. Exophiala dermatitidis was culture-positive again in his CSF, and was confirmed by PCR successfully.. The central nervous system infection caused by Exophiala dermatitidis is rare. Clinical features of this disease were similar to those of other fungal CNS infection, cerebral MRI of which could show the similar lumpy lesions. Diagnosis of the disease should be based on pathology and culture.

Topics: Amphotericin B; Antifungal Agents; Brain; Central Nervous System Infections; Cerebrospinal Fluid; Child; Drug Therapy, Combination; Exophiala; Fatal Outcome; Fluorouracil; Humans; Magnetic Resonance Imaging; Male; Mycoses; Radiography; Voriconazole

Amphotericin B deoxycholate use has increased during the past years in parallel with the increase in the number of immunosuppressed patients suffering invasive fungal infections. This drug is associated with a high rate of side effects, especially renal toxicity. Lipid formulations (liposomal, lipid complex, colloidal suspension and the Indian liposomal formulation) have been developed, which share the same antifungal spectrum but differ in efficacy and toxicity. A review of amphotericin lipid formulations is presented, focusing on differences in efficacy and, especially renal toxicity. The main problem for use of these formulations in Latin America is their highcost.

Topics: Amphotericin B; Antifungal Agents; Colloids; Excipients; Humans; Leishmaniasis; Lipids; Liposomes; Mycoses

Pseudozyma spp are amorphic yeasts. They are commonly plant pathogens, but rarely cause invasive fungal disease in humans. Only three cases of central venous catheter (CVC)-associated blood stream infections due to this organism have been reported in the literature. Main underlying risk factors for Pseudozyma spp infection are bowel surgery, CVC and total parenteral nutrition. We present a rare case of Pseudozyma spp catheter-associated blood stream infection that was successfully treated with antifungal therapy and removal of CVC. It is important to recognise and differentiate this species from other yeasts as it may require the use of amphotericin B or voriconazole instead of fluconazole, to which the organism is variably resistant.

Topics: Amphotericin B; Antifungal Agents; Catheter-Related Infections; Catheterization, Central Venous; Central Venous Catheters; Female; Fluconazole; Fungemia; Humans; Middle Aged; Mycoses; Risk Factors; Voriconazole; Yeasts

Because of the increasing prevalence and changing microbiological spectrum of invasive fungal infections, some form of amphotericin B still provides the most reliable and broad spectrum therapeutic alternative. However, the use of amphotericin B deoxycholate is accompanied by dose-limited toxicities, most importantly, infusion-related reactions and nephrotoxicity. In an attempt to improve the therapeutic index of amphotericin B, three lipid-associated formulations were developed, including amphotericin B lipid complex (ABLC), liposomal amphotericin B (L-AmB), and amphotericin B colloidal dispersion (ABCD). The lipid composition of all three of these preparations differs considerably and contributes to substantially different pharmacokinetic parameters. ABLC is the largest of the lipid preparations. Because of its size, it is taken up rapidly by macrophages and becomes sequestered in tissues of the mononuclear phagocyte system such as the liver and spleen. Consequently, compared with the conventional formulation, it has lower circulating amphotericin B serum concentrations, reflected in a marked increase in volume of distribution and clearance. Lung levels are considerably higher than those achieved with other lipid-associated preparations. The recommended therapeutic dose of ABLC is 5 mg/kg/day. Because of its small size and negative charge, L-AmB avoids substantial recognition and uptake by the mononuclear phagocyte system. Therefore, a single dose of L-AmB results in a much higher peak plasma level (Cmax) than conventional amphotericin B deoxycholate and a much larger area under the concentration-time curve. Tissue concentrations in patients receiving L-AmB tend to be highest in the liver and spleen and much lower in kidneys and lung. Recommended therapeutic dosages are 3-6 mg/kg/day. After intravenous infusion, ABCD complexes remain largely intact and are rapidly removed from the circulation by cells of the macrophage phagocyte system. On a milligram-to-milligram basis, the Cmax achieved is lower than that attained by conventional amphotericin B, although the larger doses of ABCD that are administered produce an absolute level that is similar to amphotericin B. ABCD exhibits dose-limiting, infusion-related toxicities; consequently, the administered dosages should not exceed 3-4 mg/kg/day. The few comparative clinical trials that have been completed with the lipid-associated formulations have not demonstrated important clinical differences among these a

Topics: Amphotericin B; Animals; Antifungal Agents; Chemistry, Pharmaceutical; Fungi; Humans; Lipids; Mycoses

Amphotericin B (AmB) was first approved by the US Food and Drug Administration in 1959 with sodium deoxycholate (DAmB, Fungizone®). Extensive toxicities associated with the drug led to the development of lipid formulations of AmB, including liposomal amphotericin B (L-AmB, AmBisome®). Phase I studies as well as comparative Phase III clinical trials indicate that L-AmB is associated with less nephrotoxicity and reduced infusion-related toxicity. There is, however, no recent comprehensive review of the safety and tolerability of L-AmB.. This article reviews the safety, tolerability and the mechanisms of the major toxicities associated with L-AmB, including nephrotoxicity, infusion-related reactions (IRRs), anemia and thrombocytopenia, and hepatic abnormalities. The article further discusses the mechanism of action and pharmacokinetics of L-AmB.. L-AmB is a broad-spectrum antifungal agent that has significantly reduced toxicities compared to its predecessor, DAmB.

Topics: Amphotericin B; Animals; Antifungal Agents; Clinical Trials as Topic; Drug Approval; Humans; Mycoses; United States; United States Food and Drug Administration

Treatment with Amphotericin B (AmB) deoxycholate, which is still used widely, particularly in low-resource countries, has been challenged due to nephrotoxicity. We sought to study whether continuous infusion of AmB deoxycholate reduces nephrotoxicity retaining, however, the effectiveness of the drug.. PubMed and Scopus databases were systematically searched to identify studies comparing the outcomes of patients receiving 24-h infusion of AmB ("continuous group") and those receiving 2-6-h infusion of AmB ("conventional group"). Nephrotoxicity and all-cause mortality were the primary outcomes of the review, while treatment failure was the secondary outcome.. Five studies met the inclusion criteria; one randomized controlled trial, two prospective cohort studies, and two retrospective cohort studies. The majority of patients were neutropenic with an underlying hematologic malignancy. All 5 studies (392 patients) provided data regarding the development of nephrotoxicity. A non-significant trend towards lower nephrotoxicity was observed for patients receiving continuous infusion of AmB compared with those receiving conventional infusion [RR = 0.61 (95% CI 0.36, 1.02)]. Four studies (365 patients) provided data regarding mortality; no relevant difference was detected between patients receiving continuous and those receiving conventional infusion of AmB [RR = 0.81 (95% CI 0.36, 1.83)]. Data on treatment failure of the two methods of administration was insufficient for meaningful conclusions.. The available evidence from mainly non-randomized studies suggests that continuous infusion of AmB deoxycholate might offer an advantage over the conventional infusion regarding the development of nephrotoxicity, without compromising patient survival. Further randomized studies are needed to investigate this issue.

Topics: Amphotericin B; Antifungal Agents; Deoxycholic Acid; Drug Combinations; Hematologic Neoplasms; Humans; Infusions, Intravenous; Kidney Diseases; Mycoses; Neutropenia; Prospective Studies; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Factors; Treatment Outcome

In recent years there has been an evolution of a better understanding of the pharmacology and clinical indications of existing antifungal agents and also the development of new broad-spectrum triazoles and a newer class of antifungal agents, the echinocandins. The availability of these agents has broadened the therapeutic options of invasive fungal disease among children and consequently antifungal therapy has become increasingly complex.. Adoption of adult guidelines' recommendations has been used to guide pediatric treatment as specific pediatric data were often lacking. This approach has not always selected the most appropriate therapy for newborns or young infants, as the under-dosage of voriconazole based on adult data revealed. Therefore, a detailed understanding of the available antifungal agents in children is crucial for the successful treatment of these serious infections.. In this review we summarize the main findings regarding antifungal treatment among children that have been recently published, focusing on the pharmacology and pediatric use of newer antifungal agents.

Topics: Amphotericin B; Antifungal Agents; Azoles; Child; Echinocandins; Humans; Mycoses

Topics: Amphotericin B; Antifungal Agents; Brain; Brain Abscess; Diabetes Mellitus; DNA, Fungal; Frontal Sinusitis; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Mycoses; Radiography; Schizophyllum

Invasive fungal infections (IFIs) are responsible for significant morbidity and mortality, especially in immunocompromised patients and in those requiring admission to an intensive care unit. The epidemiology of IFI is changing, and an increment in non-Aspergillus filamentous fungi and non-Candida albicans species has been observed. The present paper reviews the epidemiology and diagnosis of IFIs. Regarding the treatment of IFIs, it focuses primarily on the role of liposomal amphotericin B in this setting. The main recommendations put forth by expert societies and groups are discussed.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Candidiasis; Humans; Mycoses; Treatment Outcome

In recent years their has been an increased use of antifungal agents and has resulted in the development of resistance to drugs. Currently, use of standard antifungal therapies can be limited because of toxicity, low efficacy rates. Different types of mechanisms contribute to the development of resistance to antifungals. This has given raise to search for a new heterocycle with distinct action or multitargeted combination therapy. This review addresses the areas such as the underlying mechanisms, eight different targets such as ergosterol synthesis, chitin synthesis, ergosterol disruptors, glucan synthesis, squalene epoxidase, nucleic acid synthesis, protein synthesis, microtubules synthesis. The clinically employed drugs along with the current research work going on worldwide on different heterocycles are discussed. In recent advances various heterocycles including imidazole, benzimidazole etc., twenty three scaffolds and their lead identification are discussed.

Topics: Animals; Antifungal Agents; Azoles; Fungi; Humans; Imidazoles; Mycoses

In this paper, we present a case of cervical spondylitis due to Phaeoacremonium venezuelense, in a fifty-two-year-old male who complained about neck pain and tingles in his right arm. Fungal cervical spondylitis is extremely rare in immunocompetent patients. This case is the first case of spondylitis due to P. venezuelense.

Topics: Amphotericin B; Antifungal Agents; Ascomycota; Cervical Vertebrae; Epidural Abscess; Humans; Immunocompetence; Kidney Diseases; Magnetic Resonance Imaging; Male; Middle Aged; Mycoses; Pyrimidines; Species Specificity; Spondylitis; Tomography, X-Ray Computed; Triazoles; Voriconazole

Rhodotorula species have been increasingly recognized as emerging pathogens, particularly in immunocompromised patients. We herein report on a patient with myelodysplastic syndrome who developed fungemia due to Rhodotorula mucilaginosa after allogeneic hematopoietic stem cell transplantation (HSCT) from an unrelated donor. He developed severe acute graft-versus-host disease requiring high-dose steroids, and had serially been administered fluconazole and micafungin for the prophylaxis of fungal infection. Although several cases of Rhodotorula infection after HSCT have been reported, all of them were recipients of autologous HSCT, not allogeneic HSCT. A review of all the reported cases of Rhodotorula infection after HSCT revealed that all patients had received fluconazole or echinocandins before the onset of infection. The findings suggest that Rhodotorula species could be causative yeasts, particularly in patients receiving fluconazole or echinocandins, both of which are inactive against the species.

Topics: Amphotericin B; Antifungal Agents; Fungemia; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Male; Middle Aged; Mycoses; Myelodysplastic Syndromes; Rhodotorula; Transplantation, Homologous; Unrelated Donors

To describe the clinical and microbiological features associated with fungal peritonitis in peritoneal dialysis (PD) patients at Hôpital Maisonneuve-Rosemont, from August 1996 to July 2006.. Cases were retrieved from the microbiology laboratory culture registry. Antifungal susceptibility was determined by the Clinical and Laboratory Standards Institute M27A3 method.. Among 288 PD patients (total follow-up of 7258 patient-months), nine were found with fungal peritonitis. Candida spp were identified in all of them, with a majority of non-albicans Candida species. Resistance to fluconazole, itraconazole, or voriconazole was as frequent as potential resistance to amphotericin B. No isolate was resistant to caspofungin and one was resistant to micafungin. Prior bacterial peritonitis was frequent (67%). All patients had their PD catheter removed and all of them survived.. In our institution, fungal peritonitis in PD patients is rare. All cases were caused by Candida species. Variable susceptibility patterns were observed, which may influence the initial empirical antifungal therapy and underscore the importance of individual speciation and susceptibility testing of invasive Candida isolates.

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; Candida; Caspofungin; Drug Resistance, Fungal; Echinocandins; Female; Fluconazole; Follow-Up Studies; Humans; Itraconazole; Lipopeptides; Male; Micafungin; Microbial Sensitivity Tests; Middle Aged; Mycoses; North America; Peritoneal Dialysis; Peritonitis; Pyrimidines; Triazoles; Voriconazole

Despite the availability of newer antifungal drugs, outcomes for patients with invasive fungal infections (IFIs) continue to be poor, in large part due to delayed diagnosis and initiation of appropriate antifungal therapy. Standard histopathologic diagnostic techniques are often untenable in at-risk patients, and culture-based diagnostics typically are too insensitive or nonspecific, or provide results after too long a delay for optimal IFI management. Newer surrogate markers of IFIs with improved sensitivity and specificity are needed to enable earlier diagnosis and, ideally, to provide prognostic information and/or permit therapeutic monitoring. Surrogate assays should also be accessible and easy to implement in the hospital. Several nonculture-based assays of newer surrogates are making their way into the medical setting or are currently under investigation. These new or up-and-coming surrogates include antigens/antibodies (mannan and antimannan antibodies) or fungal metabolites (d-arabinitol) for detection of invasive candidiasis, the Aspergillus cell wall component galactomannan used to detect invasive aspergillosis, or the fungal cell wall component and panfungal marker β-glucan. In addition, progress continues with use of polymerase chain reaction- or other nucleic acid- or molecular-based assays for diagnosis of either specific or generic IFIs, although the various methods must be better standardized before any of these approaches can be more fully implemented into the medical setting. Investigators are also beginning to explore the possibility of combining newer surrogate markers with each other or with more standard diagnostic approaches to improve sensitivity, specificity, and capacity for earlier diagnosis, at a time when fungal burden is still relatively low and more responsive to antifungal therapy.

Topics: Adult; Amphotericin B; Antifungal Agents; Antineoplastic Agents; beta-Glucans; Biomarkers; Female; Fusariosis; Humans; Immunocompromised Host; Leukemia, Myeloid, Acute; Meta-Analysis as Topic; Mycoses; Opportunistic Infections; Polymerase Chain Reaction

Amphotericin B in its lipid formulation continues to be the reference drug in the treatment of systemic fungal infections despite the time elapse since the development of this compound. The absence of fungal resistance, pharmacokinetics, and the better tolerability profile as compared with the remaining formulations of amphotericin B are sufficient reasons to justify its prominent therapeutic role. The liposome containing liposomal amphotericin B is very stable in relation to the presence of cholesterol and phospholipids are not thermolabile, so that free amphotericin B is almost inexistent (<1%), which explains the reduced incidence of effects related to the drug administration, and a reduction in the incidence of nephrotoxicity (half than that with amphotericin B lipid complex) and that even in some studies at doses of 1 mg/kg has been shown to be negligible. This profile explains the very high plasma drug concentrations and the reduced distribution volume and clearance, with a very prolonged elimination half-life. There are evidences showing that the liposome through amphotericin B is capable of binding to ergosterol present in the fungal membrane and only at this moment would be the antifungal released to exert its pharmacological effects.

Topics: Amphotericin B; Antifungal Agents; Chemistry, Pharmaceutical; Drug Stability; Humans; Mycoses; Tissue Distribution

A variety of antifungal drugs, drug preparations and drug combinations are available to treat newborn infants with suspected or confirmed invasive fungal infection. There is a need to assess their relative merits.. To assess the effect of treatment with different antifungal drugs, drug preparations or drug combinations on mortality and morbidity in newborn infants with suspected or confirmed invasive fungal infection.. We used the standard search strategy of the Cochrane Neonatal Review Group. This included searches of the Cochrane Central Register of Controlled Trials (The Cochrane Library, 2012, Issue 2), MEDLINE, EMBASE, CINAHL (to March 2012), conference proceedings and previous reviews.. Randomised and quasi-randomised control trials comparing one antifungal agent or combination of agents with another in newborn infants with suspected or confirmed invasive fungal infection.. We extracted the data using the standard methods of the Cochrane Neonatal Review Group, with separate evaluation of trial quality and data extraction by each author, and synthesis of data using risk ratio and risk difference.. We identified only one small trial in which 24 newborn infants participated. This trial compared the use of fluconazole versus amphotericin B (plus 5-fluorocytosine if fungal meningitis present). The trial did not detect a statistically significant effect on mortality (risk ratio 0.73; 95% confidence interval 0.26 to 2.05).. There are insufficient data to inform practice. Large randomised controlled trials are required to compare antifungal drugs, drug preparations or drug combinations for treating newborn infants with invasive fungal infection.

Topics: Amphotericin B; Antifungal Agents; Fluconazole; Flucytosine; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Mycoses; Randomized Controlled Trials as Topic

Penicilliosis is a rare occurrence among non human immunodeficiency virus (HIV) infected patients. We report here two cases of Penicillium marneffei infection in patients with systemic lupus erythematosus (SLE). Both patients had a recent flare of lupus and were on immunosuppressive drugs when they presented with prolonged fever without an obvious foci of infection, unresponsive to broad-spectrum antibiotics. They were leucopaenic upon admission, with rapid deterioration during the course of the illness. Diagnosis of penicilliosis via fungal isolation from blood culture was delayed resulting in the late initiation of antifungal agents. While both patients ultimately recovered, the delay in diagnosis led to a prolonged hospital stay with increased morbidity. Clinicians should be aware of this uncommon but emerging fungal pathogen in SLE patients and maintain a high index of suspicion in diagnosing this potentially fatal but treatable disease.

Topics: Adult; Amphotericin B; Antifungal Agents; Delayed Diagnosis; Female; Fever; Hospitalization; Humans; Lupus Erythematosus, Systemic; Male; Mycoses; Penicillium; Young Adult

Invasive fungal diseases (IFDs) are a major cause of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplant (HSCT). Considerable progress in treating IFDs has been achieved over the last years, through the availability of new, effective drugs. However, many of these newer antifungal agents have some limitations, such as their variable toxicity and unique predisposition for pharmacokinetic drug-drug interactions.. This article reviews the literature evaluating the safety profile of the lipid formulations of Amphotericin B, echinocandins, and second-generation triazoles. It also discusses the possible drug-drug interactions with some drugs commonly used in allogeneic HSCT.. Nephrotoxicity is the most frequent side effect of lipid formulations of Amphotericin B, which may cause a reduced clearance of the renally eliminated calcineurin inhibitors used for the control of Graft Versus Host Disease. Second-generation triazoles are characterized by a limited toxicity profile, but also by frequent drug-drug interactions with other drugs metabolized by the hepatic enzymes. The echinocandins are characterized by a very low toxicity profile and negligible interactions with other drugs. Such pharmacological knowledge is crucial in the daily care of allogeneic HSCT patients.

Topics: Amphotericin B; Animals; Antifungal Agents; Drug Interactions; Echinocandins; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Mycoses; Opportunistic Infections; Pharmacovigilance; Renal Insufficiency; Stem Cell Transplantation; Triazoles

Topics: Amphotericin B; Antifungal Agents; Fungi; Humans; Mycoses

Penicillium marneffei is an important opportunistic pathogen in Southeast Asia in HIV-positive individuals, but it rarely infects non-HIV ones. Four SLE patients with disseminated penicilliosis had been previously reported out of which 3 died. We describe a 46-year-old Chinese woman who had a 10 years history of SLE, associated with disseminated Penicillium marneffei infection, which presented as fever, subcutaneous masses, and fine nodular shadows disseminated over lung fields. She was initially misdiagnosed as miliary tuberculosis and panniculitis that did not respond to anti-tubercular drugs and prednisone. The correct diagnosis was finally made by histopathology and tissue culture and also culture from exudate. She responded well to antifungal therapy in the form of intravenous amphotericin B for 2 weeks followed by itraconazole plus fluconazole. The cutaneous lesions were cured leaving behind scars by secondary suture after times of epluchage, and the fine nodular shadows over lungs disappeared finally. She had no recurrence on 8 months of follow-up. We also review the literature on this topic.

Topics: Amphotericin B; Antifungal Agents; China; Dermatomycoses; Female; Fluconazole; Humans; Itraconazole; Lupus Erythematosus, Systemic; Middle Aged; Mycoses; Opportunistic Infections; Penicillium

Over the last 20 years, there has been an increase in the total number of invasive fungal infections (IFIs) and in infections caused by rare and emerging pathogens. This is due in part to the growing population of immunocompromised patients at risk of developing fungal infections. Three classes of antifungal agents are widely used for the treatment of systemic fungal infections: polyenes, azoles, and echinocandins. Polyenes were the first antifungal agents developed and have a long-standing history in the treatment of IFIs. The use of conventional amphotericin B has been limited because of toxic side effects, which have been reduced by the lipid formulations of amphotericin B. Treatment options for invasive mycoses have expanded with the recent introduction of the second-generation triazoles (voriconazole and posaconazole) and the echinocandins (caspofungin, micafungin, anidulafungin). Despite the increased number of antifungal drugs, resistance issues present a problem in the treatment of IFIs. Although some fungal pathogens display innate resistance, others have developed resistance secondary to selective pressure. This article briefly reviews the changing epidemiology of fungal infections and associated risk factors, resistance issues with commonly administered antifungal agents, and treatment options for IFIs, with a focus on polyenes.

Topics: Amphotericin B; Antifungal Agents; Azoles; Drug Resistance, Fungal; Echinocandins; Humans; Mycoses; Polyenes; Risk Factors

The aim is to compare the available evidence on the efficacy and safety of deoxycholate and lipid amphotericin B formulations (AMBF) in the treatment of invasive fungal disease (IFD) in neonates. The review also aims to summarize current practices and recommendations.. To date most AMBF studies on neonates consist of retrospective reports and case series. The reviewed reports show that both amphotericin B deoxycholate (DAMB) and lipid formulations appear to have equal efficacy in treating IFD in neonates. The adverse effects of DAMB in neonates are considerably less than those in older children and adults. There is a trend of more nephrotoxicity reported with DAMB than with lipid formulations; however, the range reported is very wide (0-70%). Neonates with normal baseline renal function appeared to tolerate DAMB relatively well. A sodium intake of 4 mEq/kg/day may significantly reduce DAMB nephrotoxicity.. Deoxycholate amphotericin B is inexpensive and effective in treating neonatal IFD. It appears to be safe for use as first-line therapy if the underlying risk for nephrotoxicity is low and renal function and potassium are monitored closely.

Topics: Amphotericin B; Antifungal Agents; Deoxycholic Acid; Drug Combinations; Humans; Infant, Newborn; Infusions, Intravenous; Mycoses; Treatment Outcome

Currently there are three main drug groups for the prevention and treatment of fungal infections: polyenes (amphotericin B deoxycholate or its lipid formulations), azoles (fluconazole, itraconazole or posaconazole) and echinocandins (caspofungin, micafungin and anidulafungin). However, a major characteristic to be evaluated when choosing an antifungal agent -apart from antifungal spectrum, pharmacokinetics and adverse effects- is the absence of significant drug interactions. Amphotericin B lacks interactions but may cause renal dysfunction, leading to the accumulation of renally metabolized drugs. Nephrotoxicity is significantly lower with lipid formulations, especially with liposomal amphotericin B. Azoles modify the metabolism of a wide range of drugs by inhibiting their biotransformation or altering their distribution and elimination. These drugs are metabolized in the liver through the P450 cytochrome complex, inhibiting several isoenzymes, especially CYP3A4, the main drug-metabolizing enzyme. Moreover, itraconazole and posaconazole are substrates and inhibitors of the transporter protein, P-glycoprotein. Fluconazole is the azole with the fewest drug-drug interactions. The echinocandins have increased the therapeutic arsenal and a particular feature of these drugs is their safety, due to the absence of severe adverse effects and the scarce number of interactions. The echinocandin with the highest number of interactions is caspofungin. Micafungin is an echinocandin lacking in relevant interactions and consequently its dosage requires no adjustment in any of its indications. This drug can be used both in adults and in the pediatric population, including neonates.

Topics: Adult; Amphotericin B; Antifungal Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Child; Critical Illness; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Drug Therapy, Combination; Echinocandins; Humans; Infant, Newborn; Lipopeptides; Micafungin; Microsomes, Liver; Mycoses; Triazoles

Scedosporium prolificans is an emerging agent for severe infections. Although among the dematiaceous fungi Scedosporium is the most frequently isolated in blood cultures, Scedosporium endocarditis is rarely reported. We show herein a patient with acute leukaemia who developed S. prolificans endocarditis. Twelve cases were found in an extensive review of the English literature. In six cases (46%), there was predisposing heart conditions such as a prosthetic valve or an intracavitary device. Only 4 patients (31%) were immunocompromised hosts with haematologic neoplasia, solid-organ transplantation or acquired immunodeficiency syndrome (AIDS). Exposure to Scedosporium was observed in immunocompetent patients who developed infection while in the community. Scedosporium endocarditis occurred on both sides of the heart. Systemic and pulmonary emboli and other metastatic complications were seen in all of these patients. The overall mortality was 77% and, specifically, all of the immunocompromised hosts and 6 out of 7 patients with mitral or aortic valve endocarditis died. Patients with right-sided endocarditis associated with a removable intracardiac device exhibited a better prognosis. Scedosporium endocarditis, although still rare, is an emerging infection with an ominous prognosis. At the present time, valve replacement or the removal of cardiac devices plus combined antifungal treatment may offer the best possibility of cure.

Topics: Adult; Amphotericin B; Antifungal Agents; Communicable Diseases, Emerging; Embolectomy; Endocarditis; Fatal Outcome; Female; Femoral Artery; Humans; Immunocompromised Host; Mycoses; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Pyrimidines; Scedosporium; Thrombosis; Tomography, X-Ray Computed; Triazoles; Voriconazole

The pharmacokinetics and pharmacodynamics of the main antifungal drugs used for invasive fungal infections (amphotéricin B, flucytosine, triazole compounds, echinocandins) have been more or less completely investigated in the paediatric population. This article reviews the pharmacokinetic profiles of these drugs in children, with a focus on the age-related changes. The concentration/efficacy relationships that were evidenced in children are also described.

Topics: Amphotericin B; Antifungal Agents; Child; Echinocandins; Evidence-Based Medicine; Flucytosine; Humans; Mycoses; Triazoles

Invasive fungal infections are associated with a poor outcome and their incidence is rising. Amphotericin B has for a long time been the gold standard for treatment of these infections, but the conventional formulation is associated with a high incidence of adverse events. Lipid formulations of amphotericin, developed to overcome these drawbacks, are now routinely used in clinical practice for the treatment of invasive fungal infections in immunocompromised patients. Amphotericin B lipid complex (ABLC) is prepared from amphotericin complexed to two phospholipids, a process that confers a number of important pharmacodynamic and pharmacokinetic properties compared with conventional amphotericin B. The results of retrospective observational studies and the analysis of databases, including the large Collaborative Exchange of Antifungal Research (CLEAR) database, have shown ABLC to be associated with response rates of up to about 80% in patients with confirmed fungal infections and around 60% in those treated empirically. Intranasal administration of ABLC for prophylaxis of invasive fungal infection in immunocompromised patients is safe and appears to be a promising treatment strategy for the future. ABLC is associated with a substantially lower incidence of nephrotoxicity than conventional amphotericin. Infusion-related reactions also occur less frequently than with conventional amphotericin and can be managed using premedication protocols. When direct and indirect costs are measured, ABLC appears to be less expensive than conventional amphotericin. The number of approved antifungal agents that are effective treatments for invasive fungal infections is increasing. However, lipid formulations of amphotericin, such as ABLC, are effective and well tolerated and remain the standard of care in the treatment of invasive fungal infections. Treatment strategies such as intranasal administration for prophylaxis and combination therapy with newer agents are future directions for these agents.

Topics: Amphotericin B; Antifungal Agents; Humans; Immunocompromised Host; Mycoses

In this review, we aim to compare different early treatment strategies of invasive fungal diseases in patients undergoing induction chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome. Three treatment approaches--prophylactic, empiric, and preemptive treatment--are subject to continuous discussion among physicians treating patients at risk. Considering the available clinical basis of evidence, we opt for antifungal prophylaxis with posaconazole 200 mg tid po as our primary prophylactic strategy, while the employment of preemptive treatment should be delayed until more accurate diagnostic tools become available. In addition to antifungal prophylaxis, empiric treatment with caspofungin or L-AmB may be administered to patients with fever resistant to broad-spectrum antibiotic treatment and without radiographic findings typical of invasive fungal disease.

Topics: Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Caspofungin; Clinical Trials as Topic; Drug Resistance, Fungal; Echinocandins; Fever; Humans; Leukemia, Myeloid, Acute; Lipopeptides; Medical Oncology; Mycoses; Myelodysplastic Syndromes; Triazoles

Invasive fungal infections are associated with significant morbidity and mortality in children. Optimal treatment strategies are yet to be defined.. This review aims to systematically identify and summarise the effects of different antifungal therapies in children with proven, probable or suspected invasive fungal infections.. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2008, Issue 3), MEDLINE (1966 to September 2008), EMBASE (1980 to September 2008) and CINAHL (1988 to September 2008) without language restrictions. We also handsearched reference lists and abstracts of conference proceedings and scientific meetings, and contacted authors of included studies and pharmaceutical manufacturers.. We included randomised clinical trials (RCTs) comparing a systemic antifungal agent with a comparator (including placebo) in children (one month to 16 years) with proven, probable or suspected invasive fungal infection.. Two review authors independently applied selection criteria, performed quality assessment, and extracted data using an intention-to-treat approach. We synthesised data using the random-effects model and expressed results as relative risks (RR) with 95% confidence intervals (CIs).. We included seven trials of antifungal agents in children with prolonged fever and neutropenia (suspected fungal infection) and candidaemia or invasive candidiasis (proven fungal infection). Four trials compared a lipid preparation of amphotericin B with conventional amphotericin B (395 participants), one trial compared an echinocandin with a lipid preparation of amphotericin B (82 participants) in suspected infection; one trial compared an echinocandin with a lipid preparation of amphotericin B in children with candidaemia or invasive candidiasis (109 participants) and one trial compared different azole antifungals in children with candidaemia (43 participants). No difference in all-cause mortality and other primary endpoints (mortality related to fungal infection or complete resolution of fungal infections) were observed. No difference in breakthrough fungal infection was observed in children with prolonged fever and neutropenia.When lipid preparations and conventional amphotericin B were compared in children with prolonged fever and neutropenia, nephrotoxicity was less frequently observed with a lipid preparation (RR 0.43, 95% CI 0.21 to 0.90, P = 0.02) however substantial heterogeneity was observed (I(2) = 59%, P = 0.06). Children receiving liposomal amphotericin B were less likely to develop infusion-related reactions compared with conventional amphotericin B (chills: RR 0.37, 95% CI 0.21 to 0.64, P = 0.0005). Children receiving a colloidal dispersion were more likely to develop such reactions than with liposomal amphotericin B (chills: RR 1.76, 95% CI 1.09 to 2.85, P = 0.02). The rate of other clinically significant adverse reactions attributed to the antifungal agent (total reactions; total reactions leading to treatment discontinuation, dose reduction or change in therapy; hypokalaemia and hepatotoxicity) were not significantly different. When echinocandins and lipid preparations were compared, the rate of clinically significant adverse reactions (total reactions; total reactions leading to treatment discontinuation, dose reduction or change in therapy) were not significantly different.. Limited paediatric data are available comparing antifungal agents in children with proven, probable or suspected invasive fungal infection. No differences in mortality or treatment efficacy were observed when antifungal agents were compared. Children are less likely to develop nephrotoxicity with a lipid preparation of amphotericin B compared with conventional amphotericin B. Further comparative paediatric antifungal drug trials and epidemiological and pharmacological studies are required highlighting the differences between neonates, children and adults with invasive fungal infections.

Topics: Adolescent; Amphotericin B; Antifungal Agents; Candidiasis; Child; Child, Preschool; Echinocandins; Fever; Humans; Infant; Mycoses; Neutropenia; Randomized Controlled Trials as Topic

To review the data supporting available antifungal agents and compare regimens utilized to prevent fungal infection in lung transplant recipients.. Literature retrieval was accessed through MEDLINE (1950 through October 2009) and United Network for Organ Sharing online database (available data through October 2009), using the terms lung transplantation, prophylaxis, and fungal infection. In addition, reference citations from publications identified were reviewed.. All articles or related abstracts in English identified from the data sources above were evaluated. Literature including adult lung transplant recipients who received systemic antifungal prophylaxis to prevent invasive fungal infections (IFIs) was included in the review.. IFIs after lung transplantation remain a common postoperative problem and are associated with high mortality. The lung is the most vulnerable solid organ to be transplanted, as it is the main organ responsible for gas exchange and therefore the high risk for pulmonary-related IFIs. It is most susceptible to developing an IFI, as it serves as a medium for organisms traveling from air to human tissue, potentially causing life-threatening infections. Such infections typically involve Candida and Aspergillus spp. and tend to occur within the first 12 months after transplant. Although there has been an increase in lung transplants performed over the past decade, no standard antifungal prophylactic regimen exists. Literature describing antifungals used to prevent IFI after transplant is scarce, which may be due to a lack of consistency in regimens used between transplant centers. Several regimens have been described utilizing different antifungal agents as both monotherapy and combination therapy. The majority of the literature reviewed here describes aerosolized amphotericin B formulations and azole antifungals demonstrating an overall decreased risk of fungal infection after lung transplantation. It has become the standard of practice to initiate some form of antifungal prophylaxis in these patients.. The risk of fungal infection after lung transplant is multifactorial and optimal prophylactic regimens should include agents with adequate activity against the most pathogenic fungi.

Topics: Adult; Amphotericin B; Animals; Antifungal Agents; Azoles; Humans; Immunocompromised Host; Lung Transplantation; Mycoses; Risk Factors

To evaluate the tolerability and liver safety profiles of the systemic antifungal agents commonly used for the treatment of invasive fungal infection, we conducted a systematic review and meta-analysis of randomized controlled trials published before 31 August 2009. Two reviewers independently applied selection criteria, performed quality assessment, and extracted data. We used the beta-binomial model to account for variation across studies and the maximum likelihood method to estimate the pooled risks. We identified 39 studies with more than 8,000 enrolled patients for planned comparisons. The incidence rates of treatment discontinuation due to adverse reactions and liver injury associated with antifungal therapy ranged widely. The pooled risks of treatment discontinuation due to adverse reactions were above 10% for amphotericin B formulations and itraconazole, whereas they were 2.5% to 3.8% for fluconazole, caspofungin, and micafungin. We found that 1.5% of the patients stopped itraconazole treatment due to hepatotoxicity. Furthermore, 19.7% of voriconazole users and 17.4% of itraconazole users had elevated serum liver enzyme levels, although they did not require treatment discontinuation, whereas 2.0% or 9.3% of fluconazole and echinocandin users had elevated serum liver enzyme levels but did not require treatment discontinuation. The results were similar when we stratified the data by empirical or definitive antifungal therapy. Possible explanations for antifungal agent-related hepatotoxicity were confounded by antifungal prescription to patients with a high risk of liver injury, the increased chance of detection of hepatotoxicity due to prolonged treatment, or the pharmacological entity.

Topics: Amphotericin B; Antifungal Agents; Clinical Trials as Topic; Humans; Liver; Mycoses; Risk Factors

Aspergillus and Candida spp are the most frequently isolated fungi in patients with otomycosis. The diagnosis of otitis externa relies on the patient's history, otoscopic examination under microscopic control, and imaging studies. Direct preparation of the specimens, particularly with optical brighteners, mycologic culture, and histologic examination, is very important and strongly recommended for the correct diagnosis. Patients with noninvasive fungal otitis externa should be treated with intense débridement and cleansing, and topical antifungals. Topical antifungals, such as clotrimazole, miconazole, bifonazole, ciclopiroxolamine, and tolnaftate, are potentially safe choices for the treatment of otomycosis, especially in patients with a perforated eardrum. The oral triazole drugs, itraconazole, voriconazole, and posaconazole are effective against Candida and Aspergillus, with good penetration of bone and the central nervous system. These drugs are essential in the treatment of patients with malignant fungal otitis externa complicated by mastoiditis and meningitis.

Topics: Administration, Topical; Amphotericin B; Anti-Infective Agents; Antifungal Agents; Clotrimazole; Drug Resistance, Fungal; Econazole; Humans; Itraconazole; Miconazole; Mycoses; Ointments; Otitis Externa

The endemic mycoses are a diverse group of diseases caused by thermally dimorphic fungi. While they share many characteristics, each has unique aspects with regards to their clinical course, diagnosis and management. Diagnosis may be difficult and delayed owing to the varied manifestations and wide differential diagnosis. Historically, treatment has been with amphotericin B, which has been limited by its significant toxicity. The advent of the azole class of medications has allowed for safer alternatives to amphotericin B. The azoles have become the mainstay of treatment for many, if not most, forms of these diseases. Guidelines have been released for the management of each of the North American endemic mycoses; however, many questions remain as to the best strategies for the diagnosis and management of various manifestations of these diseases.

Topics: Amphotericin B; Antifungal Agents; Azoles; Diagnosis, Differential; Humans; Mycoses; North America; Practice Guidelines as Topic

The growing use of antifungal agents in patients with febrile neutropenia points at combination therapy as a strategy to face the increasing incidence of fungal infections in this population. Likewise, the low efficacy of single-drug therapies calls for research on this approach. Combination therapies should focus on extending their activity to a wider range of microorganisms, considering the mechanisms of action of major known antifungal agents, and also on enhancing the individual effect of each drug alone. In vitro and in vivo findings suggest that combination therapy may be better than single-drug therapy with amphotericin B for the treatment of emergent pathogens in immunosuppressed patients. In order to implement combination treatments, knowledge of the sensitivity profile of most prevalent species is required.

Topics: Amphotericin B; Antifungal Agents; Drug Combinations; Drug Interactions; Drug Therapy, Combination; Fever; Humans; Mycoses; Neutropenia

The need for new options for the treatment of invasive candidiasis has fuelled the use of antibodies in combination with conventional antifungal therapy. After a long period of time in which antibodies were considered irrelevant in the resistance against invasive candidiasis, it was demonstrated that a number of antibodies or their engineered derivatives directed against Candida albicans cell-wall polysaccharides and glycopeptides, as well as against some protein epitopes, confer protection against invasive candidiasis. This has confirmed this approach as a new strategy for the prophylaxis of invasive candidiasis. Of particular interest is Mycograb, a human recombinant monoclonal antibody that inhibits heat shock protein 90, and has been administrated in combination with lipid-associated amphotericin B to patients with invasive candidiasis, and the fungicidal anti-beta-glucan antibodies induced by the glycoconjugate vaccine composed of a beta-glucan polysaccharide conjugated with the diphtheria toxoid CRM 197. However, despite the promising data obtained in vitro and in animal models, at present there is very little clinical experience on the use of antibodies in Candida immunoprophylaxis.

Topics: Adult; Amphotericin B; Animals; Antibodies, Fungal; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Fungal; Bacterial Proteins; Candida albicans; Candidiasis; Caspofungin; Child; Combined Modality Therapy; Double-Blind Method; Drug Evaluation, Preclinical; Echinocandins; Fungal Vaccines; Humans; Immunization, Passive; Lipopeptides; Mice; Mycoses; Randomized Controlled Trials as Topic

Patients with acute leukemia and hematopoietic stem cell transplant recipients are at risk of a spectrum of invasive fungal diseases corresponding to the type and intensity of immunosuppression. The development of newer antifungal agents has broadened therapeutic options. In the 1990s, lipid formulations of amphotericin B became widely used as safer alternatives to amphotericin B deoxycholate. In addition, fluconazole was shown to be beneficial as a yeast-active prophylaxis in hematopoietic stem cell transplant recipients. In the past decade, the antifungal armamentarium was further enhanced with the availability of extended-spectrum azoles and echinocandins. The development of effective broad-spectrum antifungal agents has led to their use as prophylaxis rather than delaying treatment until clinical signs of infection manifest. Antigen-based and PCR-based diagnostic adjuncts facilitate earlier detection of invasive fungal diseases compared with conventional culture, and have been incorporated into strategies in which initiation or modification of an antifungal regimen is targeted to patients with the highest likelihood of having fungal disease. Here, we review the pharmacological data and major clinical trials that guide the use of antifungals, as well as areas of uncertainty and future perspectives.

Topics: Amphotericin B; Antifungal Agents; Azoles; Clinical Trials as Topic; Echinocandins; Fluconazole; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Mycoses; Yeasts

The availability of different therapeutic alternatives has modified the treatment of systemic fungal infections. There commendations of antifungal therapy vary according to species which causes the mycosis and its susceptibility. Consequently, the knowledge of action mechanism, activity profile and resistances to antifungal agents are essential for the clinical practice. Amphotericin B is the antifungal agent exhibiting the broadest spectrum of activity, it is a fungicidal drug and resistances have been hardly ever described. The triazoles compounds also have a broad spectrum, but their massive use for some therapeutic indications has led to emergence of strains and species of yeasts with resistance to fluconazole and of filamentous fungi itraconazole resistant. The echinocandins exhibit fungicidal effects for yeasts andafungistatic activity against moulds, and secondary resistance to these agents is uncommon.

Topics: Amphotericin B; Antifungal Agents; Drug Resistance, Fungal; Echinocandins; Fungi; Humans; Mycoses; Triazoles

Liposomal amphotericin B (AmBisome) is a lipid-associated formulation of the broad-spectrum polyene antifungal agent amphotericin B. It is active against clinically relevant yeasts and moulds, including Candida spp., Aspergillus spp. and filamentous moulds such as Zygomycetes, and is approved for the treatment of invasive fungal infections in many countries worldwide. It was developed to improve the tolerability profile of amphotericin B deoxycholate, which was for many decades considered the gold standard of antifungal treatment, despite being associated with infusion-related events and nephrotoxicity. In well controlled trials, liposomal amphotericin B had similar efficacy to amphotericin B deoxycholate and amphotericin B lipid complex as empirical therapy in adult and paediatric patients with febrile neutropenia. In addition, caspofungin was noninferior to liposomal amphotericin B as empirical therapy in adult patients with febrile neutropenia. For the treatment of confirmed invasive fungal infections, liposomal amphotericin B was more effective than amphotericin B deoxycholate treatment in patients with disseminated histoplasmosis and AIDS, and was noninferior to amphotericin B deoxycholate in patients with acute cryptococcal meningitis and AIDS. In adults, micafungin was shown to be noninferior to liposomal amphotericin B for the treatment of candidaemia and invasive candidiasis. Data from animal studies suggested that higher dosages of liposomal amphotericin B might improve efficacy; however, in the AmBiLoad trial in patients with invasive mould infection, there was no statistical difference in efficacy between the standard dosage of liposomal amphotericin B 3 mg/kg/day and a higher 10 mg/kg/day dosage, although the standard dosage was better tolerated. Despite being associated with fewer infusion-related adverse events and less nephrotoxicity than amphotericin B deoxycholate and amphotericin B lipid complex, liposomal amphotericin B use is still limited to some extent by these adverse events. Both echinocandins were better tolerated than liposomal amphotericin B. The cost of liposomal amphotericin B therapy may also restrict its use, but further pharmacoeconomic studies are required to fully define its cost effectiveness compared with other antifungal agents. Based on comparative data from well controlled trials, extensive clinical experience and its broad spectrum of activity, liposomal amphotericin B remains a first-line option for empirical ther

Topics: Amphotericin B; Animals; Antifungal Agents; Antineoplastic Agents; Drug Administration Schedule; Drug Resistance, Fungal; Fever; Fever of Unknown Origin; Humans; Infusions, Intravenous; Mycoses; Neutropenia

This review summarizes recent developments in the diagnosis and treatment of fungal pneumonia, with an emphasis on invasive pulmonary aspergillosis.. Improvements in nonculture-based fungal diagnostics, early implementation of pulmonary high resolution, or spiral computed tomography scanning and a recent expansion of the antifungal armamentarium have greatly improved the outcome of immunocompromised patients with invasive aspergillosis. However, the field is changing: new pathogens (such as Zygomycetes) are emerging, and novel risk groups (ICU patients in particular) are being identified.. Galactomannan antigen detection is a valuable tool for evaluating patients at risk for invasive aspergillosis (as a screening assay on serum samples from neutropenic patients or as a confirmatory assay on bronchoalveolar lavage fluid samples, in general), but should be used in conjunction with modern imaging techniques. beta-D-Glucan and PCR assays are still investigational. Voriconazole is the drug of choice for invasive aspergillosis, whereas liposomal amphotericin B at 3 mg/kg per day is the preferred alternative in case of contraindication, drug-related side-effects, or intolerance. Whenever possible, optimal antifungal therapy should be complemented by surgical debridement of necrotic tissue. The added value of combination therapy is still unproven. Therapeutic drug monitoring of mold-active azoles should be implemented in order to minimize toxicity and maximize efficacy. Lipid-based formulations of amphotericin B, and to a lesser extent voriconazole, are the drugs of choice for non-Aspergillus related fungal pneumonia. Although active in prophylaxis, the efficacy of posaconazole in confirmed infections remains controversial.

Topics: Amphotericin B; Antifungal Agents; Fungi; Galactose; Humans; Mannans; Mycoses; Pneumonia; Pulmonary Aspergillosis; Pyrimidines; Radiography, Thoracic; Triazoles; Voriconazole

Invasive fungal diseases (IFDs) remain a major cause of morbidity and mortality in allogeneic stem cell transplant (SCT) recipients. While the most common pathogens are Candida spp. and Aspergillus spp., the incidence of infections caused by non-albicans Candida species as well as molds such as Zygomycetes has increased. For many years, amphotericin B deoxycholate (AMB-D) was the only available antifungal for the treatment of IFDs. Within the past decade, there has been a surge of new antifungal agents developed and added to the therapeutic armamentarium. Lipid-based formulations of amphotericin B provide an effective and less nephrotoxic alternative to AMB-D. Voriconazole has now replaced AMB-D as first choice for primary therapy of invasive aspergillosis (IA). Another extended-spectrum triazole, posaconazole, also appears to be a promising agent in the management of zygomycosis, refractory aspergillosis, and for prophylaxis. Members of the newest antifungal class, the echinocandins, are attractive agents in select infections due to their safety profile, and are a more attractive option compared to AMB-D as initial treatment for invasive candidiasis and (based on one study) challenge fluconazole for superiority in management with this mycoses. However, challenges do exist among these newer agents in very high-risk individuals like allogeneic SCT recipients, which may include adverse drug events, drug-drug interactions, variability in oral absorption, and availability of alternative formulations. The addition of newer agents has also stimulated interest in the potential application of combination therapy in serious, life-threatening infections. However, adequate studies are not available for most IFDs; thus, the clinical use of combination therapy is not evidenced based on most cases and preciseness in its use is uncertain. Finally, therapeutic drug monitoring of select antifungals (notably posaconazole and voriconazole) may play an increasing role due to significant interpatient variability in serum concentrations after standard doses.

Topics: Amphotericin B; Antifungal Agents; Drug Therapy, Combination; Echinocandins; Humans; Mycoses; Stem Cell Transplantation; Transplantation, Homologous; Triazoles

Amphotericin B (AmB) is a parenterally administered broad-spectrum antifungal and leishmanicidal drug that has been on the market for over sixty years. Unfortunately, significant infusion-related side effects and renal toxicity often accompany treatment, limiting its clinical applications. Lipid-based formulations have somewhat ameliorated the associated toxicity, but the increased cost of formulations restricts widespread use. AmB is amphipathic and exhibits low solubility and permeability, resulting in negligible absorption when administered orally. Advances in drug delivery systems have overcome some of the solubility issues that prevent oral bioavailability and new formulations are currently in development. The existence of an effective, safe and inexpensive oral formulation of amphotericin B would have significant applications for the treatment of disseminated fungal infections and would dramatically expand access to treatment of visceral leishmaniasis by introducing a readily available highly tolerated oral formulation of a drug with known efficacy.

Topics: Administration, Oral; Amphotericin B; Animals; Antifungal Agents; Chemistry, Pharmaceutical; Humans; Leishmaniasis, Visceral; Mycoses; Trypanocidal Agents

Despite the systemic toxicity of amphotericin B (AMB), it still has a place in treatment or prophylactic regimes of fungal infections.. A strategy for minimizing the potential of systemic side effects is to bring it in direct contact with the body site most likely to be infected, such as the administration of AMB as an aerosol. Nebulized amphotericin has been used in humans since 1959. However, due to a lack of sufficient data regarding efficacy, its use is still not established. Little is known about the optimal dose, frequency, duration of administration, and the pharmacokinetics of inhaled AMB in humans.. In this review, published data regarding inhaled AMB are summarized, including available descriptions regarding preparation, dose, efficacy, and toxicity, and its place in therapy is discussed. The results from the studies that were reviewed in this article indicate that inhaled AMB may have a place in the prophylactic regimens of patients with prolonged neutropenia and in lung transplant recipients. Furthermore, nebulized (liposomal) AMB may have a place in the treatment of allergic bronchopulmonary aspergillosis (ABPA) in patients with corticosteroid-dependent ABPA.

Topics: Administration, Inhalation; Amphotericin B; Humans; Lung Transplantation; Mycoses; Nebulizers and Vaporizers; Neutropenia

Invasive fungal infections are an important cause of morbidity and mortality in critically ill and immunocompromised patients. Amphotericin B has remained the gold standard treatment for systemic fungal infections. The primary obstacle to amphotericin B therapy is its poor solubility and dose-related toxicities, especially renal impairment. As a result, newer lipid-based formulations of amphotericin B have been developed. This monograph compares available phamacokinetic, efficacy, and safety data for the 3 lipid-based formulations of amphotericin B, with reference to various patient populations. Potential causes of infusion-related reactions are described, and a premedication algorithm for the prevention of infusion-related reactions is developed.

Topics: Amphotericin B; Antifungal Agents; Humans; Mycoses; Treatment Outcome

Amphotericin B (AmB) is a well known antifungal and antiprotozoal antibiotic used in the clinic for several decades. Clinical applications of AmB, however, are limited by its nephrotoxicity and many other acute side effects which are not acceptable by patients when their life is not threaten. In order to improve the therapeutic index of this drug, lipid formulations have been introduced and many efforts have been made to obtain less toxic AmB derivatives by chemical modifications of the parent drug. This review presents concise knowledge about this fascinating compound and a critical review of the data published within last few years about the mechanism of action of this antibiotic. In particular, in the present work we discuss: i) structure and properties of AmB and its recently synthesized new derivatives; ii) antifungal and antileishmanial activity and toxicity of these compounds; and iii) mode of action of AmB and its derivatives at cellular and molecular levels, with particular attention paid to interactions of AmB and different components of cellular membranes.

Topics: Amphotericin B; Animals; Antifungal Agents; Antiprotozoal Agents; Drug Design; Humans; Kidney Diseases; Leishmaniasis; Mycoses

Amphotericin B (AmB) is a crucial agent in the management of serious systemic fungal infections. In spite of its proven track record, its well-known side effects and toxicity will sometimes require discontinuation of therapy despite a life-threatening systemic fungal infection. The mechanism of action of AmB is based on the binding of the AmB molecule to the fungal cell membrane ergosterol, producing an aggregate that creates a transmembrane channel, allowing the cytoplasmic contents to leak out, leading to cell death. Most of the efforts at improving AmB have been focused on the preparation of AmB with a lipid conjugate. AmB administration is limited by infusion-related toxicity, an effect postulated to result from proinflammatory cytokine production. The principal acute toxicity of AmB deoxycholate includes nausea, vomiting, rigors, fever, hypertension or hypotension, and hypoxia. Its principal chronic adverse effect is nephrotoxicity. AmB probably produces renal injury by a variety of mechanisms. Risk factors for AmB nephrotoxicity include male gender, higher average daily dose of AmB (> or = 35 mg/day), diuretic use, body weight > or = 90 kg, concomitant use of nephrotoxic drugs, and abnormal baseline renal function. Clinical manifestations of AmB nephrotoxicity include renal insufficiency, hypokalemia, hypomagnesemia, metabolic academia, and polyuria due to nephrogenic diabetes insipidus. Human studies show convincingly that sodium loading in excess of the usual dietary intake notably reduces the incidence and severity of AmB-induced nephrotoxicity.

Topics: Amphotericin B; Anemia; Animals; Arrhythmias, Cardiac; Calcium Channel Blockers; Cytokines; Fever; Gastrointestinal Diseases; Humans; Hyperkalemia; Kidney Diseases; Liposomes; Mycoses; Rats; Sodium Chloride

An increase in the number of immunocompromised patients has led to a rising burden of systemic fungal infections. Historically, conventional amphotericin B has been used to treat these infections due to its broad spectrum of activity. The development of lipid-based amphotericin B agents, such as Abelcet * (ABLC), has allowed clinicians to take advantage of the broad spectrum of activity of amphotericin B while reducing adverse events. As well as this, a number of new antifungal agents have been developed in recent years which have significantly added to the treating physician's antifungal armamentarium. * Abelcet is a registered trade name of Cephalon Ltd, Herts, UK.. Review the clinical data that support the use of ABLC and discuss the evidence for its continuing role in the treatment of invasive fungal infections in light of the introduction of newer antifungal agents.. Published studies were identified by searching the MEDLINE database and the Cochrane Centre for Reviews up to August 2009. The search was conducted using the following key words: Amphotericin, Lipid, Abelcet, AmBisome, Efficacy, Nephrotoxicity, Renal, Toxicity.. ABLC is effective and well-tolerated in the treatment of systemic fungal infections and remains a valuable therapeutic option in a variety of immunocompromised patients due to its broad antifungal spectrum and rarity of resistance.. Data from randomised controlled trials of lipid-based amphotericin B formulations, as well as head-to-head comparison studies between ABLC and other antifungal agents are limited. In addition, the review uses a narrative approach and relies to a great extent on the authors' personal views and experiences.

Topics: Administration, Inhalation; Amphotericin B; Antifungal Agents; Azoles; Controlled Clinical Trials as Topic; Echinocandins; Humans; Mycoses; Treatment Outcome

Fungal endocarditis is a cardiac complication that has been increasing throughout the world. We present a case of infective endocarditis by Paecilomyces variotii in a male patient with a prosthetic mitral valve. Successful treatment consisted of administration of amphotericin B (total dose 3670 mg) and mitral valve replacement. Only six cases have been reported previously, with a 100% mortality rate.

Topics: Adult; Amphotericin B; Antifungal Agents; Bioprosthesis; Combined Modality Therapy; Device Removal; Endocarditis; Heart Valve Prosthesis; Humans; Male; Mitral Valve; Mycoses; Paecilomyces; Postoperative Complications; Prosthesis-Related Infections; Pulmonary Edema; Reoperation; Rheumatic Heart Disease

In addition to their in vitro inhibitory and fungicidal effects, modern antifungal agents interact in vivo with host immune functions involved in defense against fungal pathogens. The nature of such interactions is diverse and depends on the drug, the immunological status of the host, and the fungal pathogen. Given the prominent role of the host's immune response in controlling invasive fungal infection, immunomodulation by antifungal drugs may prove to be clinically significant. Elucidation of the immunopharmacology of these drugs may aid in designing therapeutic regimens for specific clinical scenarios associated with defined immunological dysfunction.

Topics: Amphotericin B; Antifungal Agents; Antigens, Fungal; Azoles; beta-Glucans; Cytokines; Drug Combinations; Echinocandins; Humans; Immunity; Immunocompromised Host; Leukocytes; Mycoses; Phosphatidylcholines; Phosphatidylglycerols

Infectious complications after hematopoietic stem cell transplant, especially those caused by fungi, contribute to poor outcomes. Availability of new antifungal drugs has led to creative attempts to prevent infections caused by both yeasts and molds with new antifungal prophylaxis strategies; these studies will be reviewed.. Trials evaluating mold-active azoles, posaconazole and voriconazole, demonstrate that invasive aspergillosis infections can be prevented by prophylactic therapy in patients with hematologic malignancies and after allogeneic hematopoietic stem cell transplant. However, issues arise regarding appropriate dosing and levels, drug interactions, and the importance of breakthrough infections caused by organisms that demonstrate microbiologic resistance. Other recent studies evaluating efficacy and safety of aerosolized lipid formulations of amphotericin B demonstrate promise with directed delivery to the lungs; more long-term follow-up safety information is needed to be assured that this strategy is safe late after allogeneic hematopoietic stem cell transplant, in the setting of acute and chronic graft vs. host disease.. Clinicians should consider using new mold-active azole drugs for prophylaxis instead of fluconazole in allogeneic hematopoietic stem cell transplant recipients that have high risks due to prolonged neutropenia and severe graft vs. host disease. More investigations are needed to support other preventive strategies that utilize diagnostic tests and aerosolized delivery of amphotericin B formulations.

Topics: Amphotericin B; Antifungal Agents; Azoles; Chemoprevention; Fungi; Hematopoietic Stem Cell Transplantation; Humans; Mycoses

The ideal antifungal agent remains an elusive goal for treatment of life-threatening systemic fungal infections. Such an agent would have broad antifungal activity, low rates of resistance, flexible routes of administration, few associated adverse events, and limited drug-drug interactions. Only three of the seven classes of antifungal agents currently available are suitable for treatment of systemic infection: the polyenes, the azoles, and the echinocandins. None match all the characteristics of an ideal agent, the Holy Grail of antifungal therapy. Academia and industry need to collaborate in the search for new lead antifungal compounds using traditional screening methods as well as the new pharmacogenomics methods. Enhancing efficacy and reducing toxicity of the currently available therapeutic agents is also another important avenue of study. As an example, the Mycosis Research Center at the University of Mississippi Medical Center has identified pyogenic polyenes in commercial preparations of amphotericin B deoxycholate which correlate with infusion related toxicities. A highly purified formulation of amphotericin B appears promising, with a better therapeutic index compared to its parent compound as evidenced by results of in vitro and in vivo studies reviewed in this presentation.

Topics: Amphotericin B; Antifungal Agents; Azoles; Drug Contamination; Drug Design; Fungi; Genomics; Humans; Mycoses; Proteomics

Opportunistic invasive fungal infections (IFIs) have changed. Moreover, a significantly greater therapeutic armamentarium is now available, with liposomal amphotericin B (L-AmB) administered in new ways, for example in higher doses, in combination with other compounds or inhaled. The objective of this study was to review these three aspects. The AmBiLoad study was designed to clarify whether higher doses of L-AmB could be more efficacious than the licensed dose of 3-5 mg/kg. It was a multicentric study where patients were randomised to receive a 14-day course of 3 mg/kg/day or 10 mg/kg/day L-AmB. A total of 339 patients were enrolled during the study period (April 2003 to October 2004). Discontinuation of treatment, mainly due to adverse events, was frequent (13% in the standard dose group vs. 24% in the high dose group), and only 66% and 50%, respectively, completed 14 days of randomised treatment. There was no statistically significant difference with regard to favourable overall responses between the treatment groups (50% in the standard dose group vs. 46% in the high dose group; P = 0.65). In addition, there was no significant difference according to type of IFI (invasive aspergillosis, 50% vs. 46% in the standard and high dose groups, respectively). The obvious conclusion of this study was that administration of 10 mg/kg/day L-AmB to patients with IFI does not improve efficacy but increases toxicity and price. In vitro and experimental data suggest that the combination of AmB with other antifungal agents may be more effective than monotherapy; however, data regarding the clinical efficacy of L-AmB in combination with other agents are scarce. The use of inhaled L-AmB has shown promising results for use as antifungal prophylaxis in high-risk patients.

Topics: Administration, Inhalation; Amphotericin B; Antifungal Agents; Clinical Trials as Topic; Drug Therapy, Combination; Humans; Immunocompromised Host; Mycoses; Transplantation

Invasive Candida and Aspergillus infections are the most commonly encountered fungal infections. They appear to be life threatening in the setting of profound immunosuppression, whereas cases that are resistant to antifungal therapy are occasionally encountered. Novel antifungal triazole and echinocandin agents appear to exhibit good activity as first-line or salvage therapy, whereas the use of amphotericin B formulations is particularly valuable in neonates. Significant differences in toxicity have been demonstrated among various antifungal agents with in vitro activity from available comparative data on fungal infections in children: however, no clear difference in treatment efficacy has been demonstrated. However, very little data are available about neonates. Host factors and responsible fungal species most frequently guide the choice of therapy.

Topics: Amphotericin B; Antifungal Agents; Child; Child, Preschool; Drug Resistance, Fungal; Echinocandins; Humans; Infant, Newborn; Mycoses; Triazoles

The oral agents for deep-seated mycoses that can be used in Japan are amphotericin B, flucytosine, fluconazole, itraconazole, and voriconazole. There are many guidelines, for example, the Japanese "Guidelines for the Diagnosis and Treatment of Deep-Seated Mycosis 2007", IDSA guidelines for candidiasis, aspergillosis, and so on, and these agents are used in antifungal therapy while referring to these guidelines. Recently relation between serum concentration of antifungal agent with effectiveness or side effects is found gradually. After understanding not only character of antifungal agents, spectrum, side effects, and adjustment according to renal function and other drug, but also new agents and other findings, we should treat mycoses. Especially, in the diabetic, it is necessary to note the rise of the blood level of the calcium channel blocker and oral antidiabetic agents while being using these drugs together with triazoles.

Topics: Administration, Oral; Amphotericin B; Antifungal Agents; Diabetes Complications; Fluconazole; Flucytosine; Humans; Itraconazole; Japan; Mycoses; Practice Guidelines as Topic; Pyrimidines; Triazoles; Voriconazole

The incidence of fungal infection is increasing. Amphotericin B has been the gold standard in antifungal chemotherapy for a long time. Within the past few years, three novel antifungal agents have been approved to evaluate the clinical benefits in Japan. Liposomal amphotericin B is developed to reduce toxicities of amphotericin B. Voriconazole, a kind of the new broad-spectrum triazoles, is recommended for the primary treatment of invasive aspergillosis. Micafungin is a new lipopeptide antifungal agent of the echinocandin class. These drugs might provide an individualized and more effective antifungal therapy for each patient. On the other hand, we need to establish a new standard therapy.

Topics: Amphotericin B; Antifungal Agents; Drug Delivery Systems; Echinocandins; Fluconazole; Humans; Infusions, Intravenous; Injections; Itraconazole; Lipopeptides; Liposomes; Micafungin; Mycoses; Organophosphates; Pyrimidines; Triazoles; Voriconazole

Invasive candidiasis has become a public health problem due to the high associated rates of morbidity and mortality. As in other systemic infections, accurate and early diagnosis is essential. Despite its limited sensitivity (50%), blood culture continues to be the most effective technique for the diagnosis of candidemia. New culture-independent techniques have been marketed with the aim of improving diagnostic yield. Among these techniques, the most notable are (1-3)-beta-D-glucan and anti-germ-tube antibody detection. However, the best option to optimize the diagnosis of invasive candidiasis seems to be the combination of two techniques that detect antigen, antibodies, (1-3)-beta-D-glucan or DNA. Fluconazole, and sometimes amphotericin B, remain the antifungal agents of choice for the treatment of candidiasis. In the last few years, new antifungal agents have been introduced with the aim of improving the prognosis of some clinical presentations of this disease. The echinocandins and second-generation triazoles show greater antifungal activity than fluconazole. Moreover, clinical trials of candidiasis in different localizations have shown that these drugs have excellent efficacy and safety profiles. The potential for drug interactions with some of these antifungal agents is considerable. The contribution of the new antifungal drugs in the treatment of candidiasis should be defined in the near future.

Topics: Amphotericin B; Antibodies, Fungal; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Fungal; Candida; Candidiasis; Clinical Trials as Topic; DNA, Fungal; Drug Interactions; Echinocandins; Fungemia; Humans; Mycology; Mycoses; Triazoles; Yeasts

Combined, simultaneous or sequential antifungal therapy has often been considered an appropriate option to improve the results obtained with monotherapy. Anidulafungin belongs to the echinocandin family, which has a different mechanism of action from the remaining antifungal agents, a characteristic that heralds a good chance of synergy with other groups. However, most of the data available on the efficacy of different combinations comes from animal models of infection, "in vitro" data and case reports, while data from controlled clinical trials are scarce. The available data are insufficient to allow us to conclude that the efficacy of combined therapy is significantly superior to that of monotherapy. However, the efficacy of combined therapy may be adequate for the treatment of severe invasive mycoses associated with high mortality rates, such as forms of aspergillosis that provoke central nervous system involvement, extensive pulmonary involvement, cavitated areas, or respiratory failure and infections caused by multiresistant fungi.

Topics: Amphotericin B; Anidulafungin; Animals; Antifungal Agents; Azoles; Clinical Trials as Topic; Drug Evaluation, Preclinical; Drug Synergism; Drug Therapy, Combination; Echinocandins; Encephalomyelitis; Fungemia; Guinea Pigs; Humans; Lung Diseases, Fungal; Mice; Mycoses

The development of a safe and efficacious drug involves a balance between bioavailability, toxicity and disposition within the body. If the drug is hydrophobic or acid labile, oral administration may lead to poor systemic exposure, necessitating a parenteral treatment regime. Amphotericin B (AmpB) is one example of a well established, highly efficacious drug that has a 50 year history of intravenous therapy. AmpB formulated as a micellar dispersion (Fungizone; FZ) for IV use, remains one of the most effective agents in the treatment of systemic fungal infections, yet no oral formulations are currently commercially available. Recently, our laboratory has developed new oral lipid-based AmpB formulations with enhanced gastrointestinal (GI) tract absorption and antifungal activity with minimum renal toxicity. This review article will discuss these findings and present data to support two potential mechanisms for the enhanced GI tract absorption of AmpB when formulated in this oral lipid-based delivery system, namely an increase in lymphatic drug transport and a decrease in pre-systemic transporter-mediated drug efflux.

Topics: Administration, Oral; Amphotericin B; Animals; Antifungal Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport; Chemistry, Pharmaceutical; Humans; Intestinal Absorption; Lipids; Mycoses

Topics: Amphotericin B; Antifungal Agents; Azoles; Drug Interactions; Echinocandins; Humans; Mycoses; Neutropenia

To review the literature on the use of amphotericin irrigation for the treatment of chronic rhinosinusitis.. Although the etiology of acute rhinosinusitis is usually bacterial in nature, the exact etiology of chronic rhinosinusitis is unclear. Recent literature reports pointed to fungal colonization as a likely pathogenesis. It was hypothesized that a nonallergic eosinophilic immunoglobulin response to these fungi by the host was the cause of the symptoms, not a fungal invasion into the mucosa. The paper reviews the most recent articles investigating the use of amphotericin irrigation, as well as sprays and oral medications, of the nasal and sinus mucosa in patients with chronic rhinosinusitis.. The use of amphotericin for patients with chronic rhinosinusitis is not substantiated by the majority of publications. Although some studies found improvement on radiographic images, the symptoms of the disorder were not improved even with fungal eradication. Further studies need to be carried out to determine if changes in dosage, treatment time or route of administration could improve results.

Topics: Administration, Intranasal; Amphotericin B; Antifungal Agents; Chronic Disease; Humans; Mycoses; Rhinitis; Sinusitis; Therapeutic Irrigation

A systematic review was performed to examine renal function in patients with invasive fungal infections, comparing the nephrotoxicity caused by conventional amphotericin B deoxycholate (c-AmB) with that induced by the use of lipid-based amphotericin B formulations. The analysis considered all comparative studies published in the literature between January 1996 and May 2007. The outcome data reviewed herein focused on renal toxicity as measured by serum creatinine (S-Cr) and the doubling or the mean difference in S-Cr levels from baseline to the end of therapy or the need for dialysis. We found that AmB lipid complex (ABLC), liposomal AmB (L-AmB) and AmB colloidal dispersion (ABCD) were significantly less nephrotoxic than c-AmB in all reported studies. ABLC and L-AmB caused low and comparable nephrotoxicity in nine studies. In one randomized study, L-AmB was significantly less nephrotoxic than ABLC. No studies compared ABCD nephrotoxicity to the other lipid formulations. Based on our review we conclude that lipid formulations of amphotericin B are an important strategy to preserve renal function and improve survival in critically ill patients who require treatment for systemic fungal infections.

Topics: Amphotericin B; Antifungal Agents; Humans; Mycoses; Renal Dialysis; Renal Insufficiency; Treatment Outcome

To reduce the in-vivo toxicity of the broad-spectrum antifungal drug amphotericin B, various lipid formulations of amphotericin B, ranging from lipid complexes to small unilamellar liposomes, have been developed and subsequently commercialized. These structurally diverse formulations differ in their serum pharmacokinetics as well as their tissue localisation, tissue retention and toxicity. These differences can affect the choice of formulation for a given infection, the time of initiation of treatment, and the dosing regimen. Although preclinical studies have shown similarities in the in-vitro and in-vivo antifungal activity of the formulations with comparable dosing, their acute and chronic toxicity profiles are not the same, and this has a significant impact on their therapeutic indices, especially in high-risk, immunosuppressed patients. With the recent introduction of new antifungal drugs to treat the increasing numbers of infected patients, the amphotericin B lipid formulations are now being studied to evaluate their potential in combination drug regimens. With proven efficacy demonstrated during the past decade, it is expected that amphotericin B lipid formulations will remain an important part of antifungal drug therapy.

Topics: Amphotericin B; Animals; Antifungal Agents; Drug Combinations; Drug Therapy, Combination; Humans; Mycoses; Phosphatidylcholines; Phosphatidylglycerols

In recent years, the focus of attention in our understanding of pharmacokinetic antifungal drug efficacy has expanded from the vascular to the tissue compartment, since for moulds in particular, this is the primary point of encounter between the invading fungus and the host. Liposomal amphotericin B (LAB) accumulates in the reticulo-endothelial system and other tissues for several weeks after systemic administration at concentrations exceeding the MICs for many pathogenic fungi. Animal models demonstrate that such tissue depots provide effective prophylaxis and even therapeutic opportunities when LAB is given in high intermittent doses. Efficacy has been shown for even a single high dose of LAB. Human studies have also confirmed retention of amphotericin B in tissues well beyond the last administered dose. Clinical evidence has begun to accrue that suggests prophylactic efficacy in high-risk patients with haematological malignancies who have received intermittent LAB. In an exploratory study of patients with persistent and protracted neutropenic fever, one dose of 10 mg/kg, followed by two doses of 5 mg/kg given on days 1, 3 and 6, respectively, appeared to be as effective as the standard regimen of 3 mg/kg/day given for a longer period. Serum kinetics suggest a large-volume deep tissue compartment for LAB. The drug also appears to accumulate in the tissue, as reflected by bone marrow concentrations. These early observations suggest the potential for intermittent high dosing of LAB for prophylaxis and management of invasive fungal infections, thus providing an alternative option to more frequent and expensive administration of LAB, and daily administration of azoles or candins. This might offer the benefits of lower treatment costs, improved patient compliance and reduced toxicity. Further clinical studies are required to confirm the feasibility of such an approach.

Topics: Adult; Amphotericin B; Animals; Antifungal Agents; Area Under Curve; Dose-Response Relationship, Drug; Humans; Mice; Mycoses; Tissue Distribution

Although our antifungal armamentarium has been enlarged recently with new azoles (voriconazole and posaconazole) and echinocandins (caspofungin, micafungin, anidulafungin), the polyenes still have an important role in antifungal strategies because of their extended antifungal spectrum and rarity of mycological resistance. The use of conventional amphotericin B deoxycholate is limited by substantial toxicity that is either infusion-related or associated with renal failure. Its lipid derivatives, particularly liposomal amphotericin B (LAmB), are less nephrotoxic while maintaining a broad antifungal spectrum. LAmB is active against most Candida spp., including Candida glabrata and Candida parapsilosis, and against more resistant, emerging yeasts species such as Rhodotorula spp., Geotrichum spp. and Trichosporon spp.. LAmB is also active against Cryptococcus spp. and all dimorphic fungi such as Histoplasma, Blastomyces, Coccidioidomyces, and Paracoccidiodomyces. The antifungal spectrum of LAmB is particularly interesting with regard to filamentous fungi, with marked activity against Aspergillus spp. and agents of zygomycosis. The latter might emerge during long-term treatment with voriconazole or an echinocandin, as these organisms are resistant to these drugs. We review here the role of LAmB in the current antifungal management strategy, which is based on results obtained in prospective trials. LAmB can be retained as first-line treatment for human immunodeficiency virus (HIV)-positive patients with disseminated histoplasmosis and cryptococcosis, even in the setting of renal impairment or concomitant administration of potentially nephrotoxic drugs. In addition, there is sufficient evidence that the drug should be a major consideration for the empirical treatment of persistent febrile neutropenia or as an alternative to for patients with invasive aspergillosis, for those at risk of renal impairment, major drug-drug interaction or liver insufficiency, particularly in the situation of an established azole intolerance. The primary licensed indication for LAmB is empirical treatment. When zygomycosis is suspected or has been documented, high doses of LAmB should be prescribed. Finally, LAmB may also be considered as a therapeutic option for the management of candidaemia and remains a cornerstone for the treatment of some visceral localisations during systemic candidosis.

Topics: Amphotericin B; Antifungal Agents; Drug Therapy, Combination; Humans; Leishmaniasis, Visceral; Mycoses

Achievement of therapeutic drug levels appears to be mandatory when antifungal agents are used for the treatment of manifest mycoses. Based on the marked interindividual variability of trough levels, Therapeutic Drug Monitoring is of increasing concern during treatment with itraconazole, voriconazole or posaconazole. In addition, a broad spectrum of potential drug interactions has to be kept in mind during triazole treatment. In contrast, echinocandins reveal a more comfortable class of antifungal agents in this regard with no obvious incidence of nephrotoxic side effects compared to amphotericin B and its lipid formulations.

Topics: Amphotericin B; Antifungal Agents; Drug Interactions; Echinocandins; Humans; Itraconazole; Mycoses; Pyrimidines; Triazoles; Voriconazole

Amphotericin B, a broad spectrum antifungal agent, is widely used despite significant adverse events including nephrotoxicity. Nephrotoxicity occurs frequently in patients receiving amphotericin B. Different definitions for nephrotoxicity are reviewed in the context of outcome in patients with invasive fungal diseases. In most publications, mortality was higher in patients experiencing nephrotoxicity and mean hospital length of stay was prolonged. As a consequence, the use of less nephrotoxic antifungal agents could improve treatment outcomes.

Topics: Amphotericin B; Antifungal Agents; Humans; Immunocompromised Host; Kidney Diseases; Length of Stay; Mycoses; Treatment Outcome

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillus; Candida; Clinical Trials, Phase II as Topic; Cryptococcus; Drug Resistance, Fungal; Humans; Mycoses; Neutropenia; Randomized Controlled Trials as Topic

Topics: Amphotericin B; Animals; Antifungal Agents; Drug Therapy; Echinocandins; Humans; Itraconazole; Lipopeptides; Lipoproteins; Micafungin; Mycoses; Peptides, Cyclic; Pyrimidines; Stem Cell Transplantation; Triazoles; Voriconazole

Topics: Amphotericin B; Antifungal Agents; Azoles; Drug Resistance, Fungal; Flucytosine; Fungi; Humans; Mycoses

Disseminated Fusarium infection can cause significant morbidity and mortality in immunocompromised patients. We present a case of disseminated fusariosis in a patient with neutropenic fever successfully treated using both liposomal amphotericin B and voriconazole. Combination anti-fungal therapy may be considered for such patients, particularly for those failing single-drug therapy.

Topics: Aged; Amphotericin B; Antifungal Agents; Drug Therapy, Combination; Female; Fever; Fusarium; Humans; Immunocompromised Host; Liposomes; Male; Mycoses; Neutropenia; Pyrimidines; Treatment Outcome; Triazoles; Voriconazole

Fungal urinary tract infections (funguria) are rare in community medicine, but common in hospitals where 10 to 30% of urine cultures isolate Candida species. Clinical features vary from asymptomatic urinary tract colonization (the most common situation) to cystitis, pyelonephritis, or even severe sepsis with fungemia. The pathologic nature of funguria is closely related to host factors, and management depends mainly on the patient's underlying health status. Microbiological diagnosis of funguria is usually based on a fungal concentration of more than 10(3)/mm(3) in urine. No cutoff point has been defined for leukocyte concentration in urine. Candida albicans is the most commonly isolated species, but previous antifungal treatment and previous hospitalization affect both species and susceptibility to antifungal agents. Treatment is recommended only when funguria is symptomatic or in cases of fungal colonization when host factors increase the risk of fungemia. The antifungal agents used for funguria are mainly fluconazole and amphotericin B deoxycholate, because other drugs have extremely low concentrations in urine. Primary and secondary preventions are essential. The reduction of risk factors requires removing urinary catheters, limiting antibiotic treatment, and optimizing diabetes mellitus treatment.

Topics: Aged; Amphotericin B; Antifungal Agents; Candida albicans; Candidiasis; Cross Infection; Cystitis; Deoxycholic Acid; Drug Combinations; Female; Fluconazole; Fungemia; Fungi; Health Status; Hospital Mortality; Humans; Male; Mycoses; Primary Prevention; Pyelonephritis; Risk Factors; Urinary Catheterization; Urinary Tract Infections; Urine

Neonates with gastrointestinal diseases and extremely preterm infants are at highest risk for developing invasive fungal infections. Candida species are commensal organisms that colonize skin and mucosal surfaces as well as adhere to catheter surfaces. Due to the immature immune system of neonates including compromise of the developing barrier defenses of the skin or mucosal membranes, Candida can invade into the bloodstream and disseminate, often making these infections difficult to eradicate. Treatment of bloodstream infections uniquely involves both starting antifungal therapy and removing central venous catheters. Liposomal amphotericin formulations and echinochandins are currently being studied in neonates. Prevention for high risk patients is now feasible with fluconazole prophylaxis.

Topics: Amphotericin B; Antifungal Agents; Candida; Candidiasis; Drug Therapy, Combination; Echinocandins; Fluconazole; Fungal Proteins; Humans; Infant, Newborn; Mycoses; Peptides, Cyclic; Treatment Outcome

Invasive fungal infections cause substantial morbidity and mortality in immunocompromised hosts. The response rate to therapy, in particular for invasive aspergillosis and invasive mould infections, has been poor. Recently a number of techniques to facilitate early diagnosis of these infections, in parallel with the development of a number of antifungals with increased potency and lower toxicity, have raised optimism that outcomes for invasive fungal infection can be improved upon. The availability of lipid formulations of amphotericin B, azoles with extended spectrum against filamentous fungi and the development of a new class of antifungal agents, the echinocandins, presents the clinician with a range of therapeutic choices. Recent clinical trials have provided important insights into how these agents should be used. In particular, voriconazole has demonstrated superior efficacy to amphotericin B in the management of invasive aspergillosis, posaconazole has been shown to have significant efficacy in the prophylaxis of invasive fungal infection in high-risk individuals and a role in salvage therapy of invasive aspergillosis, caspofungin has demonstrated efficacy in salvage therapy of invasive aspergillosis, and each of the echinocandins show activity without significant toxicity in invasive candidiasis. Nevertheless, many therapeutic areas of uncertainty remain, including the role of combination therapy, and will provide the focus for future studies.

Topics: Amphotericin B; Antifungal Agents; Azoles; Drug Combinations; Humans; Immunocompromised Host; Mycoses; Peptides, Cyclic; Phosphatidylcholines; Phosphatidylglycerols; Treatment Outcome

Fungi, in comparison with other pathogenic factors, have high pathogenicity. The number of fungal species which are able to infect people is over 500. The upper respiratory tract and ear have permanent contact with external environment which makes their ontocenoses open to continuous exchange of microorganisms of which they consist. In etiology of inflammatory processes 21 species which belonging to 3 genera (Zygomycota, Ascomycota, Basidiomycota) of fungi play important role. Administration of antifungal drugs can be: prophylactic, empiric preemptive and therapeutic. Physicians may prescribe antibiotics (mainly pollens: amphotericin B, natamycin and nystatin) and chemiotherapeutics (mainly azoles and fluorpirymidins, pigments, chlorhexidine and chlorquinaldol). In ENT practice topical and systemic drugs can be administrated. Topical lozenges include amphotericin B, clotrimazole, chlorhexidine or chlorquinaldol and oral gels: nystatin and miconazole. Some of drugs are in the form of suspension/solution, which can be used for inhalation, into the sinus, for swabbing or for lavage: amphotericin B, natamycin, nystatin, clotrimazol, flucytosine, miconazole, fluconazole, vorykonazole, caspofungin. It should be underlined that only a few of dugs can be absorbed from the digestive tract: flucytosine, fluconazole, itraconazole, ketoconazole, miconazole, vorykonazole.

Topics: Administration, Inhalation; Administration, Oral; Administration, Topical; Amphotericin B; Antifungal Agents; Azoles; Clotrimazole; Ear Diseases; Humans; Miconazole; Mycoses; Nystatin; Otitis; Respiratory Tract Infections

Invasive fungal infections (IFI) are the main cause of infectious death in cancer patients, especially in hematological malignancies and hematopoietic transplant recipients. Current epidemiology is characterized by a predominance of IFI caused by molds, mainly aspergillosis, along with a emergence of hard-to-treat fungi such are Zygomicetes, Fusarium and Scedosporium. Voriconazole is a broad spectrum antifungal agent with oral and intravenous formulations, approved by the EMEA for the treatment of invasive aspergillosis, candidemia in non-neutropenic patients, IFI caused by fluconazole-resistant species of Candida as well as Scedosporium and Fusarium infections. However, its use in clinical practice is broader, as empirical antifungal treatment and as secondary prophylaxis. It should be kept in mind the possibility of breakthrough IFI, particularly zygomycosis, in patients treated with voriconazole for long periods.

Topics: Amphotericin B; Antibiotic Prophylaxis; Antifungal Agents; Drug Resistance, Fungal; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Multicenter Studies as Topic; Mycoses; Neoplasms; Neutropenia; Opportunistic Infections; Pyrimidines; Randomized Controlled Trials as Topic; Salvage Therapy; Spain; Triazoles; Voriconazole; Zygomycosis

Topics: Administration, Oral; Amphotericin B; Antifungal Agents; Echinocandins; Humans; Itraconazole; Lipopeptides; Lipoproteins; Micafungin; Mycoses; Pyrimidines; Triazoles; Voriconazole

The polyene antibiotic Amphotericin B (AMB) is one of the first therapeutic agents to be marketed commercially as nanosized formulations in which the drug is associated with lipids as liposomes or complexes. In this way, its renal toxicity is reduced and its therapeutic index improved. This review summarizes the particular properties of AMB which justify this type of formulation and the early work leading up to their development. The clinical results obtained in the treatment of fungal infections are reviewed and their activity against leishmaniasis is also evoked. Some newer formulations of AMB, based on both lipids and polymers are described. In particular, their potential by the oral and pulmonary routes are discussed. Finally, the development of targeted systems to deliver the drug to specific cells and tissues is considered.

Topics: Amphotericin B; Animals; Antifungal Agents; Chemistry, Pharmaceutical; Drug Carriers; Humans; Mycoses; Nanomedicine; Nanostructures

Empirical antifungal therapy has been shown to decrease the number of documented fungal infections in the setting of persistent fever during neutropenia. For decades, amphotericin B deoxycholate has been considered the agent of choice for first-line therapy in this setting. New antifungal agents associated with less toxicity, including the lipid formulations of amphotericin, voriconazole, and caspofungin, are now available and are considered to be suitable alternative first-line agents. In order to ensure appropriate therapy, however, the clinician must consider not only the differences between these antifungals but also patient-specific factors before initiating treatment.

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Clinical Trials as Topic; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Echinocandins; Fever; Humans; Immunocompromised Host; Kidney Diseases; Lipopeptides; Liposomes; Liver Diseases; Mycoses; Neutropenia; Pyrimidines; Triazoles; Voriconazole

Opportunistic fungal infections are a major cause of morbidity and mortality in neutropenic cancer patients and antifungal therapy are used both empirically and therapeutically in these patients.. To compare the benefits and harms of voriconazole with those of amphotericin B and fluconazole when used for prevention or treatment of invasive fungal infections in cancer patients with neutropenia.. MEDLINE and the Cochrane Library (May 2005). Letters, abstracts and unpublished trials were accepted. Contact to authors and industry.. Randomised trials comparing voriconazole with amphotericin B or fluconazole.. Data on mortality, invasive fungal infection, colonisation, use of additional (escape) antifungal therapy and adverse effects leading to discontinuation of therapy were extracted by two authors independently.. Two trials were included. One trial compared voriconazole to liposomal amphotericin B as empirical treatment of fever of unknown origin (suspected fungal infections) in neutropenic cancer patients (849 patients, 58 deaths). The other trial compared voriconazole to amphotericin B deoxycholate in the treatment of confirmed and presumed invasive Aspergillus infections (391 patients, 98 deaths). In the first trial, voriconazole was significantly inferior to liposomal amphotericin B according to the authors' prespecified criteria. More patients died in the voriconazole group and a claimed significant reduction in the number of breakthrough fungal infections disappeared when patients arbitrarily excluded from analysis by the authors were included. In the second trial, the deoxycholate preparation of amphotericin B was used without any indication of the use of premedication and substitution with electrolytes and salt water to avoid handicapping this drug. This choice of comparator resulted in a marked difference in the duration of treatment on trial drugs (77 days with voriconazole versus 10 days with amphotericin B), and precludes meaningful comparisons of the benefits and harms of the two drugs.. Liposomal amphotericin B is significantly more effective than voriconazole for empirical therapy of neutropenic cancer patients and should be preferred. For treatment of aspergillosis, there are no trials that have compared voriconazole with amphotericin B given under optimal conditions.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Fluconazole; Humans; Liposomes; Mycoses; Neoplasms; Neutropenia; Opportunistic Infections; Pyrimidines; Randomized Controlled Trials as Topic; Triazoles; Voriconazole

Invasive fungal infections, important causes of morbidity and mortality in critically ill patients, may be preventable with the prophylactic administration of antifungal agents.. This study aims to systematically identify and summarize the effects of antifungal prophylaxis in non-neutropenic critically ill adult patients on all-cause mortality and the incidence of invasive fungal infections.. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), (The Cochrane Library, Issue 3, 2005), MEDLINE (1966 to 2 September 2005), and EMBASE (1980 to week 36, 2005). We also handsearched reference lists, abstracts of conference proceedings and scientific meetings (1998 to 2004), and contacted authors of included studies and pharmaceutical manufacturers.. We included randomized controlled trials in all languages comparing the prophylactic use of any antifungal agent or regimen with placebo, no antifungal, or another antifungal agent or regimen in non-neutropenic critically ill adult patients.. Two authors independently applied selection criteria, performed quality assessment, and extracted data using an intention-to-treat approach. We resolved differences by discussion. We synthesized data using the random effects model and expressed results as relative risk with 95% confidence intervals.. We included 12 unique trials (eight comparing fluconazole and four ketoconazole with no antifungal or a nonabsorbable agent) involving 1606 randomized patients. For both outcomes of total mortality and invasive fungal infections, almost all trials of fluconazole and ketoconazole separately showed a non-significant risk reduction with prophylaxis. When combined, fluconazole/ketoconazole reduced total mortality by about 25% (relative risk 0.76, 95% confidence interval 0.59 to 0.97) and invasive fungal infections by about 50% (relative risk 0.46, 95% confidence interval 0.31 to 0.68). We identified no significant increase in the incidence of infection or colonization with the azole-resistant fungal pathogens Candida glabrata or C. krusei, although the confidence intervals of the summary effect measures were wide. Adverse effects were not more common amongst patients receiving prophylaxis. Results across all trials were homogeneous despite considerable heterogeneity in clinical and methodological characteristics.. Prophylaxis with fluconazole or ketoconazole in critically ill patients reduces invasive fungal infections by one half and total mortality by one quarter. Although no significant increase in azole-resistant Candida species associated with prophylaxis was demonstrated, trials were not powered to exclude such an effect. In patients at increased risk of invasive fungal infections, antifungal prophylaxis with fluconazole should be considered.

Topics: Adult; Amphotericin B; Antifungal Agents; Critical Illness; Fluconazole; Humans; Immunocompromised Host; Mycoses; Randomized Controlled Trials as Topic

Invasive fungal infections are important causes of morbidity and mortality in critically ill non neutropenic patients. For many years, amphotericin B and flucytosine have been the only available antifungal agents for invasive fungal infections. Fortunately, the antifungal armamentarium has increased during the past two decades with the addition of several new agents. In addition to itraconazole and fluconazole, lipid formulations of amphotericin B, voriconazole, and caspofungin have been recently licensed. These various antifungal agents differ in their pharmacokinetic and pharmacodynamic profile.

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Echinocandins; Forecasting; Humans; Imidazoles; Lipopeptides; Mycoses; Peptides, Cyclic

Exserohilum is a dematiaceous fungus that may cause a spectrum of diseases in humans, including skin and corneal infection, invasive disease, and allergic fungal sinusitis. The aim of this work is to describe two new cases of Exserohilum infection and to review the literature. The review yielded 33 cases of Exserohilum infection, of which 23 were reported since 1993. Most occurred in regions with hot climates, such as India, Israel, and the southern USA. Impaired immunity was present in the majority of patients with invasive and skin infections, whereas local trauma and atopy were the predisposing factors in those with corneal infections and allergic fungal sinusitis, respectively. Surgical debridement was the principal mode of therapy for allergic fungal sinusitis. Amphotericin B was the initial single antifungal agent used in all cases of invasive disease; the response rate was low but improved with the addition of triazole agents. Outcome appeared to be better than for other mold infections and depended mainly on the underlying diseases.

Topics: Adolescent; Adult; Amphotericin B; Antifungal Agents; Ascomycota; Child; Child, Preschool; Female; Humans; Male; Middle Aged; Mycoses; Nasal Mucosa; Treatment Outcome

Topics: Amphotericin B; Antifungal Agents; Bone Marrow Transplantation; Female; Humans; Male; Mycoses; Randomized Controlled Trials as Topic

Topics: Aged; Amphotericin B; Antifungal Agents; Arterial Occlusive Diseases; Cardiac Surgical Procedures; Device Removal; Endarterectomy; Endocarditis; Fatal Outcome; Female; Femoral Artery; Heart Valve Diseases; Heart Valve Prosthesis; Heart Valve Prosthesis Implantation; Humans; Leg; Mitosporic Fungi; Mitral Valve; Mycoses; Prosthesis-Related Infections; Pyrimidines; Reoperation; Triazoles; Voriconazole

The incidence of invasive fungal infections (IFIs) continues to increase, largely due to the steady rise in the number of at-risk patients and the increased use of aggressive immunosuppressant agents. Many available treatments are often limited by concerns about efficacy, safety, drug interactions, and/or cost. Owing to the poor treatment outcomes of immunosuppressed patients with IFIs, new preventative and treatment strategies are being investigated. Among these are the aerosolized formulations of amphotericin B. Published experience with the use of aerosolized amphotericin B deoxycholate (AmBd) in the prevention of IFIs has raised concerns regarding challenges in drug administration and tolerability. However, evolving data regarding administration of lipid-based formulations of amphotericin B indicate potential advantages over AmBd in the prevention and adjunctive treatment of IFIs.

Topics: Aerosols; Amphotericin B; Antifungal Agents; Chemistry, Pharmaceutical; Deoxycholic Acid; Drug Combinations; Humans; Incidence; Mycoses; Phosphatidylcholines; Phosphatidylglycerols; Treatment Outcome

The high morbidity, mortality, and healthcare costs associated with the invasive fungal infections, especially in the critical care setting, is of importance since the prophylactic, empiric, and pre-emptive therapy interventions, based on early identification of risk factors, is of common occurrence. In the last years alone there have been important developments in antifungal pharmacotherapy. Evidence-based studies using new antifungal agents are now emerging as important players in the pharmacotherapy of invasive fungal infections in seriously ill and difficult patients. However, data on critically ill patients are more limited and usually recovered from general studies. This study shows the benefits obtained by the new antifungal agents on different clinical situations in critical care units. The increasing number of non-C. albicans species and the high mortality rates in these settings suggest that the application of early de-escalation therapy in critically ill patients with fungal infection should be mandatory. The possibility of using antifungal combination therapy in these types of patients should be considered.

Topics: Amphotericin B; Antifungal Agents; Candidiasis; Critical Illness; Cross Infection; Deoxycholic Acid; Drug Combinations; Fluconazole; Humans; Intensive Care Units; Mycoses; Pyrimidines; Randomized Controlled Trials as Topic; Triazoles; Voriconazole

Topics: Amphotericin B; Antifungal Agents; Deoxycholic Acid; Drug Combinations; Hematologic Neoplasms; Humans; Infusions, Intravenous; Kidney; Mycoses; Time Factors

This is a clinical review on the current role of polyene antifungals in the treatment of invasive fungal infections. It is timely and relevant because the number of new antifungals being developed has never been greater than today. In addition to re-examining the landmark clinical trials of the past, the more recent findings are put into perspective. The past year has been particularly rich in clinical trials.. The main topics of this review are invasive candidiasis, invasive aspergillosis, and the so-called rare fungal infections: zygomycosis, fusariosis, cryptococcosis and histoplasmosis.. Practical implications of the recent developments are the almost complete replacement of amphotericin B deoxycholate by lipid-based formulations; antifungal efficacy without compromising safety; and treatment choices for infections previously considered untreatable.

Topics: Amphotericin B; Antifungal Agents; Clinical Trials as Topic; Humans; Mycoses; Polyenes

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Humans; Meningitis, Cryptococcal; Mucormycosis; Mycoses

Fungal infections and leishmaniasis are an important cause of morbidity and mortality in immunocompromised patients. The macrolide polyene antibiotic amphotericin B (AmB) has long been recognized as a powerful fungicidal and leishmanicidal drug. A conventional intravenous dosage form of AmB, AmB- deoxycholate (Fungizone or D-AmB), is the most effective clinically available for treating fungal and parasitic (leishmaniasis) infections. However, the clinical efficacy of AmB is limited by its adverse effects mainly nephrotoxicity. Efforts to lower the toxicity are based on synthesis of AmB analogues such as AmB esters or preparation of AmB-lipid associations in the forms of liposomal AmB (L-AmB or AmBisome), AmB lipid complex (Abelcet or ABLC), AmB colloidal dispersion (Amphocil or ABCD), and intralipid AmB. These newer formulations are substantially more expensive, but allow patients to receive higher doses for longer periods of time with decreased renal toxicity than conventional AmB. Modifications of liposomal surface in order to avoid RES uptake, thus increased targetability has been attempted. Emulsomes and other nanoparticles are special carrier systems for intracellular localization in macrophage rich organs like liver and spleen. Injectable nano-carriers have important potential applications as in site-specific drug delivery.

Topics: Amphotericin B; Antifungal Agents; Antiprotozoal Agents; Drug Carriers; Drug Compounding; Humans; Leishmaniasis; Mycoses; Nanomedicine; Nanostructures

Reports about the safe and successful intravenous (i.v.) use of garlic derivatives in China against invasive fungal infections have been made, but little has been done to seriously investigate the in vivo use of these derivatives in the West. Laboratories have demonstrated impressive in vitro MICs using allitridium, one of these derivatives, against a range of medically important fungi. In addition, it has been demonstrated that allitridium shows in vitro synergy with amphotericin B, one of the main i.v. antifungal agents. Some of the breakdown products of allicin, the main parent antifungal compound in garlic, have been investigated for their general antimicrobial, anticancer and anticholesterol properties, and it appears that there is a common mode of action that underlies these activities. It appears that these small molecules have the ability to cross cell membranes and combine with sulfur-containing molecular groups in amino acids and proteins, thus interfering with cell metabolism. It has been suggested that the reason human cells are not poisoned by allicin derivatives is that they contain glutathione, a sulfur-containing amino acid that combines with the allicin derivative, thus preventing cell damage. In addition to their biochemical mechanism, these derivatives appear to stimulate cellular immunity, an important ability lacking in conventional antifungal chemotherapy. These derivatives appear to be safe, cheap, wide-spectrum and immunostimulatory, as well as possibly synergistic with conventional antifungal therapy, making them ideal candidates for investigation into their use as prophylactic antifungal agents.

Topics: Amphotericin B; Antifungal Agents; Disulfides; Drug Synergism; Drug Therapy, Combination; Fungi; Humans; Immunity, Cellular; Mycoses; Sulfinic Acids

Topics: Amphotericin B; Antifungal Agents; Ascomycota; Fatal Outcome; Fungemia; Humans; Infant; Lung Diseases, Fungal; Male; Mycoses

In this article, we review the issues surrounding funguria and its management. With this background, the value of bladder irrigation with amphotericin B for the management of funguria is directly examined. Amphotericin B bladder irrigation is used frequently in clinical practice. Although its use is not standardized, there are multiple studies that attempt to show the impact on funguria management. These bladder irrigations have been used either for treatment of funguria or (less commonly) as a diagnostic test in attempts to identify upper urinary tract disease. Despite their widespread therapeutic use and relative safety, it is not clear from our experience and a review of the literature that amphotericin B bladder irrigations have any diagnostic or therapeutic value. The patient may be best served by removal of the urinary catheter, if possible, rather than by instillation of bladder irrigation with amphotericin B.

Topics: Amphotericin B; Antifungal Agents; Humans; Mycoses; Urinary Catheterization; Urinary Tract Infections

Solid organ transplantation is the best alternative for the treatment of end-stage kidney, liver, heart, pancreas and lung failure. Fungal infections (the most frequent are Candida spp. and Aspergillus spp.) are associated with highest mortality in solid organ transplantation. The systemic use of liposomal amphotericin B has only been studied in liver transplant recipients. The main conclusions that can be drawn from the five studies that have been published are: 1) for the prophylaxis to be effective against Aspergillus spp., a dose of 5 mg/kg/day must be used; 2) its use must be reserved for situations with the highest risk for invasive fungal infections: retransplantation, the need for resurgery and, mainly, for those patients needing haemodialysis. Preliminary studies for the prophylactic use of nebulized liposomal amphotericin B in lung transplant receptors are promising.

Topics: Amphotericin B; Antifungal Agents; Humans; Liposomes; Mycoses; Organ Transplantation

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis; Caspofungin; Deoxycholic Acid; Drug Combinations; Echinocandins; Hematologic Neoplasms; Humans; Itraconazole; Lipopeptides; Liposomes; Mycoses; Organ Transplantation; Peptides, Cyclic; Pyrimidines; Risk Factors; Stem Cell Transplantation; Triazoles; Voriconazole; Zygomycosis

Fungal pathogens are an increasingly recognized complication of organ transplantation and the ever more potent chemotherapeutic regimens for childhood malignancies. This article provides a brief overview of the current state of systemic antifungal therapy. Currently licensed drugs, including amphotericin B and its lipid derivates; 5-fluorocytosine; the azoles, including fluconazole, itraconazole, and voriconazole; and a representative of the new class of echinocandin agents, caspofungin, are discussed. Newer second-generation azoles (posaconazole and ravuconazole) and echinocandins (micafungin and anidulafungin) that are likely to be licensed in the United States in the next few years also are addressed.

Topics: Age Factors; Amphotericin B; Anidulafungin; Antifungal Agents; Caspofungin; Chemistry, Pharmaceutical; Child; Clinical Trials as Topic; Drug Approval; Drug Resistance, Fungal; Echinocandins; Fluconazole; Flucytosine; Humans; Itraconazole; Lipopeptides; Lipoproteins; Micafungin; Mycoses; Patient Selection; Pediatrics; Peptides, Cyclic; Pyrimidines; Safety; Thiazoles; Triazoles; United States; Voriconazole

Invasive fungal infections have increased in frequency and severity over the past two decades as a result of an increasing number of immunocompromised patients. This new age of opportunistic fungal infections extends to pediatric patients. The last decade has seen the development of several new antifungal agents for the treatment of these infections. However, there is a paucity of data on the treatment of invasive fungal infections in children. This review provides a brief overview of the current state of antifungal therapy for children, discussing the important antifungal classes and the differences in mechanisms of action and resistance, pharmacology, and efficacy and safety data in pediatric patients outside the neonatal period.

Topics: Adolescent; Amphotericin B; Antifungal Agents; Azoles; Caspofungin; Child; Child, Preschool; Drug Resistance, Fungal; Echinocandins; Flucytosine; Fungal Proteins; Humans; Infant; Lipopeptides; Lipoproteins; Micafungin; Mycoses; Peptides, Cyclic; Triazoles

There is still no consensus on the efficacy of antifungal prophylaxis in neutropenic patients after more than 50 clinical trials.. This review evaluates the current evidence from all available meta-analyses of the use of intravenous amphotericin B, fluconazole and itraconazole for this indication.. Four systematic reviews with meta-analysis and one evidence-based review without meta-analysis were evaluated. Efficacy of fluconazole has been shown on short-term follow-up after allogeneic stem cell transplantation but only itraconazole was effective in neutropenic patients with haematological malignancies for prolonged prophylaxis after allogeneic stem cell transplantation. Direct comparison between fluconazole and itraconazole for this indication shows the superiority of itraconazole which was the only drug able to prevent invasive Aspergillus infections in our previously published meta-analysis of 13 trials and 3597 patients. Efficacy of itraconazole correlates closely with its dose; an effect was seen only in clinical trials using at least 400 mg/day oral solution or 200 mg/day intravenous solution. With this dose, invasive fungal infections were reduced by 53% and mortality from invasive fungal infections was reduced by 47% (P<0.05). Toxicity of itraconazole is rare and usually not severe and drug interactions are easily manageable.. Itraconazole is recommended for antifungal prophylaxis in high-risk neutropenic patients with haematological malignancies or for prolonged prophylaxis after allogeneic stem cell transplantation based on unambiguous evidence of efficacy and low toxicity from clinical trials and systematic reviews.

Topics: Amphotericin B; Antifungal Agents; Fluconazole; Hematologic Neoplasms; Humans; Itraconazole; Mycoses; Neutropenia; Stem Cell Transplantation

For many years, amphotericin B and flucytosine have been the only antifungal agents for invasive fungal infections. Amphotericin B was the standard of care for most of these infections. However, its use was often associated with low efficacy and poor tolerance. Fortunately, the antifungal armamentarium has increased during the past two decades with the addition of several new agents. In addition to itraconazole and fluconazole, lipid formulations of amphotericin B, voriconazole, caspofungin and micafungin have arrived on the market. Other agents are expected to be licensed shortly (anidulafungin, posaconazole). These various antifungal agents differ in their spectrum, pharmacokinetic profile, route of administration, efficacy in clinical trials, safety profile, drug-drug interactions and, importantly, their cost. There is no longer a unique standard agent for all or nearly all invasive fungal infections but a real choice among several agents. The characteristics of these new agents are reviewed to help clinicians in their decision to select an antifungal agent for their patients.

Topics: Amphotericin B; Antifungal Agents; Flucytosine; Humans; Mycoses; Randomized Controlled Trials as Topic; Triazoles

Drug interactions in the gastrointestinal tract, liver and kidneys result from alterations in pH, ionic complexation, and interference with membrane transport proteins and enzymatic processes involved in intestinal absorption, enteric and hepatic metabolism, renal filtration and excretion. Azole antifungals can be involved in drug interactions at all the sites, by one or more of the above mechanisms. Consequently, azoles interact with a vast array of compounds. Drug-drug interactions associated with amphotericin B formulations are predictable and result from the renal toxicity and electrolyte disturbances associated with these compounds. The echinocandins are unknown cytochrome P450 substrates and to date are relatively devoid of significant drug-drug interactions. This article reviews drug interactions involving antifungal agents that affect other agents and implications for patient care are highlighted.

Topics: Acidosis, Renal Tubular; Amphotericin B; Antifungal Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biotransformation; Caspofungin; Clinical Trials as Topic; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Drug Interactions; Drug Therapy, Combination; Echinocandins; Enzyme Inhibitors; Fluconazole; Humans; Itraconazole; Lipopeptides; Liver; Mycoses; Patient Care; Peptides, Cyclic

Fungal infections are often challenging to manage, given the limited numbers of therapeutics and a general lack of applicable clinical literature for their use in a given animal species. This article reviews some of the underlying principles that can affect the therapeutic outcome for a given antifungal, and provides specific information from the literature that is intended to highlight the distinctive properties of the most commonly used antifungals in veterinary medicine to better facilitate their successful application in clinical practice.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillus; Candida; Fluconazole; Griseofulvin; Itraconazole; Ketoconazole; Microbial Sensitivity Tests; Mycoses; Severity of Illness Index

Increasing number of transplants worldwide has resulted in an increase in the incidence of fungal infections. Prolonged neutropenia, immunosuppression and graft vs. host disease all result in high predisposition to fungal infections. The likelihood of developing a fungal infection increases with the severity and duration of neutropenia, which, in the case of cancer or chemotherapy for the treatment of hematological malignancies, can range from a few days to several weeks. Invasive fungal infections are difficult to diagnose and neutropenic patients with fever often receive empirical antifungal therapy. This provides a rationale for the prophylactic use of antifungal agents. The empirical use of liposomal amphotericin B has overcome some of the difficulties usually found in this setting. The majority of clinical efficacy data related to liposomal amphotericin B are derived from compassionate use studies and case series. The major advantage of these liposomal formulations of amphotericin B is a reduction in amphotercin toxicity. Use of liposomal amphotericin has been shown to be a cost-effective approach abroad and the same has been our experience also. Commercially ambisome and Fungisome are the only products that contain true liposomes. Unlike ambisome, which needs to be used in dose of 3 mg/kg/day Fungisome is effective in the dose of 1-3 mg/kg bodyweight. The Indian liposomal preparation has shown to be safe and effective used in over 150 transplant patients in our experience. We conclude that the liposomal amphotericin is better-tolerated and also gives,better responses in documented fungal infections.

Topics: Amphotericin B; Antifungal Agents; Bone Marrow Transplantation; Drug Therapy, Combination; Humans; Liposomes; Mycoses

Phaeohyphomycosis refers to infections caused by darkly pigmented fungi. These fungi rarely cause life-threatening disease. We reviewed 101 cases of culture-proven primary central nervous system phaeohyphomycosis reported in the English-language literature from 1966 to 2002. The most frequently isolated species was Cladophialophora bantiana. The next most frequent isolate was Ramichloridium mackenziei, seen exclusively in patients from the Middle East. More than one-half of the cases occurred in patients with no known underlying immunodeficiency. Mortality rates were high regardless of immune status. Therapy is not standardized, although the combination of amphotericin B, flucytosine, and itraconazole may improve survival rates. Newer azoles, such as voriconazole, also have a broad spectrum of activity against these fungi, although clinical experience is limited. Complete excision of brain lesions may provide better results than simple aspiration. An aggressive medical and surgical approach is warranted in treating these infections to optimize outcomes.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Central Nervous System Fungal Infections; Child; Child, Preschool; Female; Humans; Infant; Infant, Newborn; Itraconazole; Male; Middle Aged; Mycoses; Risk Factors; Treatment Outcome

Invasive fungal infection is an increasingly common cause of mortality and morbidity in preterm infants. In addition to amphotericin B, a variety of newer antifungal drugs and drug preparations are available for treatment. There is a need to assess their relative merits.. In preterm infants with suspected or confirmed invasive fungal infection, does treatment with newer systemic antifungal drugs or drug preparations, versus conventional amphotericin B alone, reduce mortality and adverse neurodevelopmental outcomes?. We used the standard search strategy of the Cochrane Neonatal Review Group. This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2003), MEDLINE (1966 - August 2003), EMBASE (1980 - August 2003), conference proceedings, and previous reviews.. Randomised and quasi-randomised control trials comparing one antifungal agent or combination of agents with another in preterm infants with suspected or confirmed invasive fungal infection.. We extracted the data using the standard methods of the Cochrane Neonatal Review Group, with separate evaluation of trial quality and data extraction by each author, and synthesis of data using relative risk and risk difference. The pre-specified outcomes were death prior to hospital discharge, longer term neurodevelopment, and adverse drug reactions resulting in discontinuation of therapy.. We identified only one small trial. This study compared the use of fluconazole with amphotericin B (5-Fluorocytosine added if fungal meningitis present). Three of 11 infants who were treated with fluconazole died and four of 10 infants who were treated with amphotericin B died : Relative risk: 0.68 (95% confidence interval 0.20, 2.33), Risk Difference -0.13 (95% confidence interval -0.53, 0.27) There were not any data on longer term outcomes.. From this one small study there are insufficient data to favour one antifungal agent or combination to reduce mortality and adverse neurodevelopmental outcomes in preterm infants with suspected or confirmed invasive fungal infection. A large randomised controlled trial is required to compare the newer antifungal preparations with conventional amphotericin B. Further research may also determine the relative convenience and cost effectiveness of the available drugs.

Topics: Amphotericin B; Antifungal Agents; Fluconazole; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Mycoses; Randomized Controlled Trials as Topic

A phaeohyphomycotic sinusitis due to Bipolaris hawaiiensis, observed in an immunologically competent patient, is reported and a review of data from the literature is given. The patient was successfully treated by surgical drainage and amphotericin B.

Topics: Adult; Amphotericin B; Antifungal Agents; Ascomycota; Drainage; Ethmoid Sinusitis; Female; Humans; Mycoses; Sinusitis; Sphenoid Sinusitis

Amphotericin B remains the drug of choice for the treatment of invasive fungal infections and visceral leishmaniasis. However, both the dose-dependent nephrotoxicity and the low response rates (10-80%) associated with amphotericin B limit its clinical use. The first marketed formulation of amphotericin B with deoxycholate, Fungizone, remains the "gold standard" in spite of its renal toxicity. Several investigations have been made to reduce the nephrotoxicity of amphotericin B by formulation strategies. Lipid-based formulations of amphotericin B were found to reduce toxicity and to increase tolerance and therapeutic efficacy. Three lipid formulations are now available in most countries: liposomal amphotericin B (AmBisome), amphotericin B lipid complex and amphotericin B colloidal dispersion. Amphotericin B colloidal dispersion was less nephrotoxic, but immediate reactions to this formulation were as frequent and severe as those to amphotericin B. Amphotericin B lipid complex appeared to be as effective as amphotericin B, with improved general and renal tolerability. Several comparative studies have confirmed that AmBisome has similar or superior efficacy relative to amphotericin B in various fungal infections, in visceral leishmaniasis and also in the empirical treatment of febrile neutropenia. Renal and general tolerability is excellent. A significant drawback to the newer, less toxic, commercial lipid-based formulations is their cost. There is a need to develop more affordable lipid-based formulations of amphotericin B.

Topics: Amphotericin B; Antifungal Agents; Clinical Trials as Topic; Drug Carriers; Humans; Mycoses; Tissue Distribution

We compared the safety and efficacy of liposomal amphotericin B with other formulations of amphotericin B and voriconazol as an empirical treatment of febrile neutropenia.. Several randomized controlled clinical trials, designed to evaluate the safety and/or efficacy of liposomal amphotericin B in the empirical treatment of febrile neutropenia, in comparison with other amphotericin B formulations or voriconazol, were identified by means of a search in MEDLINE, EMBASE and Cochrane Controlled Trials Register's data bases. American Society of Microbiology and American Society of Clinical Oncology abstracts, presented between 1999 and 2002, were also included in the search. Prior to data extraction, concepts like nephrotoxicity, infusion-related adverse events and efficacy (success rate and mortality) were defined.. Two studies comparing liposomal amphotericin B with conventional amphotericin B, one comparing liposomal amphotericin B with amphotericin B lipid complex and one comparing liposomal amphotericin B with voriconazol were included in the analysis. Patients treated with liposomal amphotericin B had lower nephrotoxicity than patients treated with other amphotericin B formulations or with conventional amphotericin B (RR = 0.49); conversely, no statistically significant differences with regard to voriconazol were observed. In terms of efficacy, mortality rate and therapeutic failure, patients treated with limposomal amphotericin B showed a slightly higher efficacy.. Liposomal amphotericin B is a lipidic formulation with a slightly higher efficacy than other amphotericin B formulations and voriconazol. In terms of nephrotoxicity, liposomal amphotericin B showed lower nephrotoxicity than other amphotericines while its safety rates were similar to those of voriconazol.

Topics: Amphotericin B; Antifungal Agents; Clinical Trials as Topic; Fever; Humans; Liposomes; Mycoses; Neutropenia; Pyrimidines; Triazoles; Voriconazole

Topics: Amphotericin B; Antifungal Agents; Fungemia; Humans; Immunocompromised Host; Mycoses; Neoplasms; Neutropenia; Premedication; Randomized Controlled Trials as Topic; Risk Factors; Triazoles

Concurrent or sequential antifungal treatment for invasive mycoses has been typically considered as an option to improve results of monotherapy. However, data on the efficacy of combination therapy are sparse and consist largely of results from studies in vitro and experimental animal models. These studies have yielded controversial results depending on the criteria used to evaluate the antifungal interaction. Several combinations that showed synergy in vitro failed to do so in animal models. Overall, apart from cryptococcal infections, combined antifungal therapy is not significantly better than monotherapy in terms of clinical efficacy. It is questionable whether combination therapy should be used in most cases as there is a lack of evidence from well-designed clinical trials. However, combination therapy could be an alternative to monotherapy for patients with invasive infections that are difficult to treat, such as those due to multi-resistant species and for those who fail to respond to standard treatment.

Topics: Amphotericin B; Animals; Antifungal Agents; Azoles; Caspofungin; Drug Therapy, Combination; Echinocandins; Flucytosine; Humans; Lipopeptides; Microbial Sensitivity Tests; Mycoses; Naphthalenes; Peptides, Cyclic; Terbinafine

Topics: Amphotericin B; Antifungal Agents; beta-Glucans; Biomarkers; Disease Progression; Fatal Outcome; Fluconazole; Glucans; Humans; Immunocompromised Host; Male; Middle Aged; Mycoses; Otorhinolaryngologic Diseases; Risk Factors

The azole antifungal voriconazole and the echinocandin caspofungin have recently become available for the treatment of invasive mycoses. Fluconazole remains the drug of choice for candidemia, except for infections with one of the resistent species such as Candida krusei and some strains of Candida glabrata. In these cases, as well as in patients who cannot tolerate azoles in connection with side effects or drug interactions, caspofungin is an attractive alternative. Voriconazole has become the drug of choice for severe invasive aspergillosis. Itraconazole is a good alternative for milder and chronic forms of aspergillosis. The use of conventional amphotericin B will be limited by the availability of the new drugs. In view of their high costs, the lipid-bound forms of amphotericin B will usually be given only as salvage therapy in case of failure, in patients who are unable to tolerate either conventional amphotericin or one of the newer agents, and for the treatment of zygomycosis.

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Drug Carriers; Echinocandins; Fluconazole; Humans; Itraconazole; Lipopeptides; Mycoses; Peptides; Peptides, Cyclic; Pyrimidines; Species Specificity; Treatment Outcome; Triazoles; Voriconazole

Invasive fungal infections carry significant morbidity and mortality. Candida species have become one of the most frequent causes of bloodstream infections, and infections caused by molds such as Aspergillus are becoming more frequent in immunocompromised patients. As this population grows, more invasive fungal infections can be anticipated. In the past, treatment options have been limited for many of these infections due to toxicity and efficacy concerns with the available antifungals. Fortunately, the past few years have brought exciting developments in antifungal pharmacotherapy. Lipid-based formulations of amphotericin B were introduced in the 1990s to attenuate adverse effects caused by amphotericin B deoxycholate (Fungizone, Bristol-Myers Squibb). Most recently, the echinocandins have been added to our antifungal regimen with the introduction of caspofungin (Cancidas, Merck and Co.) and voriconazole (Vfend, Pfizer), a new triazole, has come to market. The introduction of the echinocandins has invigorated the discussion about combination antifungal therapy. Evidence-based studies using these new agents are accumulating, and they are assuming important roles in the pharmacotherapy of invasive fungal infections in seriously ill and complex patients.

Topics: Amphotericin B; Antifungal Agents; Aspergillus; Candida; Clinical Trials as Topic; Drug Therapy, Combination; Humans; Mycoses

To elucidate the etiology, pathohistology, clinical characteristic and differential diagnosis, reduce missed diagnosis and improve the early detection and treatment of Penicillium Marneffei infection, by means of this case report and literature review.. A patient hospitalized Penicillium Marneffei infection were presented here, together with 27 cases in the literature, among which 10 patients had complications of AIDS and 5 with other diseases.. Penicillium Marneffei is a temperature-sensitive, two-phase fungus, which can infect healthy and immunocompromised subjects. The common symptoms are lymphadenopathy and infection of the lung. The infection may be local or diffuse, involving the intestinal tract, soft tissue, bone, liver, spleen and bone marrow etc. The lesion can be classified into the granuloma type, suppurative type and anergy/necrosis type histologically. The yeast-like fungus were mainly found in the cytoplasm of macrophages, which were demonstrated by PAS and Giemsa staining. The wine red color developed on the culture confirms the diagnosis.. The diagnosis of Penicillium Marneffei infection should be considered when tuberculosis is suspected but not confirmed, and if the patient has a history of having lived or traveled in Southeast Asia, is anemic or resistant to anti-tuberculosis treatment. The major differential diagnosis is histoplasmosis. Early administration of anti-fungus drugs is essential for recovery.

Topics: AIDS-Related Opportunistic Infections; Amphotericin B; Antifungal Agents; Drug Therapy, Combination; Humans; Itraconazole; Male; Middle Aged; Mycoses; Penicillium

Candidiasis and aspergillosis are the most common fungal infections in hematopoietic stem cell transplant recipients and other hematology/oncology patients. Strategies for reducing the morbidity and mortality associated with these infections include antifungal prophylaxis, empiric therapy in patients with persistent fever and neutropenia, and preemptive therapy. Antifungal therapies include amphotericin B deoxycholate, lipid formulations of amphotericin B, the triazoles (fluconazole, itraconazole, and voriconazole), and the echinocandins (caspofungin and the investigational agents micafungin and anidulafungin). Fluconazole is a reasonable choice for the treatment of invasive candidiasis if the patient has not previously received a triazole and the institution has a low incidence of triazole resistance. If resistance is a concern, an echinocandin, such as caspofungin, is an appropriate option. Voriconazole may be the initial choice in most patients with invasive aspergillosis. If patients are intolerant of or refractory to conventional therapy, effective alternatives include a lipid formulation of amphotericin B or an echinocandin.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis; Deoxycholic Acid; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Drug Resistance, Fungal; Echinocandins; Fungal Proteins; Hematopoietic Stem Cell Transplantation; Humans; Liposomes; Mycoses; Neoplasms; Neutropenia; Peptides, Cyclic; Randomized Controlled Trials as Topic; Survival Analysis; Triazoles

Considering the significant morbidity and mortality associated with invasive fungal infections in immunocompromised patients, it is particularly important to make the diagnosis as early as possible and to make best use of the available antifungal drugs for prophylaxis and treatment. The newer antifungal drugs include the lipid products of amphotericin B, such as amphotericin B lipid complex (ABLC) and liposomal amphotericin B; voriconazole (a triazole); and caspofungin (an echinocandin). ABLC and liposomal amphotericin B are as effective as amphotericin B deoxycholate but are less nephrotoxic; ABLC is probably the drug of choice for zygomycosis. Voriconazole is approved for use in the treatment of invasive aspergillosis and may have a role in preventing breakthrough fungal infections in patients with persistent fever and neutropenia. Caspofungin is effective against both invasive aspergillosis and invasive candidiasis.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis; Caspofungin; Deoxycholic Acid; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Drug Resistance, Fungal; Echinocandins; Humans; Lipopeptides; Liposomes; Mycoses; Peptides, Cyclic; Phosphatidylcholines; Phosphatidylglycerols; Pyrimidines; Randomized Controlled Trials as Topic; Time Factors; Treatment Outcome; Triazoles; Voriconazole; Zygomycosis

Combination therapy with amphotericin B and flucytosine is considered to be the treatment of choice for cryptococcal infections. However, for other infections and combinations of antifungal infections, the data are less clear-cut. The concurrent use of amphotericin B with an azole has elicited controversy, given the potential of antimicrobial antagonism. The results of one recent candidemia study suggest that the potential antagonism may not be an issue; the combination of amphotericin B and fluconazole provided more effective clearance of Candida from the bloodstream than did fluconazole used alone. Several in vitro and animal studies have shown antagonism between the azoles and amphotericin B for aspergillosis. However, introduction of the new class of agents that target beta-glucan synthase (echinocandins) has invigorated the prospects of combination therapy. The echinocandins and polyenes are not antagonistic, and there is evidence that the echinocandins may provide additive to synergistic activity in combination with triazoles. For patients whose aspergillosis is progressing despite monotherapy, the addition of a second agent, such as an echinocandin, may be reasonable.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Azoles; Candidiasis; Caspofungin; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Echinocandins; Fluconazole; Humans; In Vitro Techniques; Lipopeptides; Lipoproteins; Micafungin; Mycoses; Peptides, Cyclic; Pyrimidines; Randomized Controlled Trials as Topic; Time Factors; Treatment Outcome; Triazoles; Voriconazole

Invasive fungal infection is an increasing source of morbidity and mortality in patients with hematologic malignancies, particularly those with prolonged and severe neutropenia (absolute white blood cell count < 100/microL). Early diagnosis of invasive fungal infection is difficult, suggesting that antifungal prophylaxis could be the best approach for neutropenic patients undergoing intensive myelosuppressive chemotherapy. Consequently, antifungal prophylaxis has been extensively studied for more than 20 years. Nonabsorbable polyenes reduce superficial mycoses but are not effective in preventing or treating invasive fungal infections. Intravenous amphotericin B and the newer azoles were used in numerous clinical trials, but the value of antifungal prophylaxis in defined risk groups with cancer is still open to discussion. Recipients of allogeneic stem cell transplants and patients with a relapsed leukemia are high-risk patient populations. In addition, certain risk factors are well defined, for example, neutropenia more than 10 days, corticosteroid therapy, sustained immunosuppression, and graft-versus-host disease. In contrast to study efforts, evidence-based recommendations on the clinical use of antifungal prophylaxis according to risk groups are rare. The objective of this review of 50 studies accumulating more than 9000 patients is to assess evidence-based criteria with regard to the efficacy of antifungal prophylaxis in neutropenic cancer patients.

Topics: Adrenal Cortex Hormones; Amphotericin B; Antifungal Agents; Antineoplastic Agents; Clinical Trials as Topic; Disease Susceptibility; Drug Carriers; Evidence-Based Medicine; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Liposomes; Mycoses; Neutropenia; Recurrence; Risk Factors; Triazoles

The antifungal agents most frequently used in prophylaxis and treatment are amphotericin B (and its new lipid forms) and azoles such as fluconazole, itraconazole, and more recently voriconazole. This review assesses the role of itraconazole in paediatric haematology/oncology practice. Its broader spectrum of activity and availability in oral and intravenous forms allow a flexible approach in the management of fungal infections.

Topics: Absorption; Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis; Child, Preschool; Cost-Benefit Analysis; Humans; Itraconazole; Mycoses

Despite significant advances in the management of immunosuppressed patients, invasive fungal infections remain an important life-threatening complication. In the last decade several new antifungal agents, including compounds in pre-existing classes (new generation of triazoles, polyenes in lipid formulations) and novel classes of antifungals with a unique mechanism of action (echinocandins), have been introduced in clinical practice. Ongoing and future studies will determine their exact role in the management of different mycoses. The acceleration of antifungal drug discovery offers promise for the management of these difficult to treat opportunistic infections.

Topics: Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Aspergillosis; Candidiasis; Deoxycholic Acid; Drug Combinations; Echinocandins; Fungal Proteins; Humans; Immunocompromised Host; Mycoses; Peptides; Peptides, Cyclic; Phosphatidylcholines; Phosphatidylglycerols; Triazoles

Amphotericin B reformulated into the liposomal formulation known as AmBisome (amphotericin B, hydrogenated soy phosphatidylcholine, cholesterol and dimyristoyl phosphatidylglycerol) can be safely administered at dosages 15 times higher than the conventional drug with the same broad spectrum of activity. Increased doses demonstrate non-linear clearance with saturation of the reticuloendothelial system (RES) and redistribution of the drug into non-RES tissues. The efficacy of this liposomal amphotericin B formulation appears to be related both to improved tissue penetration in the lungs, brain, kidneys, liver and spleen along with sustained bioactivity of therapeutic drug levels in these target tissues.

Topics: Amphotericin B; Animals; Antifungal Agents; Brain Diseases; Dermatomycoses; Humans; Liver Diseases; Lung Diseases, Fungal; Mycoses; Splenic Diseases

Topics: Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Azoles; Caspofungin; Drug Design; Drug Resistance, Fungal; Echinocandins; Fluconazole; Fluorouracil; Fungi; Humans; Itraconazole; Lipopeptides; Lipoproteins; Micafungin; Mycoses; Opportunistic Infections; Peptides; Peptides, Cyclic; Polyenes; Pyrimidines

A systematic review was performed to compare the effectiveness and tolerability of lipid-based amphotericin B (AmB) formulations and conventional AmB in the treatment of systemic fungal infections.. The literature and unpublished studies were searched using MEDLINE, EMBASE, Biological Abstracts, AIDSLINE, CANCERLIT, CRD database, Cochrane Controlled Trials Register, and other databases. Search terms included: amphotericin, liposom*, lipid*, colloid*, antifungal agents, and mycoses. Studies were selected according to predetermined criteria. The outcome measures reviewed were efficacy, mortality, renal toxicity, and infusion-related reactions. Meta-analyses and number-needed-to-treat (NNT) analyses were performed.. Seven studies (8 publications) met the entry criteria. Meta-analysis showed that lipid-based formulations significantly reduced all-cause mortality risk by an estimated 28% compared with conventional AmB (odds ratio [OR], 0.72; 95% CI, 0.54 to 0.97). There was no significant difference in efficacy between the lipid-based formulations and conventional AmB (OR, 1.21; 95% CI, 0.98 to 1.49). AmB lipid complex (ABLC) and liposomal AmB (L-AmB) significantly reduced the risk of doubling serum creatinine by an estimated 58% (OR, 0.42; 95% CI, 0.33 to 0.54). There was no significant reduction in risk of infusion-related reactions with lipid-based formulations, although this was difficult to interpret given the lack of consistent control of confounding factors. Comparing the lipid-based formulations with conventional AmB, the overall NNT to prevent 1 death was 31. The NNT to prevent a doubling of serum creatinine for both ABLC and L-AmB compared with conventional AmB was 6.. This study demonstrates advantages with lipid-based formulations over conventional AmB in terms of reduced risk of mortality and renal toxicity. Future trials in patients with proven fungal infection should control for factors such as premedication, infusion rates, fluid preloading, sodium/potassium supplementation, and concomitant medication.

Topics: Amphotericin B; Antifungal Agents; Chemistry, Pharmaceutical; Humans; Mycoses; Randomized Controlled Trials as Topic; Treatment Outcome

Amphotericin B spectrum covers most of the fungal pathogens involved in human diseases. Its use is limited by infusion-related effects and nephrotoxicity. As a result of strong lipophilic properties, encapsulation in liposomes or binding to lipid complexes led to the development of lipid formulations in an attempt to increase both efficacy and safety. Three lipid formulations of amphotericin B are commercially available: a liposomal preparation, a lipid complex and a colloidal dispersion. They differ in their lipid composition, shape, pharmacokinetic behaviour and clinical effects. The nephrotoxicity of these formulations is significantly decreased compared to their parent compound. Infusion-related events are lowest with liposomal amphotericin B. Increased efficacy of the lipid formulations over conventional amphotericin B, however, still has to be demonstrated. These formulations are mainly indicated for the treatment of documented fungal infections in patients failing conventional amphotericin B or with renal impairment. Liposomal amphotericin B is also indicated for empirical therapy of suspected fungal infections in febrile neutropenic patients giving this compound an advantage over the two other formulations. Lipid formulations of amphotericin B are extremely expensive. Whether the increase in cost translates into a long-term benefit for the patient is still unknown.

Topics: Amphotericin B; Animals; Antifungal Agents; Colloids; Excipients; Humans; Lipids; Liposomes; Mycoses

Fungal pathogens are becoming increasingly important for human and small animal medicine. This article highlights many standards-of-care and new agents for treatment of these pathogens for small animals and people.

Topics: Amphotericin B; Animals; Anti-Bacterial Agents; Antifungal Agents; Caspofungin; Cat Diseases; Cats; Dog Diseases; Dogs; Echinocandins; Fluconazole; Itraconazole; Lipopeptides; Mycoses; Naphthalenes; Peptides; Peptides, Cyclic; Terbinafine

The authors summarize the most important data of antimycotics used in the praxis. The indications of these drugs as well as the absorption, the antimycotic mechanism, the side-effects and drug-interactions of antifungal agents are discussed. The pathomechanism of amphotericin B, flucytosine, fluconasole, ketoconasole, itraconasole and the possibilities of their clinical administrations, further their side-effects and interactions are demonstrated in details. The most beneficial characteristics and more important interactions of these drugs are shown in tables for easier application in the everyday therapy.

Topics: Amphotericin B; Antifungal Agents; Drug Interactions; Fluconazole; Flucytosine; Humans; Itraconazole; Ketoconazole; Liver; Mycoses

Amphotericin B lipid complex (ABLC; Abelcet, Enzon Pharmaceuticals) has become the dominant marketed lipid amphotericin B compound to emerge since the approval of these agents from the mid-1990s onwards. This agent is a 1:1 combination of amphotericin B and a lipid moiety consisting of dimyristoyl phosphatidylcholine and dimyrisoyl phosphatidylcholine, which exists in a ribbon-like molecular structure. ABLC undergoes rapid reticuloendothelial uptake from the circulation and achieves significantly higher tissue concentrations in the liver, spleen and lung compared to comparably dosed conventional amphotericin B. ABLC is approved by the FDA for all mycoses in amphotericin B-intolerant or -refractory infection. Randomised, controlled trials of amphotericin B have shown comparable efficacy in candidiasis and an improved outcome in invasive aspergillosis versus historical controls. ABLC has demonstrated a reduced incidence of nephrotoxicity and infusion reactions versus amphotericin B. Comparative studies against other lipid formulations are quite limited and have shown variable differences in infusion toxicity, nephrotoxicity, hepatotoxicity and clinical efficacy. Postapproval experience has shown substantial efficacy for less common mycotic pathogens including zygomycosis. The precise position of ABLC versus both other lipid formulations and expanding formulary of new antifungal agents is in flux. Future studies which examine its clinical efficacy, role in combination therapy, toxicity and cost-effectiveness in these complex patients are needed.

Topics: Amphotericin B; Animals; Antifungal Agents; Excipients; Fungi; Humans; Lipids; Mycoses; Product Surveillance, Postmarketing

Topics: Amphotericin B; Antifungal Agents; Chills; Fever; Fluconazole; Humans; Itraconazole; Meta-Analysis as Topic; Mycoses; Nausea; Vomiting; Water-Electrolyte Imbalance

In the last years, the incidence of the invasive infection by moulds has increased. Also, the characteristics of invasive mycosis are changing due to the description of new pathogenic species and also because strains and species resistant to antifungal drugs are appearing. The development of mould antifungal drug resistance is the inevitable and logical consequence of their clinical use, although the frequency and clinical relevance of this is unknown. In this text current mould antifungal drugs resistance mechanisms are reviewed. The study of molecular mechanisms of antifungal drug resistance is the most valuable strategy to resistance development control and also in helping to develop safer and more active molecules able to avoid them. In the meanwhile is important the correct use of the available tools: epidemiological surveillance of resistance emergence and to use all the efforts towards prompt diagnosis in order to accomplish an adequate and effective treatment.

Topics: Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Azoles; Caspofungin; Drug Resistance, Fungal; Drug Resistance, Multiple; Echinocandins; Fluconazole; Fungi; Incidence; Itraconazole; Lipopeptides; Mycoses; Naphthalenes; Peptides; Peptides, Cyclic; Polyenes; Spain; Terbinafine

Fungal infection remains a major hurdle in solid organ transplantation. A variety of new antifungal agents have become available and new diagnostic tools are in development. This conference was convened to review current approaches to the prevention and treatment of fungal infection in transplantation. Among the keys to successful management of fungal infection are identification of patients at risk for infection (stratification), eradication or control of established infection in advance of transplantation, the demonstration of cure by radiologic and histopathologic means, and the use of surgical debridement, reduction in immune suppression, and fungicidal therapies whenever possible. The absence of sensitive diagnostic tools and standardization of antifungal susceptibility testing for the filamentous fungi are identified as major impediments to care in this area.

Topics: Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Azoles; Causality; Echinocandins; Fungal Proteins; Fungi; Humans; Mycoses; Organ Transplantation; Peptides; Peptides, Cyclic; Postoperative Complications; Risk Factors; Time Factors; Transplantation; Virus Diseases

Infection is the common cause of death following transplantation. Fungal infections are associated with high morbidity and mortality, and make up a significant proportion of infectious complications. Unfortunately, the diagnosis is usually made late--symptoms may be mild and non-specific, even with dissemination. Mortality associated with disseminated fungal infections is high, while those associated with limited fungal infections is low. Although the risk factors for invasive fungal infections in liver transplant patients are well identified, early diagnosis is challenging, and commonly used diagnostic methods lack sensitivity and specificity. Although the incidence of fungal infections following liver transplantation appears to be falling, mortality and morbidity associated with fungal infections suggests that future developments should focus on enhancing earlier diagnosis, implementing more effective and less toxic anti-fungal therapies.

Topics: Academic Medical Centers; Amphotericin B; Antibiotic Prophylaxis; Azoles; Female; Fungi; Humans; Incidence; Liver Transplantation; Male; Mycoses; Risk Factors; Survival Rate

Despite significant advances in the diagnosis, prevention, and treatment of fungal infection in transplant recipients, this infection complication remains a major cause of morbidity and mortality. Our understanding of the pathogenesis of the different fungal microorganisms has enabled us to identify patients at risk for such infections. While Candida infection remains a major complication in patients with intra-abdominal solid organ transplantations in which the bowel is surgically manipulated, Aspergillus infection remains the main fungal complication in lung transplantation recipients. The incidence of all types of fungal infection remains around 5-10%, while mortality following Aspergillus infection remains around 70%. Suppression of Candida growth at the time of surgical manipulation of the bowel should be the mainstay of prevention of this infection in intra-abdominal organ transplantation. Fluconazole is effective and relatively safe at 100-400 mg daily for the first 1-3 months post-liver transplantation. Prevention strategies toward Aspergillus infections remain elusive, but a number of manipulations, such as inhaled liposomal preparations post-organ transplantation or the preemptive use or universal prophylaxis of itraconazole are being validated. The next step is to determine the clinical value of molecular diagnostic techniques for the identification and preemptive therapy of patients at risk for the variety fungal infections.

Topics: Amphotericin B; Antifungal Agents; Basement Membrane; Candida; Candidiasis; Cytomegalovirus Infections; Fluconazole; Humans; Mycoses; Organ Transplantation; Risk Factors

Topics: Adjuvants, Immunologic; Amphotericin B; Antifungal Agents; Dose-Response Relationship, Drug; Drug Therapy, Combination; Drugs, Investigational; Humans; Mycoses

Nystatin is sometimes used prophylactically in patients with severe immunodeficiency or in the treatment of fungal infection in such patients, although the effect seems to be equivocal.. To study whether nystatin decreases morbidity and mortality when given prophylactically or therapeutically to patients with severe immunodeficiency.. MEDLINE and The Cochrane Library using a comprehensive search strategy, date of last search November 2001. Contacted industry and scanned reference lists.. Randomised trials comparing nystatin with placebo, an untreated control group, fluconazole or amphotericin B.. Data on mortality, invasive fungal infection and colonisation were extracted by both authors independently. A random effects model was used unless p>0.10 for the test of heterogeneity.. We included 12 trials (1,464 patients). The drugs were given prophylactically in ten trials and as treatment in two. Seven trials were in acute leukaemia, two in cancer, one in liver transplant patients, one in critically ill surgical and trauma patients, and one in AIDS patients. Nystatin had been compared with placebo in three trials and with fluconazole in nine; the dose varied from 1.5 MIE to 72 MIE daily. The effect of nystatin was similar to that of placebo on fungal colonisation (relative risk 0.85, 95% confidence interval 0.65 to 1.13). There was no statistically significant difference between fluconazole and nystatin on mortality (relative risk 0.76, 0.49 to 1.18) whereas fluconazole was more effective in preventing invasive fungal infection (relative risk 0.37, 0.15 to 0.91) and colonisation (relative risk 0.49, 0.34 to 0.70). The results were very similar if the three studies which were not performed in cancer patients were excluded.. Nystatin cannot be recommended for prophylaxis or treatment of Candida infections in immunodepressed patients.

Topics: Amphotericin B; Antibiotic Prophylaxis; Antifungal Agents; Fluconazole; Humans; Immunocompromised Host; Mycoses; Nystatin; Opportunistic Infections; Randomized Controlled Trials as Topic

Topics: Amphotericin B; Antifungal Agents; Arteries; Brain; Endocarditis; Hip Joint; Humans; Mycoses; Risk Factors

Topics: Amphotericin B; Antifungal Agents; Drug Therapy, Combination; Flucytosine; Humans; Mitosporic Fungi; Mycoses; Opportunistic Infections

More than 40 years after its approval, Amphotericin B is still the gold standard in the treatment of invasive fungal infections due to Candida and Aspergillus spp. Three different lipid formulations of Amphotericin B have been available for over 10 years, with only one of them, i.e. liposomal Amphotericin B (Ambisome), approved in Germany. Liposomal Amphotericin B is superior to conventional Amphotericin B due to its reduced nephrotoxicity, the option of a higher initial loading-dose, and fewer infusion-related side-effects, all this with identical or even higher efficacy.

Topics: Amphotericin B; Antifungal Agents; Aspergillus; Candida; Drug Combinations; Humans; Liposomes; Mycoses; Phosphatidylcholines; Phosphatidylglycerols

Despite a number of recent advances in diagnosis and treatment strategies, fungal infections remain an important cause of morbidity and mortality in neutropenic and immunosuppressed patients. The main fungal infections are candidosis and aspergillosis, although an increased incidence of rarer fungal infections including Fusarium spp., Aurebasidium pullulans and Mucor spp. has been noted. Mortality may be decreased with earlier diagnosis and aggressive treatment with lipid-associated amphotericin B. Invasive pulmonary aspergillosis (IPA) in the neutropenic host presents particular challenges in terms of diagnosis and therapy. We undertook a prospective study over a 36 month period to link the status of early diagnosis and early aggressive therapy with lipid-associated amphotericin B. Early investigation comprised the use of bronchoscopy and bronchoalveolar lavage together with real-time PCR to detect Aspergillus spp. This combined approach revealed the incidence of proven or probable IPA to be 19%. Early therapy resulted in no mortality from IPA. In treating the rarer fungal species, AmBisome was found to be the most effective agent, and could be used at doses of up to 12 mg/kg with few side effects.

Topics: Amphotericin B; Animals; Antifungal Agents; Controlled Clinical Trials as Topic; Humans; Liposomes; Multicenter Studies as Topic; Mycoses; Prospective Studies; United Kingdom

Our substantial experience in several trials with AmBisome in adult and paediatric patients undergoing transplantation has shown this formulation of amphotericin B to be safe and effective in therapeutic and prophylactic use. AmBisome has shown a significant reduction in fungal colonization and invasive Candida infections compared with placebo in a prospective, double-blind study in bone marrow transplantation, and eradication of invasive fungal infections in 86% of 14 children undergoing bone marrow transplantation. The main side effects of AmBisome use are elevations in serum potassium and creatinine, but these lead to very few withdrawals from treatment. Compared with conventional amphotericin B, AmBisome is very expensive, but its much improved safety profile and proven efficacy make it an excellent agent for management of invasive fungal disease in transplant recipients.

Topics: Amphotericin B; Antibiotic Prophylaxis; Antifungal Agents; Hospitals, University; Humans; Liposomes; Mycoses; Sweden; Transplantation

Systemic fungal infection is considered to be an important cause of morbidity and mortality in cancer patients, particularly those with neutropenia. Antifungal drugs are often given prophylactically, or to patients with persistent fever.. To compare the effect of fluconazole and amphotericin B on morbidity and mortality in patients with cancer complicated by neutropenia.. MEDLINE and Cochrane Library (November 2001). Letters, abstracts, and unpublished trials. The industry and authors were contacted.. Randomised trials comparing fluconazole with amphotericin B.. Data on mortality, invasive fungal infection, colonisation, use of additional (escape) antifungal therapy and adverse effects leading to discontinuation of therapy were extracted by both authors independently.. Sixteen trials (3760 patients, 341 deaths) were included. In 3 large 3-armed trials, results for amphotericin B were combined with results for nystatin in a "polyene" group. Because nystatin is an ineffective drug in these circumstances, this approach creates a bias in favour of fluconazole. Furthermore, most patients were randomised to oral amphotericin B, which is poorly absorbed and poorly documented. It was unclear whether there was overlap among the "polyene" trials. We were unable to obtain any information to clarify these issues from the trial authors or from Pfizer, the manufacturer of fluconazole. There were no significant differences in effect between fluconazole and amphotericin B, but the confidence intervals were wide. More patients dropped out of the study when they received amphotericin B, but as none of the trials were blinded, decisions on premature interruption of therapy could have been biased. Furthermore, amphotericin B was rarely given under optimal circumstances, with premedication to reduce infusion-related toxicity, slow infusion, and with potassium and magnesium supplements to prevent nephrotoxicity.. Amphotericin B had been disfavoured in several of the trials through their design or analysis. Since intravenous amphotericin B is the only antifungal agent for which there is good evidence suggesting an effect on mortality and is considerably cheaper than fluconazole, it should be preferred.

Topics: Amphotericin B; Antifungal Agents; Confidence Intervals; Fluconazole; Humans; Mycoses; Neoplasms; Neutropenia; Odds Ratio; Randomized Controlled Trials as Topic

Nystatin is sometimes used prophylactically in patients with severe immunodeficiency or in the treatment of fungal infection in such patients, although the effect seems to be equivocal.. To study whether nystatin decreases morbidity and mortality when given prophylactically or therapeutically to patients with severe immunodeficiency.. MEDLINE and The Cochrane Library using a comprehensive search strategy, date of last search November 2001. Contacted industry and scanned reference lists.. Randomised trials comparing nystatin with placebo, an untreated control group, fluconazole or amphotericin B.. Data on mortality, invasive fungal infection and colonisation were extracted by both authors independently. The outcomes were weighted by the inverse variance. A random effects model was used unless p>0.10 for the test of heterogeneity.. We included 12 trials (1,464 patients). The drugs were given prophylactically in ten trials and as treatment in two. Seven trials were in acute leukaemia, two in cancer, one in liver transplant patients, one in critically ill surgical and trauma patients, and one in AIDS patients. Nystatin had been compared with placebo in three trials and with fluconazole in nine; the dose varied from 1.5 MIE to 72 MIE daily. The effect of nystatin was similar to that of placebo on fungal colonisation (relative risk 0.85, 95% confidence interval 0.65 to 1.13). There was no statistically significant difference between fluconazole and nystatin on mortality (relative risk 0.76, 0.49 to 1.18) whereas fluconazole was more effective in preventing invasive fungal infection (relative risk 0.37, 0.15 to 0.91) and colonisation (relative risk 0.49, 0.34 to 0.70). The results were very similar if the three studies which were not performed in cancer patients were excluded.. Nystatin cannot be recommended for prophylaxis or treatment of Candida infections in immunodepressed patients.

Topics: Amphotericin B; Antibiotic Prophylaxis; Antifungal Agents; Fluconazole; Humans; Immunocompromised Host; Mycoses; Nystatin; Opportunistic Infections

The last decade has been remarkable for the dramatic increase in the prevalence of serious fungal infections in patients with haematological disorders and neutropenic cancer patients. The mortality rate of deep-seated infection has been in excess of 90% and there is no doubt that this is one of the greatest challenges currently facing haematologists and oncologists. The development of the lipid-based drugs - liposomal amphotericin (AmBisome(R)), amphotericin B lipid complex, ABLC (Abelcet(R)), amphotericin B colloidal dispersion, Amphocil (ABCD(R)), has meant that doses of amphotericin B can be safely escalated for the first time whilst the problems of nephrotoxicity, infusion related reactions (including chills, rigors, fevers and hypoxia) can be reduced. These toxicities are variably reduced with AmBisome more than Abelcet and more than Amphocil and there is little information from randomised trials other than for AmBisome. AmBisome used in the setting of persistent fever and neutropenia not responding after 3-4 days of intravenous antibiotics, is associated with less breakthrough systemic fungal infections. There is also much less need for premedication, including steroids, compared with amphotericin B and Abelcet. The use of intermittent doses of Ambisome given prophylactically is now being explored. A new and exciting era of antifungal therapy is opening up with new compounds, such as itraconazole voriconazole, posaconazole and echinocandins, being investigated and for the first time, we also have options for combination therapy and prophylaxis.

Topics: Amphotericin B; Antifungal Agents; Clinical Trials as Topic; Costs and Cost Analysis; Hematologic Diseases; Humans; Mycoses; Neoplasms; Neutropenia; Randomized Controlled Trials as Topic

We describe a case of soft tissue infection caused by Fusarium species in a heart-liver transplant recipient, and review the cases of fusarial infection reported among solid-organ transplant (SOT) recipients. Unlike fusarial infection in patients with hematologic malignancies or bone marrow transplants, fusarial infection in SOT recipients tends to be localized, occurs later in the posttransplantation period, and has a better outcome. Surgical resection, when possible, and prolonged treatment with amphotericin provide the most effective form of therapy.

Topics: Amphotericin B; Antifungal Agents; Fusarium; Heart Transplantation; Humans; Liver Transplantation; Male; Middle Aged; Mycoses; Treatment Outcome

Invasive fungal infections remain a common cause of morbidity and mortality among patients with leukemia who become further compromised by neutropenia. Candida and Aspergillus spp account for the vast majority of these infections, but other, less commonly recognized fungi can cause life-threatening infection in these hosts as well. The earlier, more limited antifungal armamentarium of ketoconazole, flucytosine, and amphotericin B has been substantially augmented by the availability of fluconazole, itraconazole, and the lipid-associated amphotericin formulations. Intense clinical study has focused on the use of these agents in empiric treatment, treatment of suspected or proven infection, and prophylaxis. Recognition of the limitations of antifungal therapy in the neutropenic host has led to evaluation of the adjunctive role of immunotherapy.

Topics: Amphotericin B; Aspergillosis; Azoles; Candidiasis; Fluconazole; Humans; Immunotherapy; Leukemia; Mycoses; Neutropenia

Amphotericin B colloidal dispersion (ABCD) is a near 1:1 discoidal complex of amphotericin B (AMB) and sodium cholesteryl sulfate (SCS) arranged as a bilayer of SCS interspersed with AMB via noncovalent interactions. The complex is stable in blood and plasma with minimal dissociation. In vitro and in vivo studies show that ABCD is as effective and four to five times safer than conventional AMB (CAB) for fungal infection. Compared with CAB treatment, ABCD demonstrates reduced peak plasma levels, prolonged residence time, and lowered AMB levels in most tissues including kidney, the major target of toxicity for CAB. In 572 patients with systemic fungal infections secondary to severe underlying disease, ABCD doses < or = 6 mg/kg/day were well tolerated, even in those who failed to tolerate or respond to CAB. Mild-to-moderate, dose-dependent, infusion-related adverse events typically seen with CAB were also observed with ABCD, with no sign of renal or hepatic toxicity. Complete or partial recovery was seen in 57.3%. Therefore, ABCD should be considered as an alternative treatment of systemic fungal infections.

Topics: Amphotericin B; Antifungal Agents; Chemistry, Pharmaceutical; Cholesterol Esters; Colloids; Humans; Mycoses; Serine Proteinase Inhibitors; Tissue Distribution

During the last decade the incidence of deep mycotic infections has continued to increase dramatically. This new epidemiological feature is mostly due to the expanding population of at risk subjects submitted to intensive and protracted immunosupression. Amphotericin B has a broad spectrum and has remained the drug of choice for these life threatening invasive fungal infections. However adverse events, particularly renal insufficiency, are limiting factors in achieving an effective dose. Since the 1990s the number of oral and parenteral antifungal agents has significantly increased. The use of phospholipid carriers for amphotericin B or cyclodextrine for triazoles improved safety profil and/or pharmacokinetics. New families of drugs with a new target in the fungal cell are under clinical investigation and should be soon available. Comparative studies, consensus on diagnosis criteria and practice guidelines for the treatment of fungal infections will contribute to a better management of the patients and optimize the use of antifungal agents.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis; Fluconazole; Flucytosine; Humans; Itraconazole; Lung Diseases, Fungal; Mycoses; Time Factors

Systemic fungal infections are an increasing problem in older adults. For several of the endemic mycoses, this increase is the result of increased travel and leisure activities in areas endemic for these fungi. Immunosuppressive agents, care in an intensive care unit, and invasive devices all contribute to infection with opportunistic fungi. Treatment of systemic fungal infections is usually with an azole or amphotericin B. The preferred regimen depends on the specific fungal infection, the site and the severity of the infection, the state of immunosuppression of the patient and the possible toxicities of each drug for a specific patient. In older adults, drug-drug interactions between the azoles and drugs commonly prescribed for older persons may lead to serious toxicity, and absorption of itraconazole can be problematic. Amphotericin B is associated with significant nephrotoxicity, especially in older adults with pre-existing renal disease, and infusion-related adverse effects. Newer lipid formulations of amphotericin B can obviate some of these toxicities, but their role in the treatment of systemic fungal infections in older adults has not yet been clarified.

Topics: Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Azoles; Dermatomycoses; Drug Interactions; Humans; Immunocompromised Host; Mycoses; Opportunistic Infections

Invasive fungal infections are rare but life-threatening infections, most often occurring in immunocompromised patients. For a long time, Amphotericin B has been the best choice for treatment, because it is fungicidal with a broad antifungal spectrum and minimal risk of resistance development. The therapeutic use of amphotericin B has, however, been limited by its toxicity-both acute as well as chronic. To counter this, amphotericin B has been encapsulated in liposomes, which reduces its toxicity and allows higher doses to be given. Ambisome is a true, spherical, small unilamellar liposome with a median size of 80 nm. The pharmacokinetic profile was changed, and the maximum concentration and AUC of amphotericin B after AmBisome treatment were greater than those found with the conventional drug. The highest tissue concentrations of AmBisome were found in the liver and spleen, and less than 1% of the administered dose was recovered in other organs. At Huddinge University Hospital, we were the first to use and report on the experience of AmBisome. We now have more than 12 years' experience in transplant recipients, with a good safety profile, improved rate of curing mycological proven infections and reduced mortality in fungal infections. In two placebo-controlled prophylactic trials, we found that AmBisome was effective for preventing fungal colonization and invasive fungal infections, respectively, in allogeneic stem cell and liver transplantation. In uncontrolled and, more recently, in randomized controlled studies at other centers, AmBisome has revealed less toxicity and an efficacy equal or superior to that of the conventional drug in treating neutropenia-associated fever and proven invasive fungal infections in both adults as well as in children. Although investigators tend to increase the dose used, the optimal dose for probable or proven infection is still under debate. Based on our own experience in using AmBisome and the experience at other centers, we can conclude that AmBisome represents a major breakthrough in the treatment of invasive fungal infections, especially in immunocompromised patients.

Topics: Amphotericin B; Antifungal Agents; Area Under Curve; Child; Female; Humans; Immunocompromised Host; Infant, Newborn; Leishmaniasis, Visceral; Liposomes; Male; Mycoses; Opportunistic Infections; Tissue Distribution; Transplantation

Acute respiratory events occasionally have been observed during the infusion of amphotericin B. Herein we analyze the 21 cases that have been reported, including a fatal reaction observed by us. Some useful guidelines are provided that likely will allow treatment to be continued safely for patients who have experienced such reactions.

Topics: Aged; Amphotericin B; Antifungal Agents; Drug Combinations; Female; Humans; Lung Diseases; Male; Mycoses; Phosphatidylcholines; Phosphatidylglycerols

Opportunistic mycoses have emerged as important causes for morbidity and mortality in pediatric cancer patients, particularly in those with intensively treated hematological malignancies, allogeneic hematopoetic stem cell transplantation, and aplastic anemia. The incidence of invasive fungal infections in these settings may range from 10 to 25 % despite empirical antifungal therapy with an overall case fatality rate of up to 50 and 75 % depending on the organism. Preventive interventions are thus warranted, including but not limited to chemoprophylaxis with antifungal agents. Effective chemoprophylaxis of invasive Candida infections with a long-term benefit for overall survival has been demonstrated in patients with allogeneic bone marrow transplantation. However, its benefit in other high-risk populations is less well established, and a clearly effective approach to chemoprophylaxis for invasive Aspergillus infections has not been documented in appropriately designed clinical trials. This article reviews epidemiology and current approaches to chemoprophylaxis of opportunistic invasive fungal infections in children and adolescents with cancer and/or stem cell transplantation, and provides evidence-based guidelines for indications and modalities of antifungal prophylaxis and antifungal infection control measures in this population.

Topics: Administration, Oral; Adolescent; Adult; Age Factors; Amphotericin B; Anemia, Aplastic; Antifungal Agents; Aspergillosis; Bone Marrow Transplantation; Candidiasis; Child; Child, Preschool; Cohort Studies; Double-Blind Method; Fluconazole; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Infant; Infant, Newborn; Itraconazole; Mycoses; Neoplasms; Neutropenia; Randomized Controlled Trials as Topic; Respiratory Therapy; Risk Factors; Time Factors

With the continuing increase in clinically important fungal disease, especially seen in the neutropenic patient, the need for new and improved systemic antifungal agents marches on. A pharmacy and therapeutics committee may select an antifungal agent based on these criteria: spectrum of action, pharmacokinetic profile, toxicity, potential for resistance, and cost. A number of agents are now available for treating deep fungal infections, including amphotericin B in conventional and liposomalformulations, and the triazoles itraconazole (Sporanox) and fluconazole (Diflucan). It is important to note that there is lack of agreement in practice over what constitutes ideal therapy. The lipidformulations of amphotericin B and the improved oral solution and new intravenous formulation of itraconazole are recent additions to therapeutic options that are already having a significant influence on drug selection and treatment practices.

Topics: Amphotericin B; Antifungal Agents; Drug Compounding; Fluconazole; Humans; Injections, Intravenous; Itraconazole; Mycoses

Blastoschizomyces capitatus infection in a 48-year-old man with acute myelocytic leukaemia is reported. A multiorgan involvement and fulminant course of the fungal infection resulted in the patient's death despite fluconazole prophylaxis, therapy with amphotericin B and administration of granulocyte colony-stimulating factor. Predisposing factors to the infection, clinical relevance of surveillance strains and in vitro antifungal susceptibility testing are discussed.

Topics: Amphotericin B; Antifungal Agents; Fatal Outcome; Fluconazole; Humans; Leukemia, Myeloid, Acute; Male; Microbial Sensitivity Tests; Middle Aged; Mitosporic Fungi; Multiple Organ Failure; Mycoses

We have yet to realize the clinical benefits of combination antifungal therapy, but the literature is beginning to show the potential positive and negative aspects of this approach. Detailed laboratory-based study of each new antifungal compound will be required in order to define the interactions between the different drugs. Most important in this discussion is that a determination of the most appropriate experimental design and parameters to reflect the outcomes in the treatment of human mycoses is required. That will be the challenge for the next several years. In the meantime, combination antifungal therapy should be approached carefully and be initiated on a case-by-case basis following consideration of all the options available for the patient.

Topics: Amphotericin B; Animals; Antifungal Agents; Drug Combinations; Fungi; Humans; Mycoses

Amphotericin B is commonly used in the intensive care unit to treat invasive fungal infection. This medication is associated with a number of adverse events during infusion, such as fever, rigors, chills, electrolyte disorders and renal insufficiency. Liposomal amphotericin B can be used as an alternative to conventional amphotericin B to treat fungal infection. Patients receiving liposomal amphotericin B experience fewer adverse events than recipients of the conventional formulation; moreover, the liposomal formulation has been found to be as effective as the conventional amphotericin B to treat specific fungal infections. Unfortunately, the pharmacoeconomics of the liposomal formulation has limited the use of this medication. The purpose of this article is to present a brief summary of conventional amphotericin B with an emphasis on the narrow therapeutic index of this antibiotic. The liposomal amphotericin B solution is compared to conventional amphotericin B regarding the pharmacokinetics and pharmacodynamics. Therapeutic use, tolerability, and pharmacoeconomic implications of liposomal amphotericin B are discussed.

Topics: Amphotericin B; Antifungal Agents; Humans; Liposomes; Mycoses

The use of liposomes as drug carriers in treatment of various diseases has been explored extensively for more than 20 years. 'Conventional' liposomes, when administered in vivo by a variety of routes, rapidly accumulate in the mononuclear phagocyte system (MPS). The inherent tendency of the liposomes to concentrate in MPS can be exploited in enhancing the non-specific host defence against infections by entrapping in them the macrophage modulators, and as carriers of antibiotics in treatment of intracellular infections that reside in MPS. This must further be enhanced by grafting on the liposome surface the ligands, e.g. tuftsin, that not only binds specifically to the MPS cells but also enhances their natural killer activity. Keeping this in view, we designed and developed tuftsin-bearing liposomes as drug carriers for the treatment of macrophage-based infections and outline these studies in this overview.

Topics: Amphotericin B; Animals; Drug Carriers; Drug Delivery Systems; Humans; Leishmaniasis; Liposomes; Macrophages; Malaria; Mycoses; Tuberculosis; Tuftsin

Trichosporon beigelii is a fungus once thought to cause only superficial infections, but recently has been increasingly identified as an opportunistic systemic pathogen in immunocompromised patients. There have been very limited reports of this organism in the burn patient population. We describe the first report of pharmacological management of invasive T. beigelii with a combination of amphotericin B and high dose fluconazole in a burn patient. Antifungal susceptibility testing of T. beigelii determined a change in minimum inhibitory concentrations (MICs) of amphotericin B and a consistent resistance pattern with the use of flucytosine. This paper will review our experience with T. beigelii fungus in a regional burn treatment center and review the literature on other experiences in the burn population.

Topics: Adult; Amphotericin B; Antifungal Agents; Burns; Catheters, Indwelling; Drug Resistance, Microbial; Fatal Outcome; Female; Fluconazole; Flucytosine; Fungemia; Humans; Immunocompromised Host; Male; Mycoses; Opportunistic Infections; Sputum; Trichosporon; Wound Infection

Systemic fungal infection is considered to be an important cause of morbidity and mortality in cancer patients, particularly those with neutropenia. Antifungal drugs are often given prophylactically, or to patients with persistent fever.. To compare the effect of fluconazole and amphotericin B on morbidity and mortality in patients with cancer complicated by neutropenia.. MEDLINE and Cochrane Library (March 2000). Letters, abstracts, and unpublished trials. The industry and authors were contacted.. Randomised trials comparing fluconazole with amphotericin B.. Data on mortality, invasive fungal infection, colonisation, use of additional (escape) antifungal therapy and adverse effects leading to discontinuation of therapy were extracted by both authors independently.. Thirteen trials (2977 patients) were included. In 3 large 3-armed trials, which comprised 43% of the patients, results for amphotericin B were combined with results for nystatin in a "polyene" group. Because nystatin is an ineffective drug in theses circumstances, this approach creates a bias in favour of fluconazole. Furthermore, 79% of the patients were randomised to oral amphotericin B, which is poorly absorbed and poorly documented. It was unclear whether there was overlap among the "polyene" trials. We were unable to obtain any information to clarify these issues from the trial authors or the manufacturer of fluconazole. There was no significant difference in effect between fluconazole and amphotericin B. Apart from the "polyene" trials, more patients dropped out of the study when they received amphotericin B.. Amphotericin B had been disfavoured in most of the trials through their design or analysis. Since intravenous amphotericin B is the only antifungal agent with a documented effect on mortality and is considerably cheaper than fluconazole, it should be preferred.

Topics: Amphotericin B; Antifungal Agents; Confidence Intervals; Fluconazole; Humans; Mycoses; Neoplasms; Neutropenia; Odds Ratio; Randomized Controlled Trials as Topic

Patients with haematological malignancies form one of the most susceptible host groups for microbial infection, especially during neutropenia. The incidence of invasive fungal infections has increased in recent years, highlighting the need for better diagnosis and more effective antifungal therapies. Amphotericin B is the drug of choice for many fungal infections, although toxicity and the need for intravenous infusion restrict its use. When possible, oral administration of antifungal agents is preferable but intravenous administration is often needed and current oral agents have their limitations: fluconazole because of a narrow spectrum of activity; itraconazole capsules because of erratic absorption. In this review, prophylactic and treatment options for systemic fungal infections are discussed. The specific needs of patients with different types of leukaemia and the benefits of new amphotericin B and itraconazole formulations are examined.

Topics: Amphotericin B; Antibiotic Prophylaxis; Antifungal Agents; Hematologic Neoplasms; Humans; Itraconazole; Leukemia; Mycoses

The incidence of systemic fungal infections, especially in immunocompromised patients, has continued to increase during the past few decades. Treatment with conventional amphotericin B has been the standard care for the majority of patients with invasive fungal infections, despite its associated toxicity. Three lipid formulations of amphotericin B have now been approved for use in the United States. The pharmacology, pharmacokinetics, clinical experience, toxicity, dosing strategies, and cost of these three preparations--amphotericin B lipid complex, amphotericin B colloidal dispersion, and liposomal amphotericin B--were reviewed in detail in this chapter. The clinical data indicate that lipid formulations of amphotericin B represent an important therapeutic modality in the management of invasive fungal infections.

Topics: Amphotericin B; Antifungal Agents; Costs and Cost Analysis; Economics, Pharmaceutical; Fever of Unknown Origin; Humans; Immunocompromised Host; Liposomes; Mycoses

There have been a number of changes in strategies in antifungal therapy in the past few years. AIDS related mycoses have decreased, and the increase of fluconazole resistant Candida albicans may be slowing because fewer severely immune depressed patients require constant fluconazole suppression. Candida species continue to be relatively common blood culture isolates. About half of these are C. albicans and half non-albicans species. In recent years, we have moved from the use of amphotericin B to fluconazole for initial treatment of candidemia. We have seen fluconazole resistant isolates emerge, primarily C. glabrata and a few C. krusei, but also C. albicans. It is unclear whether the increasing use of fluconazole in intensive care units will worsen this problem. There appears to be no advantage for the lipid formulations of amphotericin B, though they are useful to reduce or prevent renal toxicity. In the United States and Europe, prevention and treatment of aspergillosis have become increasingly important. There are increasing data suggesting that lipid formulations are more effective for both treatment and prevention of invasive disease in the most vulnerable patients with this infection. Renal toxicity is reduced but not avoided by use of the lipid formulations of amphotericin B. For those patients with less acutely progressing disease, the triazoles may be effective options. It is unclear at present whether itraconazole, voriconazole, or posaconazole will be the most favored drug. One promising new class, now in clinical trials, is the echinocandin group. Other agents, such as the sordarins, the chitin synthase inhibitors, and topoisomerase inhibitors, have promise but are much earlier in development. Unfortunately, we still have >50% treatment failure with acute invasive aspergillosis, and 20%-30% failures with candidemia. Now that we have multiple classes of antifungal drugs available, and others in preclinical trials, it would be advantageous to begin more active exploration of combination therapy with antifungals and with combined immune modulators and antifungals.

Topics: Amphotericin B; Antifungal Agents; Drug Resistance, Microbial; Fluconazole; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Mycoses

The management of invasive fungal infection utilizes a variable multidisciplinary approach involving antifungals, appropriate surgery and immuno-correction. Conventional amphotericin B has been the mainstay of treatment but newer pathogens and poor outcomes has led to new formulations of this drug as well as to new and novel antifungals.

Topics: Amphotericin B; Antifungal Agents; Cytokines; Humans; Mycoses

Fungal infections are life-threatening complications in patients with prolonged neutropenia. Amphotericin B, which is fungicidal and has a broad spectrum of antifungal activity, remains the current gold standard agent. However, because of its low therapeutic index, new lipid formulations of amphotericin B have been developed with better tolerance and less toxicity. The use of 5-fluorocytosine is waning because of the medullar toxicity of this agent. Fluconazole and itraconazole are both fungistatic and are more convenient for the treatment of fungal infections in haemodynamically stable patients.

Topics: Amphotericin B; Antifungal Agents; Fever; Flucytosine; Humans; Mycoses; Neutropenia

Over the past two decades the incidence of deep mycoses caused by several major groups of fungal pathogens such as Candida spp., aspergilli, Cryptococcus neoformans and zygomycetes has risen steadily. Moreover, opportunistic fungal infections due to Fusarium spp., Trichosporon spp., Pseudallescheria boydii and other emerging pathogens, as well as fluconazole-resistant Candida albicans, all of which are often resistant to existing antifungal drugs, are also encountered more and more frequently. This makes it more difficult for the clinician to achieve successful treatment. Thus there is an urgent need to develop new antifungal agents or formulations with advantages over and/or complimentary to existing drugs. This review focuses on current approaches to antifungal chemotherapy with special reference to the clinical development of new drugs, including (ii) lipid formulations of amphotericin B, (i) second-generation azoles and (iii) antifungal lipopeptides.

Topics: Amphotericin B; Antifungal Agents; Azoles; Chemistry, Pharmaceutical; Drug Design; Humans; Liposomes; Mycoses; Peptides

Fungal infections are an important cause of morbidity and mortality in immunocompromised patients. Treatment with amphotericin B is the main therapeutic approach. However, this treatment is limited by the substantial toxicity. We present the data of the first randomized prospective comparative trial in adults (134 patients with fever of unknown origin) with conventional amphotericin B and a liposomal formulation of amphotericin B (AmBisome, published in 1997 by Prentice et al. (Br. J. Haematol. 98, 711-718) and the data of adults with documented fungal infections (59 patients), treated in this trial. Patients received either conventional amphotericin B 1 mg kg-1 per day, liposomal amphotericin B 1 mg kg-1 per day or liposomal amphotericin B 3 mg kg-1 per day. Patients were entered if they had fever of unknown origin (FUO), defined as temperature of 38 degrees C or more, not responding to 96 h of systemic broad-spectrum antibiotic treatment, and neutropenia (< 0.5 x 10(9) l-1). Efficacy of treatment was assessed, with success defined as resolution of fever for three consecutive days (< 38 degrees C) in the group of patients with FUO and the freedom of clinical signs and/or the elimination of fungus in the group of patients with documented fungal infections. The safety of treatment and renal and hepatic toxicity of liposomal and conventional amphotericin B were compared. No statistically significant difference was found in the treatment efficacy in the three study arms. However, there is a tendency of better treatment results in the two groups of patients, who received liposomal amphotericin B. Thirty-five per cent of patients with documented fungal infections and 46% of patients with FUO responded to amphotericin B. In the patients group, that received 1 mg kg-1 liposomal amphotericin B it was 63 and 49%, in the group of patients that received 3 mg kg-1 liposomal amphotericin B it was 47 and 64%. Evidence of toxicity due to amphotericin B was seen in 50 patients (83%), toxicity due to liposomal amphotericin B, 1 mg kg-1, was seen in 35 patients (50%), and due to liposomal amphotericin B 3 mg kg-1 in 34 patients (54%). This was a statistically significant difference (P = 0.001). It was concluded that liposomal amphotericin B was safer than conventional amphotericin B, but both formulations are equivalent in treatment efficacy. The prophylactic use of amphotericin B in these immunocompromised patients is discussed.

Topics: Adult; Amphotericin B; Child; Female; Fever of Unknown Origin; Humans; Liposomes; Male; Middle Aged; Mycoses; Neutropenia

Disseminated Fusarium infection in an immunocompromised host is intractable and results in high mortality. We provide the first full case report on successful treatment of a disseminated Fusarium infection in an infant. The 6-month-old infant, whose family raised livestock, had infantile leukemia. During the neutropenic period after intensive chemotherapy, vomiting, diarrhea, fever, subcutaneous nodes, and coughing appeared. Pneumonia was diagnosed, and Fusarium moniliforme was isolated from blood culture. A central venous catheter was removed. Granulocyte colony-stimulating factor (G-CSF) and amphotericin B (AMPH-B) (total dose, 65 mg/kg) were administered continuously for 8 weeks. The infection was resolved according to improvement of clinical and laboratory findings, and intensive chemotherapy was restarted for the leukemia. Cord blood stem cell transplantation from an unrelated donor was performed. The Fusarium infection did not recur, but after transplantation, leukemia relapsed. Treatment of neutrophils using G-CSF, AMPH-B, and local treatment induced resolution of the disseminated Fusarium infection in this immunocompromised host with malignancy. We suggest caution for patients living in an environment conducive to the development of Fusarium infection because of the particular risk of infection.

Topics: Amphotericin B; Animals; Animals, Domestic; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Fusarium; Humans; Immunocompromised Host; Infant; Leukemia; Male; Mycoses

A new session in this Congress was the development of a discussion panel regarding controversies and queries about the main topics of treatment and prophylaxis of severe systemic mycoses. Experts presenting each side of three controversial areas provided an interchange of ideas and clarified those areas where there remain substantial disagreements. Some common recommendations have been made, and some differences persist. The contents of this session are compiled in this paper. Due to the limitations of space, this paper presents the most relevant parts of each presentation. The large and up-to-date list of references should be useful to gain a better understanding of these subjects.

Topics: Amphotericin B; Animals; Antifungal Agents; Chemoprevention; Drug Combinations; Humans; Mice; Mycoses; Phosphatidylcholines; Phosphatidylglycerols

Amphotericin B colloidal dispersion (ABCD) is a colloidal dispersion of a stable complex of amphotericin B with cholesteryl sulphate in a 1:1 proportion, forming uniform disk-shaped particles. ABCD is associated with less nephrotoxicity than conventional amphotericin B deoxycholate. Infusion-related adverse events are more frequent in patients receiving ABCD than in patients receiving liposomal amphotericin B or amphotericin B deoxycholate. ABCD has been shown in a randomised, double-blind study, to be an effective alternative to amphotericin B deoxycholate for empirical treatment of patients with fever and neutropenia. ABCD is active in the treatment of invasive Candida spp. and Aspergillus spp. infections in immunocompromised hosts, however most of the data supporting its use for these types of infections is derived from non-comparative open-label clinical trials of patient refractory to or intolerant of conventional antifungal therapy. ABCD is approved by the US FDA for the treatment of invasive aspergillosis in patients where renal impairment of unacceptable toxicity precludes the use of amphotericin B deoxycholate in effective doses, and in patients with invasive aspergillosis where prior amphotericin B deoxycholate therapy has failed. Two other lipid formulations of amphotericin B, amphotericin B lipid complex and liposomal amphotericin B, are available and, like ABCD, are associated with reduced nephrotoxicity as compared to amphotericin B deoxycholate. The role of ABCD in comparison with these other lipid formulations of amphotericin B is discussed herein. High cost remains an issue with all lipid formulations of amphotericin B.

Topics: Amphotericin B; Animals; Antifungal Agents; Clinical Trials as Topic; Colloids; Humans; Mycoses

Availability of lipid formulations of amphotericin B has opened up the possibility of treating invasive fungal infections in immunocompromised patients with high doses of this antifungal agent. Evidence is emerging to suggest that lipid formulations may have heightened efficacy compared to conventional amphotericin B. The issue of optimal dosage has been a neglected area. This article reviews published data accrued from clinical, open-label, salvage, and other studies, and finds little support that the use of high doses of lipid formulations are more efficacious than lower doses. The response rates for invasive fungal infection from most studies are predictably around 56%, irrespective of the lipid formulation and dose used. Animal models provide evidence that low doses of a lipid formulation are as successful in reducing fungal dissemination and in prolonging survival as higher doses, although concomitant tissue fungal eradication is not as effectively achieved by the lower doses (survival-mycologic eradication dissociation). Kinetic studies performed in the clinically relevant setting of critically ill patients give further support to the use of low doses, since levels of liposomal amphotericin B at all dosages between 1 and 4 mg/kg/day are similar and above maximum inhibitory concentrations for commonly encountered fungi. There has only been one prospective randomised study designed with the primary end-point of comparing two dosages of an amphotericin B lipid formulation on clinical response and survival. That European Organization for Research and Treatment of Cancer (EORTC) study concluded that liposomal amphotericin B given at 1 mg was as efficacious as 4 mg/kg/day in treating neutropenic patients with invasive pulmonary aspergillosis. There are a multitude of unanswered questions concerning dosing, and their answers are confounded by difficulties in performing clinical trials and the multiplicity of factors other than antifungal chemotherapy that influence outcome. Maximum tolerated dose studies using existing lipid formulations, or perhaps with the newer formulations such as pegylated immunoliposomal amphotericin B, could be performed to shed light on this difficult area.

Topics: Amphotericin B; Animals; Antifungal Agents; Chemistry, Pharmaceutical; Humans; Maximum Tolerated Dose; Mycoses

Topics: Amphotericin B; Anidulafungin; Animals; Anti-Bacterial Agents; Antifungal Agents; Echinocandins; Fungal Proteins; Humans; Mycoses; Peptides; Peptides, Cyclic

Amphotericin B colloidal dispersion (ABCD, AMPHOTEC, AMPHOCIL), a lipid complex of amphotericin B, was developed to reduce the nephrotoxicity of amphotericin B while retaining its antifungal efficacy. In this retrospective review, the efficacy and safety of ABCD were evaluated in 220 BMT recipients (167 allogeneic; 53 autologous) with suspected or documented life-threatening fungal infections (primarily Candida or Aspergillus species). Patients were treated in five open-label clinical trials of ABCD therapy. ABCD was administered intravenously once daily, median dose of 4 mg/kg, for up to 409 days (mean 23 days, median 16 days). Successful therapeutic response to treatment (complete or partial) was reported in 52% of the 99 evaluable patients with proven infection, and in 40% of all 220 patients. In the evaluable population, the response and mortality rates were 51% and 73%, respectively, in the allogeneic BMT patients, compared to 52% and 48% in the autologous BMT patients. The response rate for evaluable patients with Candida spp was 65%, 38% for patients with Aspergillus spp, and 42 % for patients with other or multiple fungal infections. In this patient population at high risk of nephrotoxicity due to concomitant cyclosporine and/or other nephrotoxic agents, ABCD did not cause renal dysfunction. Although the majority of patients had pre-existing renal impairment (median baseline serum creatinine 1.8 mg/dl), there was no trend towards increasing serum creatinine. No unexpected toxicities were observed. In conclusion, ABCD appears to be safe and effective for the treatment of severe fungal infections in BMT patients.

Topics: Adolescent; Adult; Amphotericin B; Antifungal Agents; Bone Marrow Transplantation; Child; Child, Preschool; Female; Humans; Kidney Diseases; Male; Middle Aged; Mycoses; Retrospective Studies

The frequency of life-threatening fungal infections has increased dramatically over the past few decades. For more than 30 years amphotericin B has been the standard treatment for systemic and deep-seated fungal infections, primarily because of its broad spectrum of activity. Its usefulness is limited by a relatively high frequency of significant adverse events including infusion-related reactions and nephrotoxicity. In an effort to overcome these side effects, a number of lipid-based formulations were developed, each with its own composition and pharmacokinetic behavior. The clinical significance of these differences is unknown. Available clinical data suggest the formulations have a reduced propensity for causing nephrotoxicity. However, considering limited efficacy data, they should be reserved as second-line therapy for patients who cannot tolerate or fail an adequate trial of conventional amphotericin B or cannot benefit from other antifungal agents.

Topics: Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Clinical Trials as Topic; Drug Carriers; Humans; Liposomes; Mycoses

Endemic mycoses remain a major public health problem in several countries and they are becoming increasingly frequent with the spread of HIV infection. Amphotericin B remains the drug of choice during the acute stage of life-threatening endemic mycoses occurring in both immunocompetent and immunocompromised hosts. Ketoconazole is effective in non-AIDS patients with non-life-threatening histoplasmosis, blastomycosis, or paracoccidioidomycosis. Itraconazole is the treatment of choice for non-life-threatening Histoplasma capsulatum or Blastomyces dermatitidis infections occurring in immunocompetent individuals and is the most efficient secondary prophylaxis of histoplasmosis in AIDS patients. Itraconazole is also effective in lymphocutaneous and visceral sporotrichosis, in paracoccidioidomycosis, for Penicillum marneffei infection, and is an alternative to amphotericin B for Histoplasma duboisii infection. Coccidioidomycosis may be effectively treated with prolonged and sometimes life-long itraconazole or fluconazole therapy. Fluconazole has relatively poor efficacy against histoplasmosis, blastomycosis and sporotrichosis. New antifungal agents have been tested in vitro or in animal models and may soon be evaluated in clinical trials.

Topics: AIDS-Related Opportunistic Infections; Amphotericin B; Blastomycosis; Coccidioidomycosis; Histoplasmosis; Humans; Mycoses; Paracoccidioidomycosis; Sporotrichosis

Systemic fungal infections cause almost 25% of the infection-related deaths in leukaemic patients. Particularly those with prolonged neutropenia are at risk but mycoses also feature in critically ill intensive care patients and in individuals who are treated for solid tumours and AIDS, or who received an organ transplant. The spread of AIDS and the more aggressive cytotoxic chemotherapy in combination with an improved management of haemorrhages and bacterial infections in leukaemic and other cancer patients facilitated the occurrence of these invasive fungal infections. These life-threatening complications remain both difficult to diagnose and to treat and therefore carry a poor prognosis. For many years, the only realistic option to treat systemic infections was amphotericin B, whose administration was known to be associated with numerous adverse effects. Now less toxic formulations of amphotericin have become available for clinical use, as well as several new triazoles that appear to provide an effective and less toxic alternative for the treatment of certain fungal infections.

Topics: AIDS-Related Opportunistic Infections; Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis; Cryptococcosis; Deoxycholic Acid; Drug Combinations; Fluconazole; Flucytosine; Fungemia; Histoplasmosis; Humans; Immunocompromised Host; Mycoses; Zygomycosis

Incidence and risk factors were analyzed in elderly patients with deep-seated mycosis. Twenty cases with candidiasis or aspergillosis were found in 1,663 autopsy cases. Intravascular catheters and administration of antibiotics were prominent risk factors for candidiasis as was steroid therapy. Leukocytopenia due to anti-cancer drugs caused aspergillosis. Preventive use of AMPH in patients with hematological malignancies or with steroid therapy was effective against mycosis. Although AMPH is also effective for almost all kinds of deep-seated mycosis, we rarely administered it to elderly patients because of its nephrotoxicity. The safe use of antimycotics requires checking drug sensitivity of causative fungi in a laboratory, and establishing the optimal dosage for patients with impaired renal function.

Topics: Aged; Aged, 80 and over; Amphotericin B; Antibiotic Prophylaxis; Antifungal Agents; Female; Humans; Immunocompromised Host; Male; Mycoses; Risk Factors

We investigated the efficacy of non-azole antifungal agents. Long circulating immunoliposomal amphotericin B was potent in murine invasive pulmonary aspergillosis. The concentration of AMPH-B was still high in the lung after 6 hours of 34A-PEG-liposomal AMPH-B. Lipid nanosphere amphotericin B (NS-718) showed efficacy against pulmonary aspergillosis in rats and pulmonary cryptococcosis in mice. The renal toxicity of NS-718 was estimated to be lower than that of AMPH-B from the results of the toxicity study in the rat infusion model. FK 463, a novel (1,3)-beta-D-glucan synthase inhibitor, showed efficacy against azole-resistant Candida albicans in murine experimental disseminated candidiasis. FK463 could be a promising drug and the therapy of choice for azole resistant C. albicans infection.

Topics: Amphotericin B; Animals; Antifungal Agents; Drug Carriers; Echinocandins; Flucytosine; Fungi; Glucosyltransferases; Lipopeptides; Lipoproteins; Liposomes; Membrane Proteins; Micafungin; Mice; Mycoses; Peptides, Cyclic; Rats; Schizosaccharomyces pombe Proteins

Over the past 15 years, factors suh as corticosteroid treatment, cytotoxic chemotherapy, excessive use of broad spectrum antibiotics and HIV have led to an increased risk of serious fungal infections in both adults and pediatric patients. This increase in invasive fungal infections poses increasing difficulty in their treatment. Three new lipid formulations of amphotericin B are now available in the U.S.: amphotericin B lipid complex (Abelcet), amphotericin B colloidal dispersion (Amphotec), and liposomal amphotericin B (AmBisome). These newer formulations are substantially more expensive, but allow patients to receive higher doses for longer periods of time with decreased renal toxicity than conventional amphotericin B. The properties of these new agents are summarized in this review. Discussion of current national guidelines as well as those used at our institution are presented to provide guidance for the development of institution specific guidelines for the most cost-effective drug for most patients, some may benefit more from one of the newer lipid formulations.

Topics: Amphotericin B; Antifungal Agents; Chemistry, Pharmaceutical; Humans; Lipids; Liposomes; Mycoses

During the past decades, the incidence and severity of invasive fungal infections has been increasing. These events have lead to the development of new antifungal agents, and amphotericin B no longer is the standard therapy for a variety of invasive mycoses. Fluconazole has become the drug of choice for treatment of C. albicans infections in non-neutropenic as well as neutropenic patients. For treatment of cryptococcal meningitis, amphotericin B with flucytosine, followed by fluconazole consolidation therapy is used. For therapy of invasive aspergillosis, the lipid formulations of amphotericin B may be associated with reduced toxicity and allow for larger doses, although the efficacy of each of the formulations still has to be established in randomized trials. Finally, treatment modalities aimed at improving host defense mechanisms, including adjunctive therapy with rG-CSF for disseminated candidiasis and rG-CSF-elicited granulocyte transfusions, are under way.

Topics: Amphotericin B; Antifungal Agents; Catheterization, Central Venous; Contraindications; Drug Therapy, Combination; Flucytosine; Fungemia; Granulocyte Colony-Stimulating Factor; Humans; Immunotherapy; Mycoses; Neutropenia; Triazoles

A review is presented on the hitherto clinically administered antimycotic drugs, their action mechanisms and limitations as well as on the presently newly developed antifungals and their molecular targets.

Topics: Amphotericin B; Antifungal Agents; Azoles; Mycoses; Polyenes; Pyrimidines

The extensive use of antifungal prophylaxis may have played a role in the increased incidence of invasive fungal infections in immunocompromised patients. Amphotericin B remains the antifungal agent with the broadest spectrum of action available and is thus the standard treatment for immunocompromised patients with proven or suspected fungal infections, especially aspergillosis. However, its potential for nephrotoxicity limits its usefulness. Lipid formulations of amphotericin B may allow therapy to be administered with reduced renal toxicity. Three different lipid formulations of amphotericin B are currently available. These compounds have different pharmacokinetics properties and usually achieve higher serum and/or tissue concentrations than amphotericin B. At present, there are no studies comparing the lipid formulations with each other and only a few randomized trials comparing them with conventional amphotericin B. However, a number of open clinical trials and compassionate-use protocols suggest that lipid-based forms of amphotericin B can achieve good response rates with minimal toxicity in patients with a variety of invasive mycoses, including those who have proved refractory or intolerant to previous therapy with conventional amphotericin B. Unfortunately, the cost of these compounds remains very high and may represent a limiting factor to their use.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus; Candida; Candidiasis; Drug Resistance, Microbial; Humans; Immunocompromised Host; Lipids; Liposomes; Mycoses; Neoplasms; Risk Factors

Topics: Amphotericin B; Antifungal Agents; Fluconazole; Forecasting; Humans; Itraconazole; Mycoses; Systemic Inflammatory Response Syndrome

Topics: Amphotericin B; Antifungal Agents; Azoles; Candidiasis; Child; Flucytosine; Griseofulvin; Humans; India; Mycoses

The role of itraconazole in anti-fungal prophylaxis has been limited by the low bioavailability of the capsule formulation but the bioavailability of the oral solution is much improved. Three multi-centre studies using itraconazole solution (5 mg/kg/day) have recently been completed. The UK trial compared itraconazole solution with fluconazole suspension (100 mg/day). No invasive aspergillosis occurred in the itraconazole arm and there were more fungal deaths due to proven/suspected infection in the fluconazole group than in the itraconazole group (0 versus 7, p = 0.024). An Italian study compared itraconazole solution with placebo. Proven, suspected and superficial fungal infections were fewer in the itraconazole arm compared with placebo, with significant differences in proven and suspected systemic fungal infections (itraconazole 24% versus placebo 33%, p = 0.035). The third study compared itraconazole with amphotericin B capsules (2 g/day). There were more invasive fungal infections, Aspergillus infections and fungal deaths in the amphotericin B arm than with itraconazole but none of these differences were statistically significant. Azole prophylaxis in neutropenic patients may reduce the incidence of Candida infections, empirical amphotericin B usage, and the incidence of proven fungal infections. Itraconazole may be more effective than fluconazole in preventing invasive aspergillosis. All of these effects are more pronounced in high risk patients.

Topics: Administration, Oral; Amphotericin B; Antifungal Agents; Clinical Trials as Topic; Humans; Itraconazole; Mycoses; Neutropenia

Topics: Amphotericin B; Antifungal Agents; Humans; Hypokalemia; Mycoses

Amphotericin B (amB) remains the gold standard for the treatment of invasive fungal infections. However, the efficacy is limited, with response rates from 10% to 80%. Moreover, amB is toxic, especially for the kidneys. New formulations have been developed in an attempt to improve both efficacy and tolerability. In an attempt to reduce toxicity, a number of investigators have reconstituted amB in a lipid emulsion, but few data are available on efficacy in documented infections. An improvement in immediate and renal tolerance was obtained with equivalent daily dose regimens, but the therapeutic index does not appear to be improved. This approach cannot be recommended at present. Three lipid formulations have been developed and are now available in most countries: amB colloidal dispersion (ABCD), amB lipid complex (ABLC), and liposomal amB (AmBisome). The efficacy of ABCD on various fungal infections has been assessed in open trials, with a response rate of 49% in aspergillosis, 70% in candidiasis, and 67% in mucormycosis. In two randomized trials comparing ABCD with amB in invasive aspergillosis and in persistent febrile neutropenia, the response rates were equivalent. ABCD was less nephrotoxic. In contrast, immediate reactions to ABCD were as frequent and severe as with amB. These immediate effects are more frequent during the first infusions and lessen as treatment continues. The recommended dose is 3-4 mg/kg/day. ABLC appeared to be effective as rescue therapy in various types of invasive mycoses, with a response rate of 42% in aspergillosis, 67% in candidiasis, and 82% in fusariosis. Efficacy identical to that of amB was demonstrated in a comparative randomized trial involving patients with invasive candidiasis. General and renal tolerability is improved compared with amB. The recommended dose regimen is 5 mg/kg/day. Liposomal amB (AmBisome) is the only truly liposomal formulation. The response rates in preliminary trials were 66% in aspergillosis and 81% in candidiasis. Several comparative studies have confirmed that this formulation has similar or superior efficacy relative to amB in various fungal infections and also in the empirical treatment of febrile neutropenia. Renal and general tolerability is excellent. The optimal dosing remains unclear but is generally between 3 and 5 mg/kg/day. A double-blind trial comparing the tolerance of liposomal amB and ABLC demonstrated that both infusion-related events and nephrotoxicity were significantly lower fo

Topics: Amphotericin B; Antifungal Agents; Bone Marrow Transplantation; Chemistry, Pharmaceutical; Drug Administration Schedule; Humans; Mycoses; Organ Transplantation; Postoperative Complications

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis; Chemistry, Pharmaceutical; Fluconazole; Flucytosine; Hematologic Diseases; Humans; Itraconazole; Mycoses

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Azoles; Candidiasis; Catheters, Indwelling; Diagnosis, Differential; Flucytosine; Fusarium; Humans; Iatrogenic Disease; Immunocompromised Host; Mycoses; Opportunistic Infections; Syndrome; Trichosporon

We report a case of cerebral phaeohyphomycosis in a 36-year-old male caused by the neurotropic fungus Ramichloridium obovoideum (Matushima) de Hoog 1977 (Ramichloridium mackenziei Campbell et Al-Hedaithy 1993). This man resided in the Middle East, where the fungus appears to be endemic and, possibly, geographically restricted, since all previous reports of brain abscesses due to this organism have been for patients indigenous to this area. As a servant of the Saudi Arabian royal family, he appeared in the United States seeking treatment for chronic weight loss, fatigue, decreased memory, and a more recent 2-week history of right-hand weakness which worsened to involve the entire right upper extremity. On the day prior to his admission, he had a focal motor seizure with rotation of the head and eyes to the right, followed by secondary generalization. A computerized tomogram showed a ring-enhancing hypodense lesion in the left parietal subcortical region with associated edema and mass effect. Diagnosis of a fungal etiology was made following a parietal craniotomy and excisional biopsy by observation of septate, dematiaceous hyphal elements 2 to 3 microm in width on hematoxylin-and-eosin-stained sections from within areas of inflammation and necrosis. Culture of the excised material grew out a dematiaceous mould which was subsequently identified as R. obovoideum. At two months postsurgery and with a regimen of 200 mg of itraconazole twice a day, the patient was doing well and returned to Saudi Arabia. His condition subsequently deteriorated, however, and following a 7-month course of itraconzole, he expired. We use this case to alert clinicians and personnel in clinical mycology laboratories of the pathogenicity of this organism and its potential occurrence in patients with central nervous system signs and symptoms who have resided in the Middle East and to review and/or compare R. obovoideum with other neurotropic, dematiaceous taxa and similar nonneurotropic, dematiaceous species.

Topics: Adult; Amphotericin B; Antifungal Agents; Brain; Brain Diseases; Female; Humans; Itraconazole; Male; Mitosporic Fungi; Mycoses; Opportunistic Infections; Saudi Arabia; United States

The antimicrobial management of patients in the critical care unit is complex. Not only must the clinician be familiar with a number of clinical, microbiological, pharmacological, and epidemiological observations but also fundamental pharmacodynamic concepts. It is an understanding of these concepts that forms the basis for the design of dosing strategies that maximize clinical efficacy and minimize toxicity. Antimicrobial selection is further complicated by the plethora of new antimicrobial agents available with varying clinical utility. Nowhere is this more evident than in the quinolone class of antibiotics. To aid the clinician in differentiating between quinolones it now seems reasonable to create a classification system akin to the generation grouping applied to the cephalosporins. Our classification is based upon the pharmacodynamic principles discussed within this article.

Topics: Aminoglycosides; Amphotericin B; Anti-Bacterial Agents; Anti-Infective Agents; Antifungal Agents; Community-Acquired Infections; Cross Infection; Fluoroquinolones; Humans; Intensive Care Units; Mycoses; Pneumonia, Bacterial; Skin Diseases, Bacterial; Soft Tissue Infections; United States; Urinary Tract Infections

Historical clinical observations suggested that cellular immunity is central in the outcome of deep fungal infections, and experimental observations later proved this. Unstimulated effector cells interact synergistically with antifungal drugs. Recombinant cytokines, of which interferon gamma (IFN-gamma) is the most prominent, stimulate several host-effector cells (macrophages, monocytes, neutrophils) for antifungal activity. Effector cells stimulated by such molecules (data with macrophage colony-stimulating factor, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor with azoles are presented as examples) also have enhanced synergistic activity with antifungals. A tilt toward a type 1 T-helper (Th1) cell pathway seems essential in antifungal host defenses. Cytokines (and anticytokines) that promote this pathway can be protective in vivo and act cooperatively with antifungal drugs. Observations with interleukin (IL)-12, IFN-gamma, and anti-IL4 illustrate this. The clinical applications of these strategies are just beginning.

Topics: Amphotericin B; Antifungal Agents; Cytokines; Drug Therapy, Combination; Humans; Immunotherapy; Interferon-gamma; Interleukin-4; Mycoses; Th1 Cells; Th2 Cells

AmBisome (NeXstarPharmaceuticals, San Dimas, CA) is a unilamellar liposomal formulation of amphotericin B that was recently approved for use as empirical treatment for presumed fungal infections in febrile neutropenic patients and for aspergillosis, candidiasis, and cryptococcosis infections refractory to amphotericin B. It is a small closed microscopic sphere (<100 nm in diameter) with an inner aqueous core (i.e., a true liposome). AmBisome remains as an intact sphere in vitro and for prolonged periods of time in vivo during the processes of systemic transport and pharmacologic action. As a consequence of its size and in vivo stability, AmBisome has physiochemical properties and a pharmacokinetic profile that are considerably different from those of currently available lipid-complexed amphotericin B formulations, with greatly increased area under the plasma concentration-time curve and much lower clearance at equivalent doses. AmBisome liposomes can be seen to accumulate at sites of fungal infection. Disruption of AmBisome liposomes occurs after attachment to the fungal cell wall and results in amphotericin B binding to fungal cell membrane ergosterol with subsequent cell lysis. AmBisome has been shown to penetrate the cell wall of both extracellular and intracellular forms of susceptible fungi.

Topics: Amphotericin B; Antifungal Agents; Clinical Trials as Topic; Drug Combinations; Humans; Liposomes; Mycoses; Phosphatidylcholines; Phosphatidylglycerols

Amphotericin B has long been the mainstay in the treatment of systemic fungal infections, but its nephrotoxicity limits the dosage that can be used. New lipid-based forms may allow higher dosing with less nephrotoxicity. Unfortunately, these new forms are substantially more expensive, and data from randomized clinical trials of their relative efficacy are as yet limited.

Topics: Amphotericin B; Antifungal Agents; Chemistry, Pharmaceutical; Clinical Trials as Topic; Costs and Cost Analysis; Dose-Response Relationship, Drug; Drug Carriers; Humans; Infusions, Intravenous; Kidney; Lipids; Mycoses; Tissue Distribution

Formulation of amphotericin B with sodium cholesteryl sulphate alters the pharmacokinetic properties of the drug, particularly reducing its distribution to the kidneys. The antifungal activity in vitro of amphotericin B colloidal dispersion (ABCD) is similar to that of conventional amphotericin B (C-AmB) against true pathogenic organisms including Blastomyces, Coccidioides, Histoplasma and Paracoccidioides species and the opportunistic organisms such as Candida and Cryptococcus species. In animal models, ABCD was generally less effective than an identical dose of C-AmB, but overall was more effective because of its improved therapeutic index. Although ABCD appeared to be more effective than C-AmB in resolving infection and improving survival in patients with proven or probable invasive aspergillosis, the retrospective design of the study and the greater prevalence of neutropenia in patients treated with the conventional formulation necessitate cautious interpretation of the results. ABCD has been effective and seldom caused nephrotoxicity in patients with fungal infection who had previously failed to adequately respond or had developed renal toxicity with C-AmB. Similarly, ABCD was effective in patients with proven or suspected fungal infection after bone marrow transplantation. Preliminary results from a pilot study comparing ABCD and C-AmB in patients with neutropenia and persistent fever reported similar response rates with both formulations. ABCD is an effective treatment for visceral leishmaniasis in immunocompetent patients. In 1 study, about 12% of ABCD recipients discontinued the drug because of adverse events; infusion-related events were the most common cause of discontinuation. The renal tolerability of ABCD is better than that of C-AmB. ABCD appears to be an effective alternative to conventional amphotericin B in patients with invasive aspergillosis or visceral leishmaniasis and in those with proven or suspected systemic fungal infection who are intolerant of the conventional formulation or have pre-existing renal impairment. Preliminary data also suggest that ABCD is an alternative to C-AmB when used empirically in patients with neutropenia and fever. Nevertheless, the efficacy of ABCD compared with that of the conventional formulation has yet to be adequately demonstrated and the role of ABCD relative to that of liposomal and other lipid-based formulations has not been determined.. ABCD, like other lipid-based and liposomal formulations of amphotericin B, has been designed to deliver the active drug to the target site, while reducing renal toxicity. The aim of increasing the therapeutic index compared with C-AmB has been achieved.

Topics: Amphotericin B; Animals; Antifungal Agents; Antiprotozoal Agents; Colloids; Humans; Leishmaniasis, Visceral; Mycoses

Major increases in the incidence of systemic fungal infections have been observed during the past three decades, particularly in immunocompromised patients. A critical need exists for new antifungal agents to treat these life-threatening invasive fungal infections. The review of the development of antifungal therapy provided in this chapter indicates the increased interest in this very special area of infectious diseases. Even though newer and less toxic antifungal agents are currently available for clinical use, innovative research in antifungal drug discovery may eventually produce more promising antifungal agents.

Topics: Amphotericin B; Antifungal Agents; Drug Carriers; Flucytosine; Humans; Liposomes; Mycoses; Triazoles

The incidence of systemic fungal infection has been increasing during the last two decades. Candida and Aspergillus spp. are the classical opportunistic pathogens. Rare fungi, such as Mucor, Rhizopus, Fusarium, Trichosporon, Paecilomyces, Alternaria, Cladosporium and Pseudoallescheria, are emerging as cause of systemic fungal infection in the immunocompromised host. For more than 40 years Amphotericin B has been the gold standard of antifungal treatment because of its broad spectrum comprising yeasts, dimorphic fungi and moulds. Its nephrotoxicity has led to the development of lipid-associated preparations of amphotericin B: liposomal amphotericin B, amphotericin B colloidal dispersion and amphotericin B lipid complex. These preparations are less nephrotoxic, but higher doses than those of conventional amphotericin B are needed to achieve the same effect. The triazole fluconazole is the treatment of choice in infections caused by Candida albicans. New antifungal compounds are voriconazole and the candins, the pradimicin/benanomycin family, nikkomycin Z and a liposomal preparation of nystatin.

Topics: Amphotericin B; Antifungal Agents; Drug Therapy, Combination; Fluconazole; Humans; Mycoses; Opportunistic Infections; Treatment Outcome

Topics: Amphotericin B; Antifungal Agents; Fluconazole; Flucytosine; Humans; Itraconazole; Miconazole; Mycoses

The antifungal agents currently available to treat invasive fungal infections are limited in both number and usefulness. Treatment with the polyene amphotericin B (AmB), and with several azoles, in particular fluconazole and itraconazole, is the mainstay of antifungal chemotherapy. However, the clinical usefulness of these drugs is hampered by drawbacks associated with their safety and/or efficacy. There are two approaches to overcome this situation. One is to discover and develop new antifungal agents or formulations with advantages over and/or complementary to existing drugs. For this purpose, the following three categories of new drugs have been the major targets of study and development: (i) lipid formulations of polyenes, (ii) azoles (including cyclodextrin-complexes), and (iii) nonazole compounds, particularly those of microbial origin (antibiotics).

Topics: Amphotericin B; Animals; Antifungal Agents; Clinical Trials as Topic; Combined Modality Therapy; Drug Therapy, Combination; Fungi; Humans; Mycoses; Opportunistic Infections; Randomized Controlled Trials as Topic; Triazoles

Patients with cancer and infectious disease often display dyslipidemias that result in changes in their plasma lipoprotein-lipid composition. It is likely that the interactions of liposomal polyenes with plasma lipoproteins may be responsible for the far different pharmacokinetics and pharmacodynamics of these compounds when they are administered to infected patients rather than to animals or healthy volunteers. Amphotericin B (AmpB) and nystatin are examples of such polyenes. Amphotericin B initially distributes with the high-density lipoprotein (HDL) fraction upon incubation in plasma. Over time, AmpB redistributes from HDLs to low-density lipoproteins (LDLs). This redistribution appears to be regulated by lipid transfer protein. However, when AmpB is incorporated into liposomes composed of negatively or positively charged phospholipids, not only is the capability of LTP to transfer AmpB from HDL to LDL diminished, but AmpB remains retained with only the HDL fraction. However, when liposomal nystatin is incubated in plasma, over 50% of nystatin distributes with HDLs. Over time, nystatin redistributes from HDL to the lipoprotein-deficient plasma fraction, which is composed of mainly aqueous plasma proteins. The lipid composition selected for the drug appears to be a vital constituent in regulating the drug's interaction with biological fluids. Furthermore, liposome (or liposomal particle) size, fluidity, and other physiochemical characteristics also play a role in altering the pharmacokinetics and pharmacological effects of lipid-based drug formulations. Armed with this understanding, a rational approach to clinical development of these formulations could be facilitated.

Topics: Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Humans; Immunocompromised Host; Kidney; Lipoproteins; Liposomes; Mycoses; Nystatin; Phagocytes

Topics: Amphotericin B; Animals; Antifungal Agents; Cholesterol Esters; Drug Combinations; Humans; Mycoses; Phosphatidylcholines; Phosphatidylglycerols

To determine whether antifungal agents given prophylactically or empirically decrease morbidity and mortality in patients with cancer complicated by neutropenia.. Meta-analysis of randomised trials of amphotericin B, various lipid soluble formulations of amphotericin B (for example, AmBisome), fluconazole, ketoconazole, miconazole, or itraconazole compared with placebo or no treatment.. Trials conducted anywhere in the world.. Patients with cancer complicated by neutropenia.. Mortality, invasive fungal infection (defined as positive blood culture, oesophageal candidiasis, or lung or deep tissue infection), and colonisation.. 24 trials with 2758 randomised patients were reviewed; the total number of deaths was 434. Prophylactic or empirical treatment with antifungals as a group bad no effect on mortality (odds ratio 0.92; 95% confidence interval 0.74 to 1.14). Amphotericin B decreased mortality significantly (0.58; 0.37 to 0.93) but the studies were small and the difference in number of deaths was only 15. Antifungal treatment decreased the incidence of invasive fungal infection (0.47; 0.35 to 0.64) and fungal colonisation (0.45; 0.30 to 0.69). For every 73 patients treated (95% confidence interval to 48 to 158) one case of fungal invasion was prevented in surviving patients.. There seems to be no survival benefit of antifungal agents given prophylactically or empirically to patients with cancer complicated by neutropenia. These agents should be restricted to patients with proved infection and those in randomised trials. A large, definitive placebo controlled trial of amphotericin B is needed.

Topics: Amphotericin B; Antifungal Agents; Fluconazole; Humans; Itraconazole; Ketoconazole; Miconazole; Mycoses; Neoplasms; Neutropenia; Randomized Controlled Trials as Topic

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis; Celiac Artery; Cytomegalovirus Infections; Female; Heart Transplantation; Humans; Immunocompromised Host; Immunosuppression Therapy; Incidence; Liver Transplantation; Male; Middle Aged; Mucormycosis; Mycoses; Postoperative Complications; Risk Factors; Thrombosis; Time Factors; Transplantation; Triazoles

To evaluate the published data on the effectiveness and safety of amphotericin B lipid complex (ABLC) for the treatment of invasive mycosis and to evaluate data describing the pharmacologic properties and pharmacokinetic behavior of ABLC in both animals and humans.. A MEDLINE search was conducted to identify literature published from 1965 to January 1997 for amphotericin B deoxycholate (DCAB) and ABLC. In addition, preliminary data published as abstracts and presented at national conferences on infectious disease and hematology within the last 6 years were also included in this review.. Both human and animal studies were reviewed. Animal and in vitro studies were selected to evaluate the pharmacologic and toxicologic properties of ABLC. For the evaluation of the efficacy, safety, and pharmacokinetic behavior of ABLC, large, well-controlled studies were reviewed. In addition, data from open-label and emergency use protocols were also included in the review.. The study and analytical methods, results, and conclusions of the selected studies were evaluated. Pharmacokinetic data for both ABLC and DCAB that were derived from human subjects were also evaluated.. DCAB has been the cornerstone for the treatment of invasive mycosis, even though it has a narrow therapeutic index. Infusion-related toxicities (e.g., fever, chills, rigors) are likely due to DCAB stimulation of cytokine and prostaglandin synthesis. Conversely, nephrotoxicity, the primary non-infusion-related toxicity, likely results from the nonselective cytotoxic interaction between DCAB and cholesterol-containing mammalian cells. ABLC represents a new approach to improving the therapeutic index of DCAB. Mammalian cytotoxicity is attenuated by complexing amphotericin B to a mixture of phospholipids. This alters the affinity of amphotericin B and decreases its selective transfer from the complex to cholesterol-containing mammalian cells. Fungi also possess lipase, which improves the selective transfer from the complex to ergosterol-containing cell membranes. In humans, the lipid formulation increases the volume of distribution of amphotericin B. Thus, compared with DCAB, larger doses of ABLC can be administered for a longer duration with less nephrotoxicity. However, the prevalence of infusion-related toxicities associated with ABLC is similar to that of DCAB. Whether the alteration in distribution improves efficacy by improving tissue concentrations of amphotericin B has not been determined. The cost of this agent will limit its use.. ABLC has been shown to be at least as effective as DCAB, and it has been well tolerated in the clinical studies to date. Despite large dosages and extended courses of administration, there is little nephrotoxicity associated with its use. However, the cost of this agent will limit its use to the treatment of refractory mycosis or to cases where DCAB is contraindicated due to significant renal insufficiency.

Topics: Amphotericin B; Animals; Antifungal Agents; Deoxycholic Acid; Drug Combinations; Humans; Mycoses; Phosphatidylcholines; Phosphatidylglycerols

Invasive fungal infections are one of the leading causes of morbidity and mortality in cancer patients. Amphotericin B deoxycholate is still considered the gold standard of antifungal therapy, although the new triazoles (itraconazole and, especially, fluconazole) have shown to be able to replace amphotericin B for some therapeutic indications. The new lipid formulations of amphotericin B have disclosed new therapeutic perspectives, especially in patients with severe renal failure and documented, infections. At this time, indications, contraindications and limitation of the various drugs in the antifungal armamentarium are still partially unclear. Antifungal prophylaxis with fluconazole may be indicated in high-risk patients, although the duration of such prophylaxis should be limited as much as possible, in order to prevent selection of resistant strains and acquired resistance. Empirical antifungal therapy is used extremely widely (maybe, too widely) in many cancer centres, despite being based on limited clinical data. For this indication, fluconazole may also be effective in patients not receiving fluconazole prophylaxis, in whom Aspergillus infection is unlikely.

Topics: Amphotericin B; Antifungal Agents; Drug Therapy, Combination; Fluconazole; Humans; Itraconazole; Mycoses; Neoplasms

The availability of standard guidelines (NCCLS M27 document) for antifungal susceptibility testing has facilitated the establishment of tentative interpretive breakpoints for fluconazole and itraconazole by the NCCLS. Based on correlations of MIC values with the outcomes of patients with mostly Candida infections, fluconazole MICs of > or = 64 and itraconazole MICs of > or = 1.0 microgram/mL are considered resistant. Fluconazole MICs of 16 to 32 micrograms/mL and itraconazole MICs of 0.2 to 0.5 microgram/mL were categorized as "susceptible dependent upon dose" (S-DD), that is, clinical response may be obtained with increased doses. Susceptible breakpoints for fluconazole and itraconazole correspond to < or = 8 and < or = 0.12 microgram/mL, respectively. For flucytosine, resistant and susceptible breakpoints for Candida were set at > or = 32 micrograms/mL and 4 micrograms/mL, respectively, based on historical data and the drug's pharmacokinetics for Candida. Although no breakpoints have been established for amphotericin B, clinical failure has been associated with MICs > 1.0 microgram/mL.

Topics: Amphotericin B; Animals; Antifungal Agents; Candidiasis; Cryptococcosis; Drug Resistance, Microbial; Fluconazole; Flucytosine; Humans; Itraconazole; Mycoses

The deep mycoses are uncommon infections, usually acquired from the inhalation or ingestion of fungal spores, sometimes from the soil in areas of endemicity, such as in the Americas and south-east Asia, or from decaying vegetable matter. They are also seen in immunocompromised persons and, increasingly, in HIV-infected persons. Respiratory involvement is frequent, with granuloma formation, and mucocutaneous involvement may be seen. Oral lesions of the deep mycoses are typically chronic but non-specific, though nodular or ulcerative appearances are common. Person-to-person transmission is rare. In HIV disease, the most common orofacial involvement of deep mycoses has been in histoplasmosis, cryptococcosis, aspergillosis and zygomycosis. Diagnosis is usually confirmed by lesional biopsy although culture may also be valuable. Treatment is with amphotericin or an azole.

Topics: Acquired Immunodeficiency Syndrome; Adult; AIDS-Related Opportunistic Infections; Amphotericin B; Aspergillosis; Azoles; Cryptococcosis; Female; Histoplasmosis; HIV Infections; Humans; Lung Diseases, Fungal; Male; Middle Aged; Mouth Diseases; Mucormycosis; Mycoses; Sinusitis

The use of systemic antifungal therapy has significantly increased in recent years. Individualization of antifungal therapy through the use of serum or plasma concentrations has been suggested, although no specific recommendations have been developed. The important criteria for therapeutic drug monitoring and which of these criteria are satisfied by systemic antifungal agents are presented in this review. No one antifungal is ideally suited for application of therapeutic drug monitoring, but, under certain circumstances, obtaining serum or plasma concentrations can be justified. In patients who are susceptible to flucytosine toxicity, serum flucytosine concentrations should be monitored in an effort to avoid untoward side-effects. In contrast, therapeutic drug monitoring of amphotericin B is not recommended in the clinical setting. Demonstrating that ketoconazole and itraconazole are reaching the systemic circulation by obtaining serum concentrations may be clinically useful due to the large variability in their absorption and issues of patient compliance which may be seen with these agents. The bioavailability of fluconazole is much less varied although validation of compliance is a situation where obtaining serum concentrations may provide additional information.

Topics: Amphotericin B; Antifungal Agents; Drug Monitoring; Flucytosine; Humans; Itraconazole; Mycoses

The incidence of invasive fungal infections is increasing and new fungal species are emerging as important pathogens. In cancer patients, the main risk factor for the development of systemic fungal disease is severe, prolonged neutropenia. Other factors, such as mucosal damage, presence of a central venous line, immunosuppressive therapy and treatment with broad spectrum antibiotics are contributory. Candida spp. are the fungi most commonly isolated in neutropenic patients. There has been a dramatic increase in non-C. albicans species, such as C. glabrata and C. krusei, largely as a result of extensive prophylactic and therapeutic use of fluconazole, to which these species are largely resistant. In neutropenic patients with candidaemia, amphotericin B is the drug of choice although the conventional formulation may be poorly tolerated. Lipid-based forms of amphotericin B, such as Abelcet, are better tolerated and can be given at a much higher dose and should therefore be considered in patients who fail on or are intolerant to the conventional agent. Aspergillosis is the second most frequent fungal infection in neutropenic patients. Primary invasive aspergillosis usually presents on chest X-ray with lung lesions and the brain is a frequent site of secondary infection. Fluconazole is inactive against Aspergillus spp. and amphotericin B is the standard treatment. Again, lipid-based forms are better tolerated than the conventional formulation in this setting, and have been shown to achieve response rates of 60% or more in a number of trials. Other potentially life-threatening fungal infections in which lipid-based amphotericin B may play an important therapeutic role in the future include cryptococcosis (increasingly problematic in AIDS patients), trichosporonosis, fusariosis and mucormycosis. Further randomized studies should be performed in a range of fungal infections to compare Abelcet with conventional amphotericin B and other lipid-based antifungal agents.

Topics: Amphotericin B; Humans; Incidence; Lipids; Mycoses

Topics: Amphotericin B; Aspergillosis; Candidiasis; Child; Coccidioidomycosis; Cytokines; Diagnosis, Differential; Fluconazole; Histoplasmosis; Humans; Itraconazole; Mucormycosis; Mycoses; Prognosis

Topics: Amphotericin B; Antifungal Agents; Clinical Trials as Topic; Humans; Mycoses; Reference Standards

Three lipid formulations of amphotericin B are now either marketed for clinical use or undergoing further study before they can be approved in various countries worldwide. Amphotericin B lipid complex (ABLC; Abelcet, Liposome Company, Princeton, NJ) is a concentration of ribbonlike structures of a bilayered membrane formed by combining a 7:3 molar ratio of dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol with amphotericin B. Amphotericin B colloidal dispersion (ABCD; Amphocii, Sequus Pharmaceuticals, Menlo Park, CA) is composed of disklike structures of cholesteryl sulfate complexed with amphotericin B. AmBisome (Nexstar, San Dimas, CA), the only true liposomal amphotericin B, consists of small unilamellar vesicles made up of a bilayer membrane of hydrogenated soy phosphatidylcholine and distearoylphosphatidylglycerol stabilized with cholesterol in a 2:0.8:1 ratio combined with amphotericin B. All of the preparations appear to be preferentially accumulated in organs of the reticuloendothelial system, as opposed to the kidney. In vivo animal models as well as current clinical experience suggest that use of these formulations results in overall improvement in the therapeutic index. Patients with life-threatening mycosis for whom therapy has failed or who are intolerant to therapy with amphotericin B deoxycholate have been successfully treated with these formulations. However, further study is warranted to help clarify the usefulness of each of the lipid formulations as first-line therapy for documented or suspected invasive fungal infections.

Topics: Amphotericin B; Animals; Antifungal Agents; Chemistry, Pharmaceutical; Colloids; Drug Carriers; Fat Emulsions, Intravenous; Freeze Etching; Humans; Liposomes; Microscopy, Electron, Scanning; Models, Biological; Mycoses; Research Design

In the late 1970s the options for systemic antifungal therapy doubled with the addition of intravenous miconazole and oral ketoconazole to the two previously available agents, amphotericin B and flucytosine. The 1980s ushered in the next generation of triazole antifungals, fluconazole and itraconazole. These are the present-day mainstays of treatment for some of the most serious systemic fungal infections. However, the increase in the numbers and types of fungal pathogens, and especially the emergence of azole-resistant fungi, have prompted a continuing search for new therapeutic options. This search has yielded more-potent triazole antifungals, new vehicles for both polyenes and triazoles, and entirely new classes of agents such as the echinocandin derivatives; in addition, it has prompted the evaluation of new combinations of present-day antifungals and exploration of the use of immunomodulators for treatment of fungal infections. Rapid developments in molecular mycology are permitting a concentrated search for more targets for antifungals. We are entering a new era of antifungal therapy in which we will continue to be challenged by systemic fungal diseases but will have greatly expanded options for treatment.

Topics: Adjuvants, Immunologic; Amphotericin B; Animals; Antifungal Agents; Drug Resistance, Microbial; Drug Therapy, Combination; Humans; Meningitis, Cryptococcal; Mycology; Mycoses; Research

In summary, the recent increase in frequency of systemic fungal infections has stimulated the development of new antifungal agents which are easier to use and which have decreased toxicity. This has resulted in increase in use, and along with this, the appearance of fungi resistant to antifungal agents. The medical community will have to come to terms with this newly emerging problem.

Topics: Amphotericin B; Antifungal Agents; Candidiasis; Drug Resistance, Microbial; Fluconazole; Humans; Mycoses; Sterols

A disseminated and progressive infection, penicilliosis marneffei is the third most common opportunistic infection in human immunodeficiency virus (HIV)-infected patients in certain parts of Southeast Asia. Penicillium marneffei is endemic in Southeast Asia and the southern part of China. Cases have been reported from both Eastern and Western countries. This review discusses the history, epidemiology, mycology, clinical manifestations, diagnosis, and treatment of penicilliosis marneffei, on the basis of 155 cases of the infection. About 80% of the patients are immunocompromised. P. marneffei can infect various organs, particularly the lung, liver, and skin. The most common clinical features include fever, weight loss, and anemia. The organism has been isolated most commonly from skin, blood, and bone marrow. Immunologic identification of fungal isolates can be done with exoantigen tests and immunohistochemical methods. Treatment of disseminated penicilliosis marneffei in HIV-infected patients with parenteral amphotericin B and itraconazole is relatively effective and safe.

Topics: AIDS-Related Opportunistic Infections; Amphotericin B; Antifungal Agents; Humans; Immunocompromised Host; Itraconazole; Mycoses; Penicillium

Despite its considerable toxicity, amphotericin B (AmB) remains the 'golden standard' in the treatment of many systemic fungal infections. To reduce this toxicity, with the aim of increasing its therapeutic index, AmB can be encapsulated into liposomes or bound to lipid carriers. Following promising clinical results with investigational formulations, three industrial compounds are available at this moment: Abelcet (Amphotericin B Lipid Complex, ABLC), Amphocil (Amphotericin B Colloidal Dispersion) and AmBisome. These three formulations differ significantly in composition and pharmacokinetics. All three compounds share a considerable reduction of nephrotoxicity, but the number of acute reactions differ among these compounds, Amphocil showing the highest and AmBisome the lowest rate. Increased therapeutic indexes for all three formulations were shown only in some of the animal models for several fungal infections. Four recent clinical trials comparing these formulations with AmB demonstrated their clinical efficacy but failed to clearly show an increased therapeutic index. Therefore these compounds can be recommended in cases of intolerance to or failure on AmB therapy. The optimal therapeutic dosages have not been established, but dosages as low as 1 mg/kg should probably be avoided in the initial treatment of fulminant fungal infections, since efficacy may be inferior to equal dosages of conventional AmB.

Topics: Amphotericin B; Animals; Antifungal Agents; Drug Carriers; Humans; Liposomes; Mycoses

In summary, it is clear that in vitro susceptibility testing can predict outcome in selected clinical situations. The clearest data are from the fluconazole-treated AIDS patients with oropharyngeal candidiasis. In this setting, the homogeneity of the underlying immune defect, combined with the ease of identification and monitoring of the infection, creates a near-perfect test situation. In more complex scenarios, such as the heterogeneous population of patients enrolled in a recent study of candidemia, no such clear-cut correlation was present. The importance of host factors in the correlation of the MIC with outcome cannot be overemphasized. Examples of these parameters include patient status (underlying disease, the presence of intravascular catheters, and CD4+ T-cell number), drug pharmacokinetics (absorption and distribution), patient compliance, and drug-drug interactions. Identification of relevant factors can substantially improve the degree of the MIC-outcome correlation and thus improve the clinical utility of in vitro testing. An important feature in this entire process is the role of standardized susceptibility testing procedures. While not without flaws, the proposed NCCLS reference method has been invaluable in allowing multiple investigators to contribute data that can be used to clarify the correlation between the fluconazole MIC and outcome. While the development of simplified second-generation methods is eagerly anticipated, the role of the reference method as a common touchstone is critical. Only by use of either the reference method itself or methods with a known relationship to the reference method can this broad collaborative process really proceed. Current work is focusing on defining interpretive breakpoints for fluconazole and Candida species, refinement of the in vitro procedures used to measure susceptibility to amphotericin B, ketoconazole, and itraconazole, and the acquisition of a broad base of data on the relationship between the MIC and outcome for these three drugs. Although considerable work remains to be done, the available data suggest that solutions to each of these problems are possible and that routine susceptibility testing of fungi will become meaningful for clinical decision making in the foreseeable future.

Topics: Amphotericin B; Animals; Fluconazole; Fungi; Humans; Microbial Sensitivity Tests; Mycoses

Fungal infections have emerged as a major complication of marrow transplantation in children. Most episodes occur within the first 100 days and are often difficult to diagnose. Until recently, a limited number of therapeutic options were available but with new antifungal agents, including azole compounds and less toxic preparations of amphotericin, there is promise for improvements in the prevention of fungal infections as well as the treatment of established infections. This review will summarize the current approach towards therapeutic options available for the supportive care of children undergoing marrow transplantation.

Topics: Amphotericin B; Antifungal Agents; Bone Marrow Transplantation; Child; Clinical Trials as Topic; Fluconazole; Flucytosine; Humans; Imidazoles; Immunocompromised Host; Itraconazole; Mycoses; Neutropenia; Transplantation Conditioning; Triazoles

Topics: Amphotericin B; Antifungal Agents; Candidiasis; Flucytosine; Humans; Mycoses; Myocarditis; Prognosis

A case of disseminated invasive fusarial infection (DFI) with sinus involvement in a patient with acute myeloblastic leukaemia is reported. Amphotericin B with rifampin were administrated and wide radical sinus surgery was performed. Nevertheless, the patient died six weeks later. The four principal forms of fusarial infections in humans are discussed: toxicosis, allergic fungal sinusitis, locally invasive infection, and disseminated invasive infection. Prognosis of DFI in the immunocompromised host is usually poor, and treatment is difficult. Profound and prolonged neutropaenia appears to be the major predisposing factor. The literature on infections caused by Fusarium species in immunocompromised hosts is reviewed, especially those where the sinuses were involved.

Topics: Amphotericin B; Antifungal Agents; Fatal Outcome; Fusarium; Humans; Immunocompromised Host; Leukemia, Myeloid, Acute; Male; Middle Aged; Mycoses; Opportunistic Infections; Sinusitis

The observation of a considerable incidence of fungal infections in oncology patients has promoted a large number of studies both on prophylaxis and treatment in this patient group. Trials using triazoles, especially fluconazole, have shown effect in preventing fungal infections. In neutropenic patients, their role in therapy still remains less clear. Amphotericin B is the drug of choice for most life-threatening infections. With this drug, efforts concentrate upon the amelioration of side effects by sodium loading, administration in lipid emulsions or liposomes. The use of AMB as low-dose systemic prophylaxis or by inhalation needs further study.

Topics: Amphotericin B; Antifungal Agents; Fluconazole; Humans; Incidence; Mycoses; Neoplasms; Triazoles

We report a clinical case of severe medullary aplasia complicated by fungal antritis. The treatment adopted for this patient consists in a clean operation of the infective focus and the local instillation of Amfotericina B during the post operative period. In this way the systemic circulation is not interested by the use of Amfotericina B, which is extremely important to avoid the inevitable onset of several unwanted side-effects; besides, we avoid the progression of the infective focus and its systemic diffusion.

Topics: Adult; Amphotericin B; Aspergillosis; Aspergillus flavus; Bone Marrow Diseases; Combined Modality Therapy; Fusarium; Humans; Immunosuppression Therapy; Male; Mycoses; Opportunistic Infections; Recurrence; Sinusitis

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Bone Marrow Transplantation; Candidiasis; Clinical Trials as Topic; Disease Susceptibility; Drug Administration Routes; Hematopoietic Cell Growth Factors; Humans; Immunocompromised Host; Leukocyte Transfusion; Mycoses; Neoplasms; Neutropenia; Triazoles

Topics: Amphotericin B; Antifungal Agents; Child; Child, Preschool; Fluconazole; Humans; Itraconazole; Ketoconazole; Mycoses

Topics: Amphotericin B; Drug Resistance, Microbial; Drug Therapy, Combination; Flucytosine; Forecasting; Humans; Mycoses

Fungal prosthetic valve endocarditis is an unusual cause of endocarditis, yet very important because of its historical poor prognosis. This article will review the incidence, presentation, diagnosis, and treatment results of fungal prosthetic valve endocarditis. In addition, 11 patients at The Cleveland Clinic over the last 16 years were treated with a strategy consisting of aggressive perioperative amphotericin B therapy, radical surgical debridement of all infected tissue and prosthetic valve replacement with biological tissue when possible, as well as the chronic use of oral azole antifungal agents for suppression. This combined approach has resulted in 82% of patients being discharged and a 55% 5-year survival rate. Unfortunately, 36% of patients developed recurrent fungal prosthetic valve endocarditis, at an average of 25.8 months after their first operation for fungal prosthetic valve endocarditis. The use of oral antiazole antifungal agents for suppression may prevent the high incidence of recurrent endocarditis in this patient population.

Topics: Amphotericin B; Antifungal Agents; Azoles; Combined Modality Therapy; Endocarditis; Heart Valve Prosthesis; Humans; Mycoses; Prosthesis-Related Infections; Recurrence; Survival Rate

Topics: Amphotericin B; Animals; Antifungal Agents; Azoles; Drug Synergism; Fungi; Humans; Mycoses

The benefits of fungal prophylaxis with fluconazole in BMT patients appear to outweigh the risks of a possible increase in colonization and infection by C. krusei or T. glabrata. Disseminated fungal infections caused by C. tropicalis and C. albicans have a 38.8% mortality rate, and these infections may be prevented by the prophylactic use of fluconazole. C. krusei and T. glabrata infections generally do not contribute to increased mortality, and most patients infected by these organisms recover after appropriate antifungal therapy. The use of amphotericin B as prophylaxis may have some efficacy. One retrospective study found low-dose amphotericin B therapy to be effective in preventing Candida infections, but results from a placebo-controlled, randomized prospective trial with 0.1 mg/kg/d failed to support this claim. Low-dose amphotericin B prophylaxis (0.1-0.25 mg/kg/d) shows promise against aspergillosis, an opportunistic infection associated with high morbidity and mortality. The literature suggests the possible value of using oral or intravenous fluconazole 200-400 mg/d or intravenous amphotericin B 0.1-0.25 mg/kg/d as antifungal prophylaxis in patients after autologous or allogeneic BMT. Many questions remain unanswered, however. These studies described the potential decrease in morbidity and mortality of BMT patients with the use of either fluconazole or amphotericin B, but it is not known whether all patients after BMT or only those at high risk of fungal infection may benefit from prophylaxis. Optimal dosing of either antifungal agent has not been defined in the studies. Clinicians should be aware of the possible increase in colonization by less pathogenic fungal species, such as C. krusel and T. glabrata, when prescribing fluconazole prophylaxis.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amphotericin B; Antifungal Agents; Bone Marrow Transplantation; Fluconazole; Humans; Mycoses

In clinical medicine mere colonization with yeasts is often hardly to be discriminated from true infection. Thus, a clear-cut separation of preventive from therapeutic use of antimycotics is not possible in practical medicine. The problem is that on the one hand one has no exact diagnosis of yeast infection, but on the other hand best therapeutic results are obtained when the drugs are given as early as possible. In comparison to the huge number of antibacterial compounds, the members of antimicrobials are limited. For prophylaxis, one can use the polyenes, such as amphotericin B and nystatin, or the azoles, such as fluconazole or itraconazole. Thereby the azoles act not only locally at the site of application but are absorbed and thus are distributed to remote sites, where the non-resorbable polyenes never arrive. Among the azoles, fluconazole has the advantage that resorption is independent from an acid pH in the stomach, whereas itraconazole resorption is variable in severely ill persons with neutralized gastric fluid. For therapeutic use systemically applied amphotericin B has certain disadvantages. Because of toxic reactions an optimal dose cannot be given; furthermore in some sites insufficient concentrations are achieved, particularly in the kidney and also in the CSF. In contrast, the azoles possess better pharmacologic and toxicologic properties. Resistance to antimycotics is principally possible but still rare, so that in practice a routine testing is not necessary. Candida glabrata as well as Candida krusei are primarily resistant to fluconazole.

Topics: Amphotericin B; Antifungal Agents; Candida; Candida albicans; Candidiasis; Chemistry, Pharmaceutical; Drug Resistance, Microbial; Ergosterol; Fluconazole; Humans; Mycoses; Yeasts

Invasive fungal infection remains a major problem in transplant recipients. The commonest causes of infection are Candida, and Aspergillus spp., although a growing number of other organisms (including species of Fusarium and Trichosporon) have been reported to cause infection in neutropenic bone marrow transplant recipients. The clinical manifestations of these infections are described and methods of diagnosis are discussed. As in other groups of immunocompromised patients, the diagnosis is often difficult to establish, but transplant recipients who are given empirical treatment with amphotericin B have increased rates of survival. The roles of lipid-associated forms of amphotericin B and of the triazole compounds, itraconazole and fluconazole, in the treatment and prevention of fungal infection are discussed.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Azoles; Candidiasis; Humans; Mucormycosis; Mycoses; Postoperative Period; Risk; Transplantation

Phaeohyphomycosis due to Dactylaria (Ochroconis) spp. is a rare infection of man. It was first reported in 1986. All patients have had significant immunosuppression. To our knowledge, this is the second case of phaeohyphomycosis caused by Dactylaria constricta var. gallopava in a liver transplant patient and it developed even though he had been receiving fungal prophylaxis with fluconazole. Moreover, this case may represent nosocomial acquisition. In addition, we have reviewed the English language literature of previously reported patients with phaeohyphomycosis caused by Dactylaria spp.

Topics: Amphotericin B; Antifungal Agents; Brain Diseases; Fluconazole; Humans; Immunosuppression Therapy; Liver Transplantation; Male; Middle Aged; Mitosporic Fungi; Mycoses

Topics: Amphotericin B; Antifungal Agents; Azoles; Flucytosine; Humans; Immunocompromised Host; Mycoses; Neoplasms; Neutropenia

Topics: AIDS-Related Opportunistic Infections; Amphotericin B; Antifungal Agents; Aspergillosis; Bone Marrow Transplantation; Clinical Trials as Topic; Female; Fluconazole; Fungi; Heart Transplantation; Humans; Immunosuppression Therapy; Male; Mucormycosis; Multicenter Studies as Topic; Mycoses; Peritoneal Dialysis, Continuous Ambulatory

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Bone Marrow Transplantation; Candidiasis; Candidiasis, Chronic Mucocutaneous; Clinical Trials as Topic; Cryptococcosis; Double-Blind Method; Fluconazole; Humans; Itraconazole; Ketoconazole; Mucormycosis; Mycoses; Neutropenia; Nystatin; Primary Prevention; Recurrence; Retrospective Studies

Topics: Amphotericin B; Antifungal Agents; Clinical Trials as Topic; Fluconazole; Heart Transplantation; Humans; Itraconazole; Ketoconazole; Kidney Transplantation; Liver Transplantation; Lung Transplantation; Multicenter Studies as Topic; Mycoses; Pancreas Transplantation; Risk Factors; Transplantation

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Blastomycosis; Candidiasis; Clinical Trials as Topic; Coccidioidomycosis; Cryptococcosis; Fluconazole; Flucytosine; Hematologic Diseases; Histoplasmosis; Humans; Itraconazole; Ketoconazole; Kidney; Mycoses; Thrombophlebitis

Topics: AIDS-Related Opportunistic Infections; Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis; Candidiasis, Oral; Clinical Trials as Topic; Dermatomycoses; Esophageal Diseases; Humans; Itraconazole; Meningitis, Cryptococcal; Mycoses; Pharyngeal Diseases; Tropical Medicine

Sinonasal infection with fungi of the order Mucorales--termed mucormycosis or zygomycosis--is sometimes seen in immunosuppressed patients, including those with diabetic ketoacidosis and malignancy. We describe a case of invasive sinonasal infection with Scopulariopsis candida (not among the Mucorales organisms) in a 12-year-old girl who was being treated for non-Hodgkin's lymphoma. Only a few cases of invasive infection with Scopulariopsis species have been reported previously; five of six of these cases were associated with persistent or fatal disease. Our patient survived without undergoing radical surgical debridement and was treated with granulocyte colony-stimulating factor, amphotericin B, and itraconazole; chemotherapy was stopped. In vitro susceptibility testing of our patient's Scopulariopsis isolate showed that it was resistant to amphotericin B and that it was relatively susceptible to itraconazole and miconazole. The case described herein demonstrates the expanding spectrum of fungal organisms that may cause invasive sinonasal infection in immunocompromised hosts and the need for reliable antifungal susceptibility testing.

Topics: Amphotericin B; Child; Drug Therapy, Combination; Female; Granulocyte Colony-Stimulating Factor; Humans; Itraconazole; Lymphoma, Non-Hodgkin; Maxillary Sinus; Mitosporic Fungi; Mycoses; Paranasal Sinus Diseases

During the last years, the proportion of cancer patients who develop systemic fungal infections has increased steadily. These infections are characterised by high mortality, especially in patients with persistent granulocytopenia and in those receiving allogeneic bone marrow transplants. The most important pathogens in neutropenic patients are Candida and Aspergillus spp. Usually, Candida infections arise from overgrowth in the gastrointestinal tract, while Aspergillus infections are acquired by inhalation of spores. Prophylaxis of systemic fungal infections seems mandatory since optimal strategies for diagnosis and treatment of these infections are lacking. Treatment with the non-absorbable polyenes nystatin and amphotericin B is useful for prophylaxis of superficial fungal infections, provided that compliance of the patients is optimal. The imidazoles ketoconazole and miconazole can reduce the incidence of superficial fungal infections, but there are conflicting data regarding their value for prevention of systemic mycoses. There are several studies indicating that prophylactic use of fluconazole reduces the incidence of mucosal and systemic fungal infections, especially in patients receiving allogeneic bone marrow transplants. Fluconazole shows reduced activity against several Non-albicans spp. and is not active against Aspergillus spp. Itraconazole has in vitro and in vivo activity against several Aspergillus spp. but high serum and tissue levels are necessary. However, bioavailability of itraconazole is reduced in patients with raised gastric pH and no i.v. formulation is available. Although there is some evidence for its prophylactic activity against Aspergillus infections in neutropenic patients, more studies are necessary to confirm these findings. Intravenous amphotericin B cannot be recommended for routine prophylactic use because of its toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Bone Marrow Transplantation; Candidiasis; Fluconazole; Granulocyte Colony-Stimulating Factor; Humans; Incidence; Itraconazole; Mycoses; Neoplasms; Neutropenia; Opportunistic Infections

AmBisome is a small unilamellar liposome preparation (45-80 nm) containing amphotericin B in the bilayer. The reduced toxicity and elevated peak plasma level of AmBisome compared with amphotericin B is achieved without loss of the broad-spectrum antifungal activity of amphotericin B. Various investigators have documented its efficacy in treating systemic fungal infections. When in vitro and in vivo studies were done to elucidate the antifungal mechanism of action of AmBisome, the results showed that there was a direct interaction between AmBisome and fungi. Freeze-fracture electron microscopy, fluorescently-labeled liposomes and gold-labeled liposomes were used in these studies. Fluorescence microscopy and electron microscopy showed that AmBisome and liposomes, with the same lipid composition, but without drug, targeted to fungi in vitro. Intact liposomes of either type could be seen attached to the outer surface of the fungal cell wall within an hour after exposure to the liposomes. Only AmBisome was disrupted by this interaction resulting in death of the fungi to which the AmBisome had bound. As the fungal cells died, lipid from the AmBisome could be detected in the cytoplasm. Liposomes without drug remained intact on the surface of viable fungi for prolonged periods of time. When fluorescently-labeled liposomes with or without drug were injected into Candida-infected mice, the results showed bright fluorescence localized at the sites of fungal infection. The in vitro data suggest that only the AmBisome could kill the fungus growing in vivo and that the antifungal efficacy of AmBisome was related to its ability to target to fungi.

Topics: Amphotericin B; Animals; Candida albicans; Humans; Liposomes; Mice; Mycoses

Topics: Amphotericin B; Azoles; Drug Resistance, Microbial; Flucytosine; Fungi; Humans; Mycoses; Treatment Failure

A 68-year-old liver transplant recipient who was being treated with FK 506 and immunosuppressive steroid therapy was admitted to our medical center because of a tonic-clonic seizure. Computed tomography of the head revealed multiple discrete cerebral abscesses, and culture of fluid drained intraoperatively yielded a dematiaceous fungus. The isolate was susceptible to amphotericin B and itraconazole but was resistant to flucytosine and fluconazole. The patient was successfully treated with a prolonged course of amphotericin B colloidal dispersion and itraconazole, as evidenced by both clinical and radiographic resolution of disease over a 2-year follow-up.

Topics: Aged; Amphotericin B; Brain Abscess; Humans; Immunosuppression Therapy; Itraconazole; Liver Transplantation; Male; Mitosporic Fungi; Mycoses

Topics: Amphotericin B; Animals; Fat Emulsions, Intravenous; Female; Humans; Kidney Diseases; Male; Mycoses; Randomized Controlled Trials as Topic

We report four cases of Scedosporium inflatum (S. inflatum) infection in severely immunocompromised haematological patients. Six well-documented cases of S. inflatum disseminated infection in haematological patients have been reported: four in Australia and two in Spain. Their clinical and pathological characteristics are heterogenous, particularly in the Australian cases. However, the clinical and pathological profile emerging from our and other Spanish cases is homogenous and very similar to the clinico-pathological spectrum of other disseminated mycoses, including Aspergillus and S. apiospermum. The optimal treatment of S. inflatum infection is unknown and the outcome in haematological patients is very poor. Eight patients died despite systemic antifungal treatment.

Topics: Amphotericin B; Child, Preschool; Female; Humans; Immunocompromised Host; Leukemia; Male; Middle Aged; Multiple Myeloma; Mycoses; Opportunistic Infections; Treatment Outcome

Combination drug therapy is widely used for the management of many common medical conditions. The concurrent use of more than one drug can significantly alter the therapeutic and side-effect profile of each individual agent. Such drug-drug interactions are generally classified either as pharmacokinetic or pharmacodynamic. Oral agents used for the management of superficial fungal infections can have both types of interactions. This article describes common drug-drug interactions observed with amphotericin B, flucytosine, griseofulvin, ketoconazole, fluconazole, and itraconazole.

Topics: Amphotericin B; Antifungal Agents; Drug Interactions; Drug Synergism; Drug Therapy, Combination; Fluconazole; Flucytosine; Griseofulvin; Humans; Itraconazole; Ketoconazole; Mycoses

Effective broad spectrum antifungal therapy has been available since the introduction of amphotericin B three decades ago. Amphotericin B must be given intravenously, and thus access to the bloodstream is assured. Because of the great toxicity of this agent, initial studies were directed at determining a dose which was tolerable and clinically effective. In part because of few data and in part because of major concerns with toxicity, there is at present no established relationship with amphotericin B serum concentrations and clinical outcome, and there is no clear indication for measurement of serum concentrations of this drug. More recently there has appeared a variety of orally administered antifungal azole derivatives. Oral absorption is affected by a variety of factors, and drug access to the blood stream is not readily predictable for some of these drugs. Serum concentrations have not been consistently assessed in clinical studies. Where they have been measured, there does appear to be a loose correlation of clinical response with the detection of some amount of drug in the bloodstream. However, beyond this 'threshold' concentration, there is no compelling evidence for a correlation of serum concentration and clinical outcome. While serum concentration of azoles may be useful in determining absorption of drug, at present there is no impetus for achieving a given concentration in the blood to improve chances of a good outcome.

Topics: Administration, Oral; Amphotericin B; Antifungal Agents; Humans; Injections, Intravenous; Itraconazole; Ketoconazole; Liver; Microbial Sensitivity Tests; Mycoses; Piperazines; Risk Factors; Treatment Outcome

The unilamellar liposomal formulation of amphotericin B, AmBisome, is composed of hydrogenated soy phosphatidylcholine, distearoyl phosphatidylglycerol and cholesterol. Early studies of its efficacy in an open design showed that remissions could be induced in candidosis and aspergillosis and that doses of up to 5 mg/kg could be used. Adverse events were infrequent, with the main abnormality seen being hypokalaemia in about 18% of patients. Subsequent developments have extended this work. AmBisome has been used in two open studies of patients with invasive aspergillosis; in one of these remission was achieved in 77% of 17 patients with confirmed infection who had failed to respond to conventional amphotericin B. In AIDS patients with cryptococcosis AmBisome given for 6 weeks at 3 mg/kg daily produced mycological remission of meningitis in 67%. Other infections treated with the drug include zygomycete (mucormycosis) and Fusarium infections. AmBisome has also been used as preventative therapy in bone marrow transplant recipients and was found to reduce fungal colonisation rates. There were fewer systemic fungal infections in the treated versus placebo groups although this did not achieve statistical significance. Lack of renal and liver toxicity or anaemia has been confirmed in subsequent studies. In addition febrile reactions to the AmBisome are rare. The drug has also been used effectively in children, including infants, with systemic fungal infections. In visceral leishmaniasis patients, including HIV positive individuals, remissions have been obtained using drug regimens of 1-2 mg/kg of 2.1 days and 3 mg/kg for 10 days.

Topics: Amphotericin B; Aspergillosis; Clinical Trials as Topic; Cost-Benefit Analysis; Cryptococcosis; Drug Carriers; Humans; Liposomes; Mycoses

Numerous studies performed in the field of antifungal therapy during the last decade have resulted in major developments in new modalities of administering amphotericin B including liposomes or other lipid vehicles. Current data available are very encouraging and several preparations are already commercially available in some countries. An improved therapeutic index has been shown in humans but large comparative trials are still needed to establish the definite role and indications of the various preparations as well as the optimal therapeutic regimens. These studies will make a significant contribution to improving the prognosis of patients predisposed to life threatening invasive fungal infections.

Topics: Amphotericin B; Animals; Drug Carriers; Humans; Liposomes; Mycoses

Despite the introduction in recent years of novel antifungal agents, the potency and broad spectrum of activity of amphotericin B have ensured that it remains the treatment of choice for most deep-seated mycoses. However, this agent is not without significant toxicity, particularly in patients who are already seriously ill and/or who are receiving other potentially nephrotoxic drugs. We review the various routes by which amphotericin B can be administered, focusing mainly on the intravenous route. The use of more rapid infusion rates, lipid-complexed preparations, sodium supplementation in salt-depleted patients and strategies to reduce the incidence of infusion-related reactions and nephrotoxicity are also considered. Finally, detailed recommendations for the administration of amphotericin B are provided.

Topics: Amphotericin B; Chemistry, Pharmaceutical; Drug Administration Routes; Drug Interactions; Fungi; Humans; Infusions, Intravenous; Kidney Diseases; Mycoses

Two cases of disseminated Penicillium marneffei infection, as an imported disease, in HIV-1-infected patients with a severe immunodeficiency are reported. These patients had a history of travel in Southeast Asia where P. marneffei is endemic. Fever, cough, malaise, hepatosplenomegaly, anaemia, skin lesions and mucosal ulcers are the main clinical characteristics. Differentiation from histoplasmosis and leishmaniasis might be difficult. Treatment with amphotericin B was successful. Anti-fungal maintenance therapy is most likely indicated.. A 33-year-old, HIV-1 positive, white, homosexual man was hospitalized in May, 1991, because of fever, cough, skin eruptions, anorexia, and weight loss during the previous 2 months. In October, 1990, he had traveled in Sumatra. On examination he was ill, tachypneic, normotensive with a temperature of 39.1 degrees Celsius. The spleen was substantially enlarged. Laboratory investigations showed: ALAT 72 U/I (normal 23 U/1), LDH 508 U/1 (normal 275 U/1). A bronchoscopy with bronchoalveolar lavage revealed yeast cells. Gastroscopy showed an ulcer in the hypopharynx and an erosion in the stomach. Biopsies of this ulcer demonstrated the presence of Penicillium marneffei. Biopsies of the liver showed the same organism. The patient was treated with amphotericin B induction therapy (1 dd 0.5 mg/kg for 21 days, total dose of 730 mg) in combination with flucytosine (3 dd 2500 mg, total dose 142 g in 19 days). In the following 2 weeks the temperature became normal, and the dyspnea and the skin eruptions disappeared, except for the mollusca contagiosa. The spleen diminished by 50%. LDH and ALAT became normal. Oral maintenance therapy followed with fluconazole (the first 3 months 400 mg daily, followed by 200 mg a day). 24 months later, no recurrence had been observed. Case 2 was a 28-year-old, HIV-infected, homosexual man, born in Suriname, who was hospitalized in October, 1991, with prolonged fever, dyspnea, and a painful throat. In March, 1991, he had traveled in rural Thailand. AIDS was diagnosed on the basis of cerebral toxoplasmosis in August, 1991. A biopsy of the ulcer in the oropharynx showed an active aspecific inflammation and also P. marneffei. Treatment with amphotericin B intravenously (0.5 mg/kg, total dose 1052 mg in 32 days) was commenced. The lesions in the oral cavity and throat, the lymph nodes, and the shortness of breath disappeared within a few days. Ten months later he died from emaciation caused by cryptosporidiosis.

Topics: Adult; AIDS-Related Opportunistic Infections; Amphotericin B; Asia, Southeastern; Diagnosis, Differential; Fatal Outcome; Fluconazole; HIV-1; Humans; Male; Mycoses; Netherlands; Penicillium; Travel

Fungal infections have become an important cause of mortality in patients with hematological malignancies. In recent years, fungi such as Candida tropicalis, Aspergillus spp, Fusarium spp and Trichosporon spp have emerged as important pathogens. Amphotericin B remains the antifungal agent with the broadest spectrum of activity, although some of the newer pathogens may be resistant. The administration of this drug in lipid vehicles reduces the toxicities, permitting the administration of higher doses that may be more effective. The new agents, fluconazole and itraconazole, have activity against some fungal pathogens, although their role in therapy has not been fully determined. Fluconazole has been shown to be effective for prophylaxis of Candida infections.

Topics: Amphotericin B; Drug Resistance, Microbial; Humans; Leukemia; Mycoses

Neutropenic patients are at high risk of developing invasive fungal diseases. A number of studies, both randomized and historical, have demonstrated that empiric therapy with amphotericin B in neutropenic patients with fever, refractory to antibiotics, results in a decrease in the frequency and mortality of deep fungal infections. Recent years have seen a number of advances in the management of neutropenic patients. Reasonably effective antifungal prophylaxis now exists and in many centres forms part of the routine care of neutropenic patients. Other centres advocate the use of selective decontamination and/or protective isolation. Furthermore the duration of neutropenia can be reduced with the use of haematopoetic growth factors. The impact of empiric amphotericin B in patients already benefiting from such treatments has not been adequately studied. The optimum dose of empiric amphotericin B is not defined. The criteria for commencing amphotericin B therapy in febrile neutropenic patients must therefore be redefined on the basis of further studies carried out in the context of these developments. We offer an approach to the use of empiric amphotericin B based on risk factors and prophylaxis.

Topics: Amphotericin B; Bone Marrow Transplantation; Clinical Trials as Topic; Fever of Unknown Origin; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immunologic Factors; Leukemia; Multicenter Studies as Topic; Mycoses; Neutropenia; Patient Isolation; Randomized Controlled Trials as Topic; Risk

Fever is associated with malignancy and is a common problem in cancer patients. Fever in the cancer patients is closely linked with infection, especially when the patient is granulocytopenic. When fever appears, a series of diagnostic and therapeutic measures must be taken even if precise knowledge of the cause of the infection is lacking. Fever can be caused by infection or by the cancer itself through tumor-related necrosis, hemorrhage or pyrogens. Infection is the more common cause, however. Bacterial and fungal sepsis can coexist and the bacteremia can overshadow the more difficult to determine fungal infection. For this reason it has become accepted practice to administer amphotericin B to granulocytopenic patients who remain febrile after a few days of broad-spectrum antimicrobial therapy and in whom no bacteria can be documented. Viral infection is rarely diagnosed in neutropenic patients without concomitant immunosuppression.

Topics: Amikacin; Amphotericin B; Bacteremia; Bacterial Infections; Ceftazidime; Clinical Trials as Topic; Drug Therapy, Combination; Fever; Fever of Unknown Origin; Humans; Mycoses; Neoplasms; Neutropenia; Vancomycin; Virus Diseases

Fungal infections continue to cause major complications in cancer patients. With the increasing use of aggressive chemotherapy causing prolonged granulocytopenia, and the progress made in the prophylaxis and treatment of bacterial infections, the risk of invasive mycoses has increased, particularly in patients with hematological malignancies. The prognosis of these infections is poor unless they are diagnosed and treated promptly. Early diagnosis, particularly in neutropenic cancer patients, is often difficult and antifungal therapy is frequently unsuccessful because it is not instituted until the infection is in an advanced, fatal phase. In order to reduce the mortality associated with invasive fungal infections, antifungal therapy, usually amphotericin B, has been empirically carried out in neutropenic patients with fever unresponsive to broad-spectrum antibacterial therapy. However, the absence of a marker of the fungal infection, the frequent occurrence in these patients of non-infective fever, which does not require any antimicrobial therapy, and the possible toxicity of amphotericin B represent the major limits of empiric antifungal therapy. In view of the above, the study of improved and less toxic antifungal agents, and the evaluation of new clinical and laboratory methods for an early diagnosis, have been the major goals in research on the opportunistic invasive fungal infections in the last years.

Topics: Amphotericin B; Aspergillosis; Fluconazole; Humans; Itraconazole; Lung Diseases, Fungal; Mycoses; Neoplasms; Serologic Tests; Tomography, X-Ray Computed; Ultrasonography

Invasive fungal sinusitis is becoming increasingly common in patients undergoing BMT. This study was undertaken to evaluate the incidence, presenting symptoms, diagnosis procedures, treatment and outcome of invasive fungal sinusitis. The study population comprised 423 consecutive BMT patients at Hadassah University Hospital from January 1986 to August 1992. Eleven patients (2.6%) developed invasive fungal sinusitis, 8 had underlying hematologic malignancies and 3 severe aplastic anemia (SAA). Median interval between BMT and fungal sinusitis was 22.5 days (range 2-106 days). Eight of 11 patients had protracted neutropenia (median 8 days with median neutrophil count at the time of fungal sinusitis diagnosis of 0.25 x 10(9)/l). Four patients developed GVHD before fungal sinusitis was diagnosed. Presenting symptoms were fever (100%), orbital swelling (63%), facial pain (54%) and nasal congestion (36%). In 8 patients Aspergillus species were isolated (A. flavus in 7, A. quadrilineatus in 1); in 1 patient Candida albicans was isolated and in the other 2 fungal elements were detected histologically (Fusarium and Mucor, respectively). Six of the patients underwent surgical debridement at diagnosis. Three received granulocyte transfusions. All patients received systemic amphotericin B (7 conventional and 4 amphotericin B colloidal dispersion (ABCD)). Only 2 of the 11 patients responded completely to therapy with a follow-up of 15 months. It appears that invasive fungal sinusitis is a potentially fatal complication in immunocompromised patients post-BMT. Current treatment approaches are largely ineffective and new methods of management of this serious problem are needed.

Topics: Adolescent; Adult; Amphotericin B; Anemia, Aplastic; Bone Marrow Purging; Bone Marrow Transplantation; Child; Child, Preschool; Cohort Studies; Combined Modality Therapy; Debridement; Drainage; Female; Follow-Up Studies; Graft vs Host Disease; Granulocytes; Humans; Immunocompromised Host; Incidence; Infant; Leukemia; Leukocyte Transfusion; Lymphoma; Male; Middle Aged; Mitosporic Fungi; Mycoses; Neutropenia; Sinusitis; Survival Rate; Treatment Outcome

Fungal infections continue to be a major problem in the management of immunocompromised patients. Despite its formidable toxicity and treatment failures, amphotericin B is still the drug of choice for most of these infections. One strategy for reducing the toxicity of amphotericin B and thus permitting administration of higher doses is that of using less toxic formulations. Entrapping amphotericin B into liposomes or binding it to other substances reduces its toxicity to host cells, whereas the selective binding of amphotericin B to ergosterol preserves its toxicity to fungal cells. Adding fungus-specific antibodies to such liposomes may further increase the efficiency of drug targeting. The initial unpublished data from controlled clinical trials of various liposomal preparations of amphotericin B are less encouraging than anticipated, but additional trials are needed for a proper evaluation. Another strategy for improving efficacy of amphotericin B is that of bringing it directly into contact with the body sites most likely to be infected. Intranasal delivery of amphotericin B for prevention of invasive aspergillosis has been evaluated in at least three different clinical trials with conflicting results; no controlled trials are available. Prophylactic administration of low doses of amphotericin B as an aerosol was the most effective of the regimens tested in an animal model of pulmonary aspergillosis and was also judged to be effective in a clinical trial using historical controls. Independent of the route of administration, in both an animal model was various clinical studies, early administration of amphotericin B was more effective than late administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Intranasal; Aerosols; Amphotericin B; Animals; Aspergillosis; Dosage Forms; Humans; Immunocompromised Host; Mycoses; Time Factors

Topics: Amphotericin B; Animals; Drug Carriers; Humans; Liposomes; Mycoses

Topics: Amphotericin B; Anti-Bacterial Agents; Bacterial Infections; Ganciclovir; Humans; Immunocompromised Host; Mycoses; Pneumonia; Pneumonia, Pneumocystis; Pneumonia, Viral; Trimethoprim, Sulfamethoxazole Drug Combination

Fusariosis, a rare infectious disease of the immunocompromised host, is relatively resistant to amphotericin B (AmB) or other antifungal agents. We describe a 5-year follow-up of a 40 year old woman with T-type acute lymphoblastic leukemia who following chemotherapy developed prolonged high fever, chills, night sweats, and severe weakness. Liver function tests were impaired and abdominal computerized tomography (CT) showed multiple lesions in the liver and abnormal structure of the spleen. A laparotomy revealed multiple granulomas containing Fusarium sp. in the liver, and the spleen was heavily infiltrated by the same fungus. The patient failed to respond to the conventional AmB dosage form (Fungizone) even after a total dose of 3.0 g was given, and developed significant renal impairment. AmB was complexed (in a mole ratio of 1:16) with a mixture of the phospholipids dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol (mixed in 7:3 mole ratio). The resulting drug complex, AmB-PLC, was then administered (1-4 mg/kg/day, total dose 4.2 g) and subsequently the patient was cured of all symptoms of fusariosis. There were only mild side effects and no nephrotoxicity was evident. On the contrary, marked improvement of the renal function tests occurred during AmB-PLC treatment. Eight months later, she developed a spinal lesion with dense consistency in L5 and S1, and after receiving another course of AmB-PLC (3.1 g) she recovered completely. In a 2 year follow-up period the patient had no further relapse of the fungal disease. Subsequent chemotherapy given for relapse of the leukemia was followed by a new fungal infection, which was treated with AmB-cholesteryl sulfate complex (Amphocil).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Amphotericin B; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Daunorubicin; Dimyristoylphosphatidylcholine; Drug Carriers; Female; Follow-Up Studies; Fusarium; Granuloma; Hepatitis; Humans; Immunocompromised Host; Kidney Diseases; Leukemia-Lymphoma, Adult T-Cell; Mycoses; Neutropenia; Phosphatidylglycerols; Prednisone; Recurrence; Splenic Diseases; Vincristine

We report on an HIV positive patient with a disseminated Penicillium marneffei infection. A 35-year-old Swiss homosexual male with HIV-associated immunodeficiency with a CD4 cell count of 90/mm3 presented with a two-month history of malaise, intermittent fever, loss of weight, unproductive cough and widespread molluscum contagiosum-like skin lesions, mainly on the face. The patient had travelled extensively and had last visited Thailand 19 months before admission. The chest X-ray showed bilateral diffuse reticulonodular markings. The diagnosis was suspected in bronchoalveolar lavage, which showed round-to-oval intracellular yeast cells but also elongated sausage-shaped extracellular forms. The diagnosis was confirmed on culture. Penicillium marneffei was further isolated from the following specimens: blood cultures, bone marrow, stool, skin and tracheal mucosa biopsy. Intravenous amphotericin B therapy led to a complete subsidence of all symptoms and the skin lesions healed without leaving a scar. The infection, with its clinical presentation, epidemiology, diagnostic problems and therapy is reviewed. We stress that since Penicillium marneffei is an increasingly important pathogen in HIV positive patients in Southeast Asia, this fungus can also be imported to Europe by travellers. If immunocompromised patients have molluscum contagiosum-like skin lesions, pneumonitis and a history of travelling in Southeast Asia, disseminated Penicillium marneffei infection should be considered in differential diagnosis.

Topics: Adult; AIDS-Related Opportunistic Infections; Amphotericin B; Humans; Male; Mycoses; Penicillium

A number of substances that directly or indirectly affect the cell walls of fungi have been identified. Those that actively interfere with the synthesis or degradation of polysaccharide components share the property of being produced by soil microbes as secondary metabolites. Compounds specifically interfering with chitin or beta-glucan synthesis have proven effective in studies of preclinical models of mycoses, though they appear to have a restricted spectrum of coverage. Semisynthetic derivatives of some of the natural products have offered improvements in activity, toxicology, or pharmacokinetic behavior. Compounds which act on the cell wall indirectly or by a secondary mechanism of action, such as the azoles, act against diverse fungi but are usually fungistatic in nature. Overall, these compounds are attractive candidates for further development.

Topics: Aminoglycosides; Amphotericin B; Animals; Anthracyclines; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Cell Wall; Chitin; Echinocandins; Fungal Proteins; Fungi; Glucans; Mice; Mycoses; Peptides; Peptides, Cyclic; Pyrimidine Nucleosides

Topics: Amphotericin B; Antifungal Agents; Cell Wall; Coccidioidomycosis; Fungi; Histoplasmosis; Humans; Meningitis, Cryptococcal; Mycoses

An 8-year-old boy who had chronic granulomatous disease developed a soft tissue infection of the right heel after riding on a motor scooter. Infection was insidious, and minor heel pain and fevers occurred only on the day interferon-gamma was injected. Soft tissue biopsy showed hyphal elements, and Paecilomyces varioti grew in culture. The infection was treated with amphotericin B for 7 weeks (total dose, 40 mg/kg) followed by 1 year of therapy with itraconazole (100 mg twice daily). Complete cure was achieved during the follow-up period of 10 months.

Topics: Amphotericin B; Antifungal Agents; Child; Drug Therapy, Combination; Follow-Up Studies; Granulomatous Disease, Chronic; Heel; Humans; Interferon-gamma; Itraconazole; Ketoconazole; Male; Mycoses; Paecilomyces; Treatment Outcome

Among the opportunistic infections in patients with leukemias systemic fungal infections contribute a major part if not the majority. This results from autopsy data and is supported clinically when using new criteria by imaging techniques, while microbiological documentation shows a low sensitivity in this situation. Those lessons require a change in strategy toward an earlier and empiric use of systemic antifungal drugs in the frequent infections appearing as fever of unknown origin. By its high systemic activity and low toxicity Fluconazole facilitates this approach. Amphotericin B with 5-Flucytosine remain as the most established standard. Liposomal Amphotericin B allowing higher dosage by lower toxicity appears effective as salvage treatment especially in aspergillosis which also responds to Itraconazole available as oral formulation so far.

Topics: Amphotericin B; Antifungal Agents; Drug Therapy, Combination; Fluconazole; Flucytosine; Humans; Itraconazole; Ketoconazole; Leukemia; Mycoses; Tomography, X-Ray Computed

Systemic antifungal agents express great diversity in their pharmacokinetic profiles, mechanisms of action, and toxicities. Understanding the diverse pharmacokinetic properties of systemic antifungals is critical to their appropriate application. Amphotericin B, drug of choice for most invasive mycoses, has unique pharmacokinetic properties, binding initially to serum lipoproteins and redistributing from blood to tissues. Dosing recommendations are based on the specific infection and the status of the host. Lipid formulations of amphotericin B may be able to attenuate some of its toxicities. Flucytosine is a water-soluble, fluorinated pyrimidine that possesses excellent bioavailability. It is administered only in combination with amphotericin B because of frequent development of secondary drug resistance, and is associated with dose-dependent bone marrow suppression. The antifungal azoles are relatively well tolerated, have broad spectrum antifungal activity, and are fungistatic in vitro. Ketoconazole and itraconazole are highly bound to plasma proteins, are extensively metabolised by the liver, and are relatively insoluble in aqueous solution. By comparison, fluconazole is only weakly bound to serum proteins, is relatively stable to metabolic conversion, and is water soluble. Fluconazole penetrates the cerebrospinal fluid well and is approved for primary and suppressive therapy of cryptococcal meningitis in AIDS patients. The echinocandins have a narrow spectrum of antifungal activity, being effective only against Candida spp.

Topics: Amphotericin B; Antifungal Agents; Azoles; Drug Resistance, Microbial; Drugs, Investigational; Flucytosine; Fungi; Humans; Mycoses

A 76-year-old male with chief complaints of back and right leg sciatica was hospitalized. His abdominal CT scan revealed lumber spondylitic stenosis. A laminectomy was performed. Postoperatively, he became febrile, aphasic and had grand mal seizure. A left craniotomy of the front abscess, seen in the CT scan, was performed. H and E stained smears of drainage revealed dematiaceous, septate hyphae. Cultures of the abscess drainage grew an olivaceous-grey fungus. Based on macro- and micro-morphological characters, growth at 42 degrees C, and exoantigenic analysis, the patient's fungus was identified as Xylohypha bantiana. Treatment with amphotericin B and 5-fluorocytosine was initiated. Despite surgical procedures and antifungal therapy, the patient's condition deteriorated and he died a few weeks later due to cerebral edema. The case reported here is the first microscopically, culturally, histopathologically and exoantigenically proven case of phaeohyphomycosis caused by X. bantiana in the province of Alberta and from Canada. A review of the literature on cases of X. bantiana infections has also been presented.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antibodies, Fungal; Brain Abscess; Child; Cladosporium; Female; Flucytosine; Humans; Male; Middle Aged; Mycoses; Tomography, X-Ray Computed

Phaeohyphomycosis caused by Exophiala species is an unusual infection, but it has been reported with increasing frequency as immunosuppressive therapy has become more widespread and laboratory methods for diagnosis have improved. To our knowledge, the first case of subcutaneous phaeohyphomycosis due to Exophiala jeanselmei in a cardiac transplant patient is presented, and previously reported cases of exophiala infection are reviewed. This patient was successfully managed with surgical excision of the lesion and combination therapy with amphotericin B and 5-fluorocytosine.

Topics: Adult; Amphotericin B; Combined Modality Therapy; Drug Administration Schedule; Drug Therapy, Combination; Exophiala; Flucytosine; Heart Transplantation; Humans; Immunosuppression Therapy; Male; Mycoses; Opportunistic Infections

Flucytosine is an antifungal agent useful in combination with amphotericin B in the treatment of several deeply invasive mycoses. The potentially dose-limiting, hematologic, gastrointestinal, and hepatic toxicities of flucytosine lead to a reluctance to use it in myelosuppressed patients. To investigate the safety and tolerability of flucytosine in this setting, we evaluated its use in 17 patients with cancer or aplastic anemia during a 2 1/2-year period at our institution and reviewed the literature describing mechanisms of action, resistance, in vitro and in vivo antifungal activity, clinical antifungal activity, pharmacokinetics, and toxicity. The combination of amphotericin B plus flucytosine eradicated the mycosis in 12 (71%) of 17 patients, whereas 3 (18%) of 17 died of progressive fungal infection. Serial serum levels of flucytosine measured by a creatinine iminohydrolase assay permitted reliable dosage adjustment. During therapy, only 2 (12%) of 17 patients had elevated mean serum levels of flucytosine (> 100 micrograms/mL) and 3 (18%) other patients had transiently elevated levels. Paired serum samples (n = 45) obtained at steady state during therapy with orally administered flucytosine showed similar peak and trough levels. Adverse effects of flucytosine therapy included one case each of reversible nausea, diarrhea, elevated transaminase levels, and thrombocytopenia. No cases of bone marrow aplasia, enterocolitis, hepatitis, or death due to flucytosine toxicity were encountered. We conclude that flucytosine in combination with amphotericin B is well tolerated in myelosuppressed patients when serum flucytosine levels are serially monitored.

Topics: Adolescent; Adult; Amphotericin B; Child, Preschool; Drug Therapy, Combination; Female; Flucytosine; Humans; Immunocompromised Host; Male; Middle Aged; Mycoses

Since 1955, when amphotericin B was introduced into clinical therapy, a lore has grown up surrounding its use that often lacks evidential basis. Matters such as rate of intravenous injection, periodicity of administration, dosage, and the monitoring of therapy should not be shrouded in a mystique that is passed on from one generation of house officers to another. Factual rationalization of the use of amphotericin B should be pursued and is attempted in this article.

Topics: Amphotericin B; Anemia; Heart; Humans; Kidney; Molecular Structure; Mycoses; Nervous System

Systemic antifungal chemotherapy frequently is more difficult to conduct than antibacterial therapy. Factors that make it difficult include, but are not limited to, common biosynthetic pathways among the eukaryotes and humans, a relative lack of agents, imprecise modes of use, general lack of standardization of in vitro susceptibility tests that have clinical correlations, and, with certain exceptions, lack of clinical correlations with in vitro results of combination antifungal chemotherapy. Amphotericin B has been available for intravenous administration for greater than 30 years and, despite its shortcomings, remains the drug of choice or reference agent in the therapy for many specific systemic fungal infections in various clinical settings. The current role of amphotericin B therapy in these situations and the need for additional controlled, comparative clinical trials with azoles, liposomal amphotericin B, and amphotericin B complex are discussed.

Topics: Amphotericin B; Candidiasis; Cryptococcosis; Drug Resistance, Microbial; Humans; Infusions, Intravenous; Mycoses

The increased use of immunosuppressive regimens in organ transplantation and in the treatment of malignant lesions and the epidemic of acquired immunodeficiency syndrome (AIDS) are major reasons for the greater prevalence of fungal infections seen in clinical practice during the past decade. The traditional cornerstone of antifungal treatment, amphotericin B, continues to play a major role in deep-seated mycotic infections. The indications for intravenously administered miconazole have become limited. Orally administered flucytosine remains useful in certain infections, particularly cryptococcal meningitis. The new orally administered antifungal agents ketoconazole and fluconazole have been approved for clinical use and have supplanted amphotericin B in certain situations. Investigational antifungal agents, including liposomal amphotericin B, itraconazole, and saperconazole, hold promise for the future. Active investigation in the development of new antifungal agents is expected to continue.

Topics: Amphotericin B; Antifungal Agents; Flucytosine; Humans; Imidazoles; Mycoses; Thromboxane-A Synthase; Triazoles

Topics: Amphotericin B; Animals; Antifungal Agents; Flucytosine; Humans; In Vitro Techniques; Itraconazole; Ketoconazole; Miconazole; Mycoses; Rabbits

Topics: Adult; Amphotericin B; Antifungal Agents; Chromatography, High Pressure Liquid; Drug Resistance; Drug Therapy, Combination; Fluconazole; Flucytosine; Humans; Immunodiffusion; Itraconazole; Ketoconazole; Microbial Sensitivity Tests; Mycoses

Amphotericin B has a broad spectrum of action that includes most of the major fungal pathogens of man. This drug binds to the membrane sterols of fungal cells, causing impairment of their barrier function and loss of cell constituents. Metabolic disruption and cell death are consequent upon membrane alterations. Investigations of the sterol content of mutant strains of Candida albicans and Cryptococcus neoformans has demonstrated that resistance is often associated with alterations in membrane sterol composition. Treatment failure due to the development of amphotericin B resistance is an uncommon problem. It has tended to occur in patients receiving treatment with cytotoxic drugs. Interactions between amphotericin B and a number of other antimicrobial drugs have been observed in tests in vitro and in vivo. However, apart from one report that the combination with flucytosine is superior to amphotericin B on its own in the treatment of cryptococcal meningitis, there have been no controlled trials to support the use of drug combinations in human infections.

Topics: Amphotericin B; Animals; Humans; Mycoses

118 episodes of fungemia occurring at Rigshospitalet, Copenhagen, between 1984 and 1988 were reviewed retrospectively. Underlying diseases in the patients were dominated by malignancies, primarily hematological disorders, and intraabdominal diseases requiring major abdominal surgery. Predisposing factors identified in the patients were ongoing antibacterial chemotherapy (83%), central venous catheters (72%), major abdominal surgery (39%), and neutropenia (32%). 120 fungal strains were isolated, of which 88 (73%) were Candida albicans, 23 strains representing 8 other Candida species were also isolated, as were 9 strains belonging to 7 other fungal genera. There were only 5 strains resistant to 5-fluorocytosine (MICs greater than or equal to 25 mg/l), and no strain was resistant to amphotericin B. Treatment with antifungal agents was given in 78 patients, generally a combination of amphotericin B and 5-fluorocytosine. In 14 patients (all non-hematological) the only treatment was removal of a permanent central venous catheter. The outcome was poor in patients with hematological disorders (mortality 76%), whereas patients with malignant and non-malignant intraabdominal diseases had a mortality of 35%. All patients with a permanent central venous catheter as the only risk factor recovered rapidly after removal of the catheter.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Candida albicans; Candidiasis; Child; Child, Preschool; Female; Flucytosine; Hospitals, University; Humans; Infant; Infant, Newborn; Male; Middle Aged; Mycoses; Retrospective Studies; Risk Factors

Topics: Amphotericin B; Antifungal Agents; Humans; Mycoses

The first oral agents for treatment of mycoses included potassium iodide, griseofulvin and flucytosine. While each is still used in specific indications, the advent of ketoconazole in the late 1980s radically expanded the spectrum and efficacy of oral antifungals. Ketoconazole was the first drug sufficiently potent and benign to permit use for both superficial and deep fungal infections. Ketoconazole quickly proved highly effective in many systemic and cutaneous infections, but it was soon appreciated that high doses caused impairment of testosterone and ultimately cortisol synthesis. Dose-dependent nausea and vomiting also became apparent, as did the necessity for very high doses for treatment of fungal meningitis. Hepatic cellular toxicity was also noticed, particularly after prolonged treatment at high doses. Just as these limitations became apparent, Janssen, Pfizer and, most recently, Schering brought forth the triazole antifungals. These differ markedly in pharmacokinetics and fungal spectrum, requiring careful consideration of the appropriate drug. In addition to the above, terbinafine has been recently developed for dermatophytes, particularly refractory onychomycoses.

Topics: Amphotericin B; Antifungal Agents; Fluconazole; Humans; Itraconazole; Ketoconazole; Mycoses; Naphthalenes; Terbinafine; Triazoles

Invasive fungal infections are common in immunocompromised patients. Early diagnosis is still difficult and prophylactic modalities seems mandatory but are yet to be defined. Standard therapy of invasive fungal infections relies on the administration of intravenous amphotericin B. This agent is difficult to administer and toxic. Recently, new antifungal agents have been developed and are currently under investigation. Those new agents included itraconazole and fluconazole as well as new galenic preparations of amphotericin B such as liposomes. All these studies should provide optimal management of invasive fungal infections and improve the prognosis of those patients.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis; Cryptococcosis; Fluconazole; Humans; Itraconazole; Ketoconazole; Mycoses

Amphotericin B (Fungizone) remains the cornerstone of antifungal therapy because of its broad-spectrum fungicidal activity and rapid onset of action. Ketoconazole (Nizoral) and the new triazoles are welcome additions to the therapeutic armamentarium but do not replace amphotericin B. Adverse side effects of amphotericin B treatment are usually manageable and often preventable. Careful attention to detail reduces immediate toxicity and allows completion of the desired therapeutic course without an undue risk of permanent nephrotoxicity.

Topics: Acquired Immunodeficiency Syndrome; Amphotericin B; Humans; Ketoconazole; Mycoses; Risk Factors

Topics: Acquired Immunodeficiency Syndrome; Amphotericin B; Female; Genital Diseases, Female; Genital Diseases, Male; Humans; Male; Mycoses; Urologic Diseases

Antibacterial therapy in chronic granulomatous disease requires antimicrobials active on Staphylococcus aureus and enterobacteria, which also have a good intracellular penetration and activity as rifampicin, fluoroquinolone, fosfomycin, cotrimoxazole. Several trials showed that cotrimoxazole was effective for the prevention of bacterial infection: thus, this antimicrobial can be used as long-term and continuous prophylaxia. Fungal infections require the use of amphotericin B. The place of new imidazole compounds as itraconazole should be assessed.

Topics: Amphotericin B; Anti-Bacterial Agents; Anti-Infective Agents; Bacterial Infections; Drug Combinations; Granulomatous Disease, Chronic; Humans; Mycoses; Premedication; Sulfamethoxazole; Trimethoprim

Because deep opportunistic mycoses are relatively rare, clinicians frequently lack routine in the application of antimycotics. It is the purpose of this review to summarize, from a practical point of view, rationale, indications, applications and toxicity of antimycotic therapy for the mycoses autochthonous to Europe. Amphotericin B remains the standard therapy for most deep opportunistic mycoses, while the newer azoles are the first line agents to be used for superficial forms of candidiasis.

Topics: Amphotericin B; Antifungal Agents; Azoles; Drug Therapy, Combination; Humans; Mycoses; Opportunistic Infections

Topics: Amphotericin B; Aspergillosis; Candidiasis; Cryptococcosis; Drug Synergism; Drug Therapy, Combination; Flucytosine; Humans; Mycoses; Prospective Studies; Rifampin

We report the first know case of disseminated fungal infection due to Fusarium proliferatum in a bone marrow transplant recipient to our knowledge. Fusarium was cultured from the blood, a paranasal sinus, and necrotic skin lesions. The isolate was sensitive to amphotericin B and on further sensitivity testing, synergy was demonstrated using rifampin in combination with amphotericin B. The patient had this infection while she was receiving alternate-day amphotericin, rifampin, and 5-flucytosine (5-FC) therapy. The infection was documented within 48 h of discontinuing daily granulocyte transfusions, which she had received for 3 weeks. The 5-FC was discontinued when sensitivities showed the organism resistant. After 6 weeks of treatment she showed complete remission of the infection, although neutrophil counts remained below 0.25 X 10(9)/L. From this case and from a review of the literature, it appears that synergic antifungal agents combined with leukocyte transfusions may be beneficial in the successful treatment of fusariosis in the compromised host.

Topics: Amphotericin B; Antineoplastic Combined Chemotherapy Protocols; Aspergillosis; Bone Marrow Transplantation; Child, Preschool; Combined Modality Therapy; Female; Fusarium; Humans; Mycoses; Neutropenia; Opportunistic Infections; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Rifampin; Skin; Spider Bites; Staphylococcal Infections

Persistent fever that is refractory to broad-spectrum antibacterials is common in neutropenic patients undergoing induction chemotherapy of acute leukemia. Clinical experience suggests that many of these patients are infected with fungi. Until recently, data supporting the role of empiric antifungal therapy in this setting were limited to small groups of patients or postmortem reports. Evolving evidence in larger patient populations supports data from smaller series: febrile neutropenic patients who have failed to respond to a 4- to 7-day course of broad-spectrum antibacterials may benefit from the early initiation of antifungal therapy. Patients with fungal colonization or pulmonary infiltrates and adult patients who have not received previous fungal prophylaxis may especially benefit from the early use of antifungal drugs. Amphotericin B has been the "gold standard" for empiric antifungal therapy, although the newer azoles may be useful in certain situations.

Topics: Acute Disease; Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Antineoplastic Agents; Bacterial Infections; Clinical Trials as Topic; Fever; Humans; Leukemia; Mycoses; Neutropenia; Remission Induction

Topics: Adult; Amphotericin B; Antifungal Agents; Drug Therapy, Combination; Humans; Immunosuppression Therapy; Itraconazole; Ketoconazole; Male; Mitosporic Fungi; Mycoses; Paranasal Sinus Diseases

Pythium infection (pythiosis) in humans has not previously been described, even in areas endemic for animal pythiosis. We report five patients with a unique presentation of fungal arteritis. The medium- to large-sized arteries were involved, and in some cases this involvement led to gangrene of the limbs, aneurysm formation, and ultimately fatal arterial leakage. All five patients were farmers. All patients, with the possible exception of one who had hemoglobin typing performed after receiving a blood transfusion, had thalassemia hemoglobinopathy syndrome. Fungal isolation was difficult. Amphotericin B treatment seemed to be ineffective. Radical surgical removal of infected tissues and oral administration of a saturated solution of potassium iodide are proposed therapy. In the tropics, where Pythium is ubiquitous, one should actively look for this fungal infection in patients with unexplained arterial occlusion, especially in the case of patients with thalassemia hemoglobinopathy syndrome.

Topics: Amphotericin B; Chytridiomycota; Female; Humans; Middle Aged; Mycoses; Pythium; Syndrome; Thalassemia

Topics: Amphotericin B; Antifungal Agents; Flucytosine; Humans; Imidazoles; Mycoses

Topics: Amphotericin B; Drug Resistance, Microbial; Humans; Mycoses; Vascular Diseases

Disseminated trichosporonosis due to Trichosporon beigelii is an uncommon but increasingly reported infection in immunocompromised patients. It often presents as fungemia, cutaneous lesions, pulmonary infiltrates, and azotemia. This systemic mycosis is often refractory to conventional antifungal therapy and is frequently fatal.

Topics: Amphotericin B; Antifungal Agents; Humans; Immune Tolerance; Mycoses; Opportunistic Infections; Trichosporon

Case 1. A 34-year-old male was admitted in July, 1986 with a diagnosis of AML (M2). Two courses of BHAC-DMP regimen induced complete remission in October, while marked pyrexia resistant to antibiotics remained. An ultrasonography (US) and computed tomography (CT) revealed multiple liver and spleen abscesses suspected of mycotic etiology. Administration of amphotericin B (AMPH-B) by intravenous injection was difficult owing to its severe side effect. Multiple abscesses increased in the size and number despite treatment with Miconazole (MCZ) and Ketoconazole. Exploratory laparotomy was performed with splenectomy, and splenic specimens were found to contain Candida organisms. Soon AMPH-B was administered through a catheter inserted into the portal vein at the same time. A side effect by AMPH-B was tolerable and his fever resolved to normal in 2 weeks after institution of this therapy, and the sizes of abscesses were markedly reduced. The patient remained in remission through 23 months, free of fungal infection. Case 2. A 23-year-old female was admitted for relapse of ALL (L2), in April, 1987. Reinduction therapy with BHAC-L-AVP achieved again in May but fever unresponsive to antibiotics occurred. Since multiple liver-spleen abscesses were showed by US and CT suspected mycotic etiology, antimycotic therapy with Miconazole and AMPH-B was performed but clinical findings were deteriorated. AMPH-B was administered through a catheter inserted into the hepatic artery for two weeks, following into the splenic artery for a week. Splenic abscesses were resolved in a week and liver abscesses were markedly reduced at three weeks after initiation of intra-arterial antifungal treatment. Through the analysis of these case studies we confirmed the usefulness of intraportal and intrahepatosplenic arterial administration of AMPH-B.

Topics: Abscess; Acute Disease; Adult; Amphotericin B; Catheters, Indwelling; Female; Hepatic Artery; Humans; Leukemia; Liver Abscess; Male; Mycoses; Portal Vein; Splenic Artery; Splenic Diseases

Topics: Amphotericin B; Anti-Infective Agents; Drug Carriers; Humans; Infections; Liposomes; Mycoses

Topics: Amphotericin B; Animals; Fever; Humans; Kidney Diseases; Liposomes; Mycoses

Fungal infections of the upper extremity are of four main types: cutaneous, subcutaneous, deep, and systemic. Cutaneous infections are caused by organisms capable of utilizing keratin. They involve skin and nails. Most respond to local therapy. Subcutaneous infections are caused most typically by Sporothrix. Diagnosis is often delayed as associated bacterial colonization may be mistaken for the primary infectious agent. Treatment with systemic antibiotics is usually successful. Deep infections are usually caused by direct inoculation of fungus into deep soft tissues. Systemic fungal infections are of two types--those that occur in normal hosts and those that occur primarily in immunosuppressed patients. For both deep and systemic fungal infections, permanent impairment is common. Diagnosis is often delayed for many months. Treatment usually requires a combination of surgical excision and systemic antifungal therapy with Amphotericin B.

Topics: Amphotericin B; Hand Dermatoses; Humans; Mycoses

Topics: Acquired Immunodeficiency Syndrome; Amphotericin B; Cryptococcosis; Histoplasmosis; Humans; Immune Tolerance; Immunity, Cellular; Mycoses; Opportunistic Infections

Amphotericin B remains the treatment of choice for systemic fungal infections, but amphotericin B is toxic and is often not effective in treating disseminated infections. Liposome intercalation of amphotericin B reduces the toxicity associated with amphotericin B and targets reticuloendothelial tissues most heavily involved in fungal infections. The targeted delivery and reduced toxicity of liposomal amphotericin B improves the therapeutic index of amphotericin B. Although liposomes have been shown to effectively treat a variety of experimental and human fungal infections, the optimal composition of liposomal amphotericin has not been established. Vesicle type, lipid content, size, and conditions of storage markedly affect toxicity, therapeutic efficacy, and tissue distribution. In vitro studies have been poor predictors of in vivo efficacy and toxicity. Animal models can be used to evaluate in vivo the optimal liposome preparation. Liposomal amphotericin B appears to be an improved means of amphotericin B delivery and may improve the treatment of patients with systemic fungal infections.

Topics: Amphotericin B; Drug Carriers; Humans; Liposomes; Mycoses

Systemic mycoses continue to emerge as life-threatening infections. Considerable progress in treating these infections is being achieved through better application of established available antifungal agents (amphotericin B, flucytosine, miconazole and ketoconazole), and through development of promising investigational agents (fluconazole, itraconazole). Systemic fungal infections, however, continue to present major problems, including clinical resistance, microbiological resistance, emergence of new pathogens, and involvement of more immunocompromised patients. The purpose of this paper, therefore, is to review the recent progress and current problems in treatment of systemic fungal infections.

Topics: Amphotericin B; Antifungal Agents; Chemical Phenomena; Chemistry; Fluconazole; Flucytosine; Humans; Itraconazole; Ketoconazole; Miconazole; Mycoses; Triazoles

Topics: Amphotericin B; Antifungal Agents; Cross Infection; Fungi; Humans; Immunologic Deficiency Syndromes; Mycoses; Risk Factors; Virulence

We present six cases of fusariosis caused by Fusarium solani that were diagnosed over a three-year period in 166 adult patients undergoing chemotherapy for acute leukemia. Necrotic skin lesions were evident in four patients, fungemia in three, and a deep cellulitis around a great toe nail at the time of a febrile illness in two. The mean minimal inhibitory concentration (MIC) of amphotericin B was 3.3 micrograms/mL and of miconazole, 5.3 micrograms/mL; all isolates were resistant to 5-fluorocytosine. All patients received amphotericin B (1.0-1.5 mg/kg per d) plus 5-fluorocytosine. In contrast to results found in the literature, five patients had resolution of their infections, and the one patient who died had necropsy evidence of disseminated fusariosis. Review of our cases and of the literature did not reveal a definitive source for the organism or its portal of entry. Fusarium spp. must be recognized as opportunistic pathogens that cause a potentially fatal infection in compromised patients.

Topics: Adult; Amphotericin B; Female; Flucytosine; Fusarium; Humans; Immune Tolerance; Leukemia; Leukemia, Megakaryoblastic, Acute; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Leukemia, Prolymphocytic; Male; Middle Aged; Mycoses; Opportunistic Infections

Amphotericin B is the treatment of choice for most deep-seated mycoses; however, doses may have to be limited because of concern over adverse effects such as nephrotoxicity. Evolving evidence suggests that the extent of amphotericin B-induced renal impairment may be modified via alteration of a normal physiologic feedback response that further contributes to changes due to direct nephrotoxicity. As such, renal impairment has a substantial theoretically preventable and reversible element. In animals exposed to amphotericin B, sodium loading interferes with this response. Mounting clinical evidence also supports the usefulness of sodium supplementation to prevent as well as to reverse amphotericin B-induced nephrotoxicity. At this time, the use of sodium supplementation (eg, intravenous saline and/or ticarcillin disodium, which contains 5.2 mEq of sodium per gram of drug) along with avoiding dehydration appears to be a safe and effective means of reducing the risk of nephrotoxicity associated with amphotericin B administration; however, it is not known whether renal changes can be entirely prevented. These preliminary observations merit confirmation in a prospective, randomized clinical trial.

Topics: Amphotericin B; Animals; Humans; Kidney; Kidney Diseases; Mycoses; Sodium

The story of antifungal agents has not been a stately procession from one development to another. For many years there was no agent of value for systemic mycoses. Then, with the advent of amphotericin B, we have had for over two decades essentially one effective agent, but a difficult drug to manipulate. The appearance of ketoconazole, the first systemic drug with relatively little toxicity, along with the appearance of ominous new forms of mycotic diseases, sharply stimulated interest in development of antifungal agents, initially in the azole classes, but now including a variety of other classes as well. We have very little idea how all of these drugs will act independently, and much less how they may interact together. Indeed, one of the most exciting developments is the return to amphotericin B, with repackaging in liposomes having created a markedly less toxic, and possibly much more potent, antifungal agent than "traditional" amphotericin B. There are indeed so many developments under way that the only safe conclusion that can be made is that within a few years current recommendations will be replaced by very different ones for most if not all of the major fungal pathogens.

Topics: Amphotericin B; Antifungal Agents; Humans; Ketoconazole; Mycoses; Triazoles

Superficial fungal infections are frequent and can cause considerable morbidity. Many topical agents are available that are effective against most of these infections. Systemic fungal infections are increasing in frequency, especially among immunocompromised hosts. Amphotericin B remains the most important therapeutic agents but is associated with significant acute and chronic toxicities.

Topics: Administration, Topical; Amphotericin B; Antifungal Agents; Dermatomycoses; Flucytosine; Humans; Ketoconazole; Miconazole; Mycoses

Systemic mycosis due to Penicillium marneffei is described in a man infected with human immunodeficiency virus and who had travelled in S.W. China. He responded completely to treatment with amphotericin B and a prolonged course of ketoconazole. Problems of diagnosis are discussed and all previously reported cases reviewed.

Topics: Acquired Immunodeficiency Syndrome; Amphotericin B; Humans; Ketoconazole; Male; Middle Aged; Mycoses; Penicillium

Systemic fungal infections are life-threatening diseases that are occurring with increasing frequency, especially in immunocompromised patients. Advances in the treatment of systemic fungal infections have been achieved through better understanding of two classic antifungal drugs, amphotericin B and flucytosine, and through the recent development of several antifungal azole derivatives. The purpose of this paper is to review the recent advances in pharmacology, toxicology, formulation and clinical trials of antifungal agents for the treatment of systemic mycoses.

Topics: Acquired Immunodeficiency Syndrome; Amphotericin B; Antifungal Agents; Drug Resistance, Microbial; Drug Therapy, Combination; Fluconazole; Flucytosine; Humans; Itraconazole; Ketoconazole; Miconazole; Mycoses; Triazoles

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillosis, Allergic Bronchopulmonary; Candidiasis; Humans; Lung Diseases, Fungal; Miconazole; Mucormycosis; Mycoses

Topics: Amphotericin B; Anti-Infective Agents; Humans; Liposomes; Mycoses

A neutropenic patient with acute myeloid leukemia developed nasal and perinasal infection caused by the fungus Exserohilum rostratum. Early amphotericin B treatment along with marrow recovery resulted in resolution of the infection. A review of other previously reported cases of Exserohilum and Bipolaris infections show a favourable outcome in most patients who receive systemic antifungal treatment with amphotericin B.

Topics: Agranulocytosis; Amphotericin B; Humans; Immune Tolerance; Leukemia, Myeloid, Acute; Male; Middle Aged; Mitosporic Fungi; Mycoses; Nasal Mucosa; Neutropenia; Nose Diseases; Paranasal Sinus Diseases

Amphotericin B (Am. B), a polyene heptaene, is an antifungal antibiotic substance produced by Streptomyces nodosus, a telluric actinomycetal from Venezuela. Although it is a very toxic substance and its pharmacokinetic is not completely known, Am. B is yet the former antifungal substance utilised against number of pathogenic agents of systemic mycoses. Am. B binds irreversibly to sterols of fungal cytoplasmic membranes causing a leak of potassium and other impairments leading the fungal cell to death. Further, Am. B might to induce an enhancement of humoral and cellular immunity. After intravenous perfusion, 95 per cent of Am. B binds to plasma lipoproteins. Only a low proportion of the Am. B serum level is detected in the CSF. Distribution of Am. B to extravascular inflammatory fluids and secretions might be letter. Am. B might be eliminated essentially by biliary way. Am. B toxic effects are very frequent. Generalized reactions are observed to the earlier doses. Toxic visceral, above all, nephrotoxic manifestations, appearing later. Recent results, from experimental and human infections suggest that Am. B encapsulated in liposomal vesicles is more active, less toxic and more easily administered.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Child; Female; Humans; Infant; Male; Middle Aged; Mycoses

Genitourinary fungal infections have become increasingly common in clinical practice. We review the literature on such infections, emphasizing recognition of fungal disease, predisposing factors, pathogenesis, and approaches to therapy.

Topics: Amphotericin B; Aspergillosis; Blastomycosis; Candidiasis; Coccidioidomycosis; Cryptococcosis; Female; Genital Diseases, Female; Genital Diseases, Male; Histoplasmosis; Humans; Infant, Newborn; Male; Mycoses; Urinary Tract Infections

The deep mycoses are increasing in importance both as opportunistic infections and from exposure in geographically defined areas. Diagnosis may be difficult in both groups. Mucosal involvement may be non-specific (e.g., in disseminated candidiasis) or highly predictive of disseminated disease (e.g., histoplasmosis, blastomycosis and paracoccidioidomycosis). Skin involvement is generally uncommon in disseminated aspergillosis, mucormycosis and cryptococcosis but is more common in candidemia and coccidioidomycosis. Manifestations of mucosal and cutaneous lesions of the deep mycoses are reviewed and the need for an aggressive diagnostic approach stressed. Culture is more specific than histopathologic examination alone but the latter may have to suffice in some cases. Control of underlying disease and administration of amphotericin B remain the mainstays of therapy. Ketoconazole is being evaluated as an alternative in therapy of some deep mycoses.

Topics: Amphotericin B; Aspergillosis; Blastomycosis; Candidiasis; Candidiasis, Cutaneous; Coccidioidomycosis; Cryptococcosis; Dermatomycoses; Flucytosine; Histoplasmosis; Humans; Immunosuppression Therapy; Ketoconazole; Miconazole; Mouth Diseases; Mouth Mucosa; Mucormycosis; Mycoses; Paracoccidioidomycosis; Sporotrichosis; Travel

It appears that the use of antibiotic combinations, especially synergistic ones, is indicated for the management of gram-negative bacillary sepsis in granulocytopenic patients. Synergism is a valuable factor in increasing the serum bactericidal activity, which is highly likely to be important for a favorable outcome in these infections. The potential side effects of antimicrobial combinations should not deter clinicians from their use. The most frequently used combinations for gram-negative bacillary infections are those involving beta-lactams and aminoglycosides. Other potentially synergistic combinations exist as well; however, the clinical experience with these combinations is limited, and, as with double beta-lactam combinations, their potential for antagonism necessitates care when using them. Besides gram-negative bacillary sepsis in granulocytopenic patients, severe staphylococcal infections might represent an indication for the use of combination therapy, especially in patients with compromised mechanisms of defense against infection.

Topics: Agranulocytosis; Aminoglycosides; Amphotericin B; Anti-Bacterial Agents; Bacterial Infections; Blood Bactericidal Activity; Drug Resistance, Microbial; Drug Synergism; Drug Therapy, Combination; Fever; Humans; Lactams; Mycoses; Sepsis; Staphylococcal Infections

During the last three years, several studies have investigated the potential of ketoconazole for antifungal prophylaxis in immunocompromised patients. Ketoconazole 200 mg o.d. seems to have some effect, but this daily dose is considered too low. Studies using higher doses suggest an increased prophylactic effect with 400 mg and adequate prophylaxis with 600 mg ketoconazole daily. When compared with other antifungals, ketoconazole seems to be superior to nystatin and as effective as amphotericin B (500 mg t.i.d.).

Topics: Amphotericin B; Drug Administration Schedule; Humans; Immunosuppression Therapy; Ketoconazole; Miconazole; Mycoses; Nystatin

Topics: Amphotericin B; Antifungal Agents; Chemical Phenomena; Chemistry; Dermatomycoses; Flucytosine; Griseofulvin; Humans; Imidazoles; Kidney Diseases; Mycoses

As invasive fungal infection remains a common problem in the management of cancer patients, chemoprophylaxis of these opportunistic infections is desperately needed. The most frequently investigated antifungal agents have been nystatin, amphotericin B, and ketoconazole. In placebo-controlled studies, high doses of antifungal agents decreased the positive results from surveillance cultures, and there is some suggestion that such chemoprophylaxis may reduce the incidence of invasive candidiasis in neutropenic cancer patients. However, no oral chemoprophylaxis has effectively prevented aspergillosis or mucormycoses in these patients. There are still many areas of controversy, and the most adequate regimens, if any, remain to be defined.

Topics: Administration, Oral; Administration, Topical; Amphotericin B; Antifungal Agents; Candidiasis; Clinical Trials as Topic; Humans; Ketoconazole; Miconazole; Mycoses; Neoplasms; Nystatin

In the past 20 years, there has been a marked increase in the number of reported cases of meningitis and brain abscess due to fungi and yeasts. This increase is due in part to better diagnostic techniques and greater awareness of the possibility of fungal invasion of the nervous system; but the increase can also be attributed to a growing pool of severely compromised hosts, many of whom are undergoing treatment with adrenal glucocorticoids or immunosuppressive agents. The diagnosis and treatment of aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, cryptococcosis, infections caused by dematiaceous fungi, histoplasmosis, paracoccidioidomycosis, petriellidosis, and sporotrichosis, as well as relatively rare infections of the central nervous system caused by other fungi, are discussed. The efficacy of amphotericin B and 5-fluorocytosine in the treatment of CNS fungal and yeast infections is also evaluated.

Topics: Adult; Amphotericin B; Antifungal Agents; Aspergillosis; Blastomycosis; Candidiasis; Central Nervous System Diseases; Chromoblastomycosis; Cladosporium; Coccidioidomycosis; Cryptococcosis; Female; Fungi; Histoplasmosis; Humans; Male; Meningitis; Meningoencephalitis; Middle Aged; Mucormycosis; Mycoses; Paracoccidioidomycosis; Phialophora; Sporotrichosis

Topics: Aminoglycosides; Amphotericin B; Anemia, Aplastic; Bacterial Infections; Bone Marrow Transplantation; Graft Survival; Graft vs Host Disease; Humans; Immunosuppression Therapy; Leukemia; Mycoses; Patient Isolation; Postoperative Complications; Sulfamethoxazole; Time Factors; Trimethoprim; Virus Diseases

Hospital acquired infections due to fungi are primarily caused by yeast species of the genus Candida and mould species of the genus Aspergillus. Underlying disease with severely impaired defence mechanisms as well as certain forms of immunosuppressive and aggressive chemotherapy are the most important prerequisites for such secondary fungal infections. Aspergillus spec. usually infect man via exogenous routes, whereas Candida spec. mostly originate from the patient's own microbial flora. Under certain circumstances invasion of tissues follows (endomycoses). Exogenous Candida infections may likewise occur through contaminated hands of personnel and medical devices. The density of yeast cell distribution in hospital wards decreases with the distance from the primary source: the Candida infected human patient. Preventive measures protecting the patient at risk include: Permanent surveillance by routine cultural and serological examinations for the detection of an early infection of the skin, mouth, oesophagus, urinary tract, vagina and the bowel. Monitoring of patients is essential for early detection of dissemination and contributes to the control of fungal decontamination measures. Selective local decontamination is effected by the use of nonabsorbable compounds such as nystatin and amphotericin B in the gastrointestinal tract, and in oral and genital mucous membranes. Oral administration of ketoconazole has also been recommended. For the disinfection of skin appropriate chemicals are available. In the control of the environment of the endangered patient special attention must be paid to meticulous management of catheters.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amphotericin B; Aspergillus; Candida; Catheters, Indwelling; Cross Infection; Cryptococcus neoformans; Disinfection; Environmental Microbiology; Humans; Hygiene; Microbiological Techniques; Mycoses; Nystatin; Patient Isolators; Species Specificity

The development of the polyene antibiotic, amphotericin B, provided for the first time a drug which was clinically effective in many serious mycotic diseases. Unfortunately, it requires parenteral administration and is often toxic, factors which limit the total cumulative dose which can be given. Efforts to utilise combinations of amphotericin B with other agents were best realised with amphotericin B/flucytosine in cryptococcal meningitis, and to a lesser degree in systemic candidiasis. More recently, the introduction of new imidazoles has extended the range of applications of these drugs to fungal diseases. Two members of this group, miconazole and ketoconazole, are promising agents. Miconazole is a parenterally administered agent for patients acutely ill with candidiasis and other mycotic infections. It may be the drug of choice for Petriellidium boydii infections and it is an attractive alternative to amphotericin B for intrathecal administration to patients with fungal meningitis. Ketoconazole offers much less toxicity, the advantage of oral administration, and the possibility of indefinitely prolonged therapy. However, it does not attain high concentrations in either the urine or cerebrospinal fluid. With the imidazoles, we have entered a new era of antifungal therapy which may produce even better antifungal agents than those currently available.

Topics: Amphotericin B; Antifungal Agents; Central Nervous System; Flucytosine; Humans; Imidazoles; Ketoconazole; Kidney; Kidney Diseases; Kinetics; Miconazole; Mycoses; Piperazines

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Blastomycosis; Candidiasis; Chromoblastomycosis; Coccidioidomycosis; Cryptococcosis; Flucytosine; Histoplasmosis; Humans; Imidazoles; Ketoconazole; Lung Diseases, Fungal; Miconazole; Mycoses; Nausea; Piperazines; Vomiting

Topics: Amphotericin B; Animals; Antifungal Agents; Binding, Competitive; Cholesterol; Ergosterol; Flucytosine; Fungi; Humans; Imidazoles; Ketoconazole; Membranes, Artificial; Miconazole; Mycoses; Phospholipids; Piperazines; Sterols

When the decision to treat a fungal infection is made, there are several antifungal agents available for use. AmB remains the first-line drug in the treatment of most systemic fungal infections. Miconazole should be used to treat patients who cannot tolerate AmB or who are infected with AmB-resistant organisms. Ketoconazole has a distinct advantage in that it is a relatively nontoxic oral agent and may prove very effective in treating non-life-threatening chronic fungal infections. Clinical experience with miconazole and ketoconazole is too limited at present to recommend them as first-line therapeutic agents, except in a limited number of clinical situations. 5-FC should only be used in combination with AmB to treat yeast infections.

Topics: Amphotericin B; Antifungal Agents; Child; Child, Preschool; Drug Combinations; Flucytosine; Humans; Imidazoles; Infant; Mycoses; Potassium Iodide; Structure-Activity Relationship

The main antifungal agents used for deep-seated mycotic infections are the broad-spectrum antifungal drug amphotericin B, the narrow-spectrum agent flucytosine, and the newer broad-spectrum agents miconazole and ketoconazole. Amphotericin B remains the cornerstone of antifungal therapy. For the treatment of cryptococcal meningitis, the current recommendation is for the combined use of amphotericin B and flucytosine. 2-Hydroxystilbamidine is used only in indolent cases of blastomycosis; however, this condition is usually treated with amphotericin B. Clinical experience with the newer agents is limited. Not all patients from whom fungal agents have been isolated require treatment; the extent of the fungal infection should be determined, when possible, for evaluation of the need for treatment.

Topics: Amphotericin B; Antifungal Agents; Candidiasis; Cryptococcosis; Flucytosine; Humans; Imidazoles; Mycoses; Stilbamidines

Topics: Amphotericin B; Animals; Antifungal Agents; Drug Interactions; Drug Resistance, Microbial; Drug Therapy, Combination; Flucytosine; Fungi; Humans; Imidazoles; Mice; Molecular Conformation; Mycoses; Time Factors

Topics: Amphotericin B; Aspergillosis; Candidiasis; Cryptococcosis; Drug Therapy, Combination; Flucytosine; Humans; Imidazoles; Mucormycosis; Mycoses; Prognosis

Topics: Amphotericin B; Blood Group Incompatibility; Blood Transfusion; Granulocytes; Histocompatibility Antigens; Humans; Immunization; Indium; Infection Control; Leukapheresis; Leukemia; Methods; Mycoses; Radioisotopes

Topics: Amphotericin B; Antifungal Agents; Flucytosine; Griseofulvin; Humans; Imidazoles; Ketoconazole; Miconazole; Mycoses; Piperazines

Fungal infections of the gastrointestinal tract have risen to higher levels of prevalence in the past decade. Major factors accounting for this increase are social changes, such as the increased ease and frequency of travel, which exposes the individual to environmental conditions that may result in fungal infection; increasing use of antibiotic and hormonal medications by otherwise healthy persons; and improved therapy for other diseases, such as polychemotherapy of cancer with its immunosuppressive effects. Both noninvasive and invasive fungal disease of the intestinal tract in otherwise healthy individuals can be successfully treated. The invasive fungal infections in patients with severe prior underlying disease are often first diagnosed postmortem, but improvement in serologic techniques now offers a possibility of earlier diagnosis and therapeutic intervention.

Topics: Amphotericin B; Antifungal Agents; Candidiasis; Diarrhea; Enteritis; Histoplasmosis; Humans; Imidazoles; Immunosuppression Therapy; Ketoconazole; Miconazole; Mycoses; Neoplasms; Nystatin; Paracoccidioidomycosis; Piperazines; Sulfadiazine

Topics: Amphotericin B; Drug Therapy, Combination; Flucytosine; Griseofulvin; Humans; Imidazoles; Iodides; Ketoconazole; Miconazole; Mycoses; Piperazines; Transfer Factor

Topics: Amphotericin B; Animals; Candida albicans; Candidiasis; Cell Membrane; Cell Membrane Permeability; Chemical Phenomena; Chemistry; Chromatin; Dogs; Dose-Response Relationship, Drug; Drug Evaluation; Drug Evaluation, Preclinical; Humans; In Vitro Techniques; Kinetics; Mice; Microbial Sensitivity Tests; Mycoses; Neoplasms; Neoplasms, Experimental

Topics: Amphotericin B; Flucytosine; Humans; Imidazoles; Mycoses; Potassium Iodide; Stilbamidines

The recent development of new antifungal antimicrobials that can be administered in combination with amphotericin B or as alternatives to it has expanded the dimensions of treatment for fungal infections of the central nervous system. These disorders have acquired increasing importance as patients with malignant and other illnesses associated with immunosuppression survive longer and as renal transplantation is more widely applied. Amphotericin B has remained the most effective therapeutic preparation for most types of neurological fungal disease, although important roles for 5-fluorocytosine, miconazole, and, more recently, ketoconazole are being recognized.

Topics: Amphotericin B; Antifungal Agents; Central Nervous System Diseases; Chemical Phenomena; Chemistry; Flucytosine; Humans; Kidney Diseases; Miconazole; Mycoses

Topics: Amphotericin B; Animals; Antifungal Agents; Clotrimazole; Drug Resistance, Microbial; Drug Therapy, Combination; Flucytosine; Fungi; Humans; Imidazoles; Iodides; Miconazole; Mycoses; Piperazines; Structure-Activity Relationship

Before 1950 no reliable or safe therapy existed for systemic and invasive mycoses, and only traditional and empirical topical preparations were available for dermatomycoses. Two distinct eras of rapid progress in antifungal therapy followed: first, in the 1950's came the introduction of the polyenes, nystatin and pimaricin for cutaneous, vaginal and intestinal candidiasis, and amphotericin B for the treatment of severe systemic mycoses. The second phase saw the successful introduction and clinical use of 5-fluorocytosine and several imidazole derivatives some twenty years later, at a time when the vast increase in iatrogenic systemic mycoses caused by opportunistic fungi had created an urgent and pressing need for new agents in addition to those still effective.

Topics: Amphotericin B; Antifungal Agents; Blastomycosis; Candidiasis; Flucytosine; Humans; Imidazoles; Mycoses; Natamycin; Nystatin; Polyenes

The literature on the clinical use of rifampicin in combination for the treatment of non-mycobacterial diseases is reviewed. From the published evidence, the most promising associations are, for staphylococcal infections, gentamicin, erythromycin, kanamycin and fusidic acid. In the field of Gram-negative infections, Psuedomonas-induced sepsis in particular, data are not so impressive but promising results have been obtained with the associated use of rifampicin and gentamicin or colistin. Some systemic fungal diseases may be successfully treated with rifampicin in combination with amphotericin-B. Although only few reports are available on this subject, the importance of such an application is stressed in view of the severity of these diseases and of the lack of appropriate treatments.

Topics: Amphotericin B; Cephalosporins; Chloramphenicol; Colistin; Drug Therapy, Combination; Endocarditis, Bacterial; Erythromycin; Gentamicins; Humans; Kanamycin; Lincomycin; Mycoses; Nalidixic Acid; Penicillins; Pseudomonas Infections; Respiratory Tract Infections; Rifampin; Staphylococcal Infections; Sulfamethoxazole; Tetracyclines; Trimethoprim; Urinary Tract Infections; Vancomycin

Topics: Amphotericin B; Animals; Eukaryota; Flucytosine; Helminths; Humans; Miconazole; Mycoplasma; Mycoses; Viruses

Topics: Amphotericin B; Aspergillus; Candida; Clotrimazole; Cryptococcus; Drug Therapy, Combination; Flucytosine; Miconazole; Mucor; Mycoses

Topics: Amphotericin B; Cytosine; Drug Evaluation; Drug Resistance, Microbial; Drug Therapy, Combination; Flucytosine; Humans; Mycoses

Flucytosine is a systemic antifungal drug that is readily absorbed from the gastrointestinal tract. The most clearly documented therapeutic effect has been in cryptococcosis, candidiasis, and chromomycosis. An important limitation of the use of flucytosine in all three diseases has been drug resistance arising during therapy. The addition of low-dose, intravenous amphotericin B to flucytosine therapy of cryptococcosis has appeared to decrease the frequency of secondary flucytosine resistance. In addition, the two drugs have an additive or slightly synergistic effect against flucytosine susceptible isolates of Cryptococcus and Candida. The combination is probably the treatment of choice in cryptococcal meningitis and offers promise in the therapy of systemic candidiasis and nonmeningeal cryptococcosis.

Topics: Amphotericin B; Candidiasis; Chromoblastomycosis; Cryptococcosis; Cytosine; Drug Therapy, Combination; Flucytosine; Mycoses

Topics: Amphotericin B; Antifungal Agents; Cell Membrane; Chemical Phenomena; Chemistry; Clotrimazole; Drug Resistance, Microbial; Drug Therapy, Combination; Flucytosine; Fungi; Griseofulvin; Miconazole; Microtubules; Mitosis; Mycoses; Nystatin; Phenyl Ethers; Structure-Activity Relationship; Tolnaftate

Topics: Acute Disease; Adrenal Cortex Hormones; Amphotericin B; Aspergillosis; Blood Transfusion; Candidiasis; Cryptococcosis; Drug Therapy, Combination; Flucytosine; Hodgkin Disease; Humans; Iron; Leukemia; Leukemia, Lymphoid; Lymphoma; Mucor; Multiple Myeloma; Mycoses; Neutropenia; Rhizopus

Although fungal urinary tract infections occur less frequently than bacterial urinary tract infections their incidence has increased during the last several decades and their clinical importance to the urologist should not be underestimated. Herein the pertinent literature on fungal urinary tract infections is reviewed, with emphasis on the predisposing factors, pathogenesis, host defense mechanisms and the clinical spectrum of the disease. An approach to the evaluation of positive cultures and therapy is presented.

Topics: Amphotericin B; Animals; Candida; Candidiasis; Female; Flucytosine; Genital Diseases, Female; Genital Diseases, Male; Humans; Male; Mice; Mycoses; Urinary Tract Infections

Effective antifungal therapy must be long-term, nondamaging, penetrating to the eye, and highly active against each patient's fungus. Results of antifungal sensitivity testing of 61 collected ocular fungal pathogens and observations in 25 cases treated with one of the nonpolyene antifungal drugs indicated that infection was rapidly controlled and eradicated with restoration of visual acuity, determined by the degree of disorganization present at the time of commencement of rational specific antifungal therapy. Pimaricin has the widest spectrum, a medium level of activity, and rather poor penetration but is recommended as an antifungal prophylactic and as first-line-therapy for ocular fungal disease while awaiting identification and sensitivity testing of the fungus. Flucytosine combined with amphotericin B, or possibly with clotrimazole or miconazole, is recommended for Candida infections. Clotrimazole is the drug of choice for Aspergillus species although miconazole and econazole are more effective with some isolates. Miconazole and econazole are recommended for miscellaneous filamentous fungi although clotrimazole or thiabendazole are superior in some cases. Each of these drugs may be useful in patients infected with Fusarium who do not respond to primaricin. In these cases, drug use should be guided by the results of antifungal sensitivity testing. In addition to medical antifungal therapy some eyes may require excisional keratoplasty with the lens removal and evacuation of the posterior chamber and anterior vitreous cavity.

Topics: Adrenal Cortex Hormones; Adult; Aged; Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Aspergillus; Blindness; Candida; Candidiasis; Clotrimazole; Cornea; Eye Diseases; Female; Fusarium; Glaucoma; Humans; Imidazoles; Male; Middle Aged; Mycoses; Natamycin; Polyenes

Topics: Amphotericin B; Animals; Bicarbonates; Dose-Response Relationship, Drug; Drug Therapy, Combination; Humans; Infusions, Parenteral; Injections, Intra-Articular; Injections, Intravenous; Injections, Spinal; Kidney; Mannitol; Meningitis; Mycoses; Rifampin

Topics: Alkenes; Amphotericin B; Animals; Antifungal Agents; Flucytosine; Humans; Injections, Intravenous; Mice; Mycoses; Peptides; Stilbamidines; Streptomyces

Topics: Administration, Topical; Amphotericin B; Candidiasis; Coccidioides; Flucytosine; Fusarium; Griseofulvin; Histoplasma; Humans; Mycoses; Natamycin; Nystatin; Streptomyces

Topics: Amphotericin B; Antifungal Agents; Chronic Disease; Flucytosine; Humans; Imidazoles; Mycoses; Natamycin; Nystatin; Peptides; Polyenes; Trityl Compounds

Topics: Amphotericin B; Ampicillin; Antifungal Agents; Bacterial Infections; Blood Transfusion; Bone Marrow Transplantation; Carbenicillin; Cephalothin; Diagnosis, Differential; Fever; Gentamicins; Humans; Infections; Leukemia; Leukocytes; Lymphoma; Methicillin; Mycoses; Patient Isolators; Penicillin Resistance; Pneumonia, Pneumocystis; Polymyxins; Sepsis; Toxoplasmosis; Virus Diseases

Topics: Alkenes; Amphotericin B; Animals; Antifungal Agents; Aspergillus; Benzene Derivatives; Candida; Dermatomycoses; Flucytosine; Griseofulvin; Humans; Imidazoles; Kinetics; Mice; Microsporum; Mycoses; Natamycin; Nystatin; Trichophyton

Topics: Actinomycosis; Amphotericin B; Antifungal Agents; Aspergillosis; Blastomycosis; Candidiasis; Coccidioidomycosis; Cryptococcosis; Flucytosine; Histoplasmosis; Humans; Mucormycosis; Mycoses; Nocardia Infections; Sporotrichosis

Topics: Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Cytosine; Fluorine; Griseofulvin; Humans; Mycoses; Nystatin; Penicillin G; Peptides; Potassium Iodide; Stilbamidines; Sulfonamides

Topics: Administration, Oral; Alkenes; Amphotericin B; Antifungal Agents; Cytosine; Drug Resistance, Microbial; Fluorine; Fungi; Griseofulvin; Humans; Injections; Mycoses; Peptides

Topics: Administration, Oral; Adolescent; Aged; Amphotericin B; Anemia; Anterior Chamber; Blastomycosis; Bronchi; Child; Cryptococcosis; Drug Resistance, Microbial; Fungi; Histoplasmosis; Humans; Injections; Injections, Intravenous; Injections, Spinal; Kidney Diseases; Male; Microbial Sensitivity Tests; Middle Aged; Mycoses; Thrombophlebitis; Water-Electrolyte Balance

Topics: Amphotericin B; Coccidioidomycosis; Female; Humans; Injections, Intravenous; Injections, Spinal; Meningitis; Methods; Mycoses

Topics: Amphotericin B; Aspergillosis; Candida; Candidiasis; Child; Child, Preschool; Coccidioidomycosis; Coccidiosis; Cryptococcosis; Endocarditis; Granuloma; Histoplasmosis; Humans; Infant; Kidney; Kidney Function Tests; Meningitis; Mycoses; Pneumonia

Topics: Adult; Amphotericin B; Candidiasis; Female; Gastrointestinal Diseases; Histoplasmosis; Humans; Infant; Leukemia; Lymphoma; Male; Mucormycosis; Mycoses; Nystatin

Topics: Amphotericin B; Cephalothin; Diagnosis, Differential; Endocarditis; Endocarditis, Bacterial; Humans; Infections; Mycoses; Penicillins; Streptomycin; Tetracycline; Vancomycin

Topics: Actinomycosis; Adolescent; Adult; Amphotericin B; Animals; Aspergillosis; Basidiomycota; Blastomycosis; Candidiasis; Cephalosporins; Child; Chromoblastomycosis; Coccidioidomycosis; Conjunctiva; Cryptococcosis; Drug Synergism; Eye Diseases; Female; Fungi; Geotrichosis; Guinea Pigs; Histoplasmosis; Humans; Male; Mucor; Mycetoma; Mycoses; Natamycin; Nystatin; Penicillium; Pityriasis; Rabbits; Rhinosporidiosis; Sporotrichosis; Tinea

Topics: Actinomycosis; Amphotericin B; Aspergillosis; Biopsy; Blastomycosis; Candidiasis; Cystoscopy; Humans; Mycoses; Penicillins; Penicillium; Sporothrix; Surgical Procedures, Operative; United States; Urinary Tract Infections; Urography

Topics: Actinomycosis; Amphotericin B; Anti-Bacterial Agents; Aspergillosis; Blastomycosis; Candidiasis; Coccidioidomycosis; Cryptococcosis; Griseofulvin; Histoplasmosis; Humans; Iodides; Mucormycosis; Mycoses; Nocardia Infections; Nystatin; Penicillins; Sporotrichosis; Stilbamidines; Sulfadiazine; Surgical Procedures, Operative; Toxicology

Fungal infections are a major complication of neutropaenia following chemotherapy. Their early diagnosis is difficult, and empirical antifungal treatment is widely used, and uses of less toxic drugs that reduce breakthrough infection are required.. We conducted a multicentre, open-label, randomised, non-inferiority trial to compare the safety and efficacy of intravenous itraconazole (ivITCZ) and liposomal amphotericin B (LAmB) as empirical antifungal therapy in patients with haematological malignancies with neutropaenia and persistent fever.. Patients with haematological malignancies who developed fever refractory to broad-spectrum antibacterial agents under neutropaenia conditions were enrolled. Patients were randomised for treatment with LAmB (3.0 mg/kg/d) or ivITCZ (induction: 400 mg/d, maintenance: 200 mg/d).. Observed overall favourable response rates of 17/52 (32.7%) and 18/50 (36.0%) in the LAmB and ivITCZ groups, with a model-based estimate of a 4% difference (90% CI, -12% to 20%), did not fulfil the statistical non-inferiority criterion. In the LAmB group, there were two cases of breakthrough infection and five cases of probable invasive fungal disease, whereas in the itraconazole group, neither breakthrough infection nor probable invasive fungal disease occurred. Patients in the ivITCZ group had significantly fewer grade 3-4 hypokalaemia-related events than LAmB group patients (P < .01). The overall incidence of adverse events tended to be lower in the ivITCZ group (P = .07).. ivITCZ showed similar efficacy and safety as LAmB as empirical antifungal therapy in haematological malignancy patients with febrile neutropaenia, although the small sample size and various limitations prevented demonstration of its non-inferiority.

Topics: Administration, Intravenous; Adult; Aged; Amphotericin B; Antifungal Agents; Chemotherapy-Induced Febrile Neutropenia; Female; Hematologic Neoplasms; Humans; Itraconazole; Male; Middle Aged; Mycoses; Young Adult

Amphotericin B is widely used for the treatment of Macrorhabdus ornithogaster infections. To date, however, there have been no randomized controlled trials confirming its efficacy where cure was confirmed by postmortem examination. To determine the efficacy of amphotericin B against M. ornithogaster, a three-part study was undertaken. Treatment outcomes of M. ornithogaster infected birds treated amphotericin B were reviewed. A pilot treatment trial with two naturally infected birds (Melopsittacus undulatus and Agapornis roseicollis) was undertaken, administering amphotericin B at 100 mg/kg twice daily for 30 days. Finally, a randomized controlled trial using experimentally infected chickens treated with amphotericin B at 25 mg/kg and 100 mg/kg twice daily for 10 days was performed. Retrospective analysis indicated treatment failure in 80.4% of 36 cases that met the inclusion criteria. The pilot study showed that amphotericin B did not clear, but significantly decreased Macrorhabdus ornithogaster burden, followed by profound rebound effect of the number of organisms shed in the feces. Finally, the randomized controlled trial found that amphotericin B given at 100 mg/kg did not clear, but significantly decreased the burden of M. ornithogaster compared with both the 25 mg/kg group (P = .037) and the no treatment control group (P = .001). A strong curvilinear correlation between body weight and M. ornithogaster infection burden was present in the infected chickens. These findings represent treatment failure in three scenarios and indicate that treatment with amphotericin B has poor efficacy against Macrorhabdus ornithogaster.

Topics: Amphotericin B; Animals; Antifungal Agents; Australia; Bird Diseases; Birds; Chickens; Colony Count, Microbial; Disease Models, Animal; Drug Resistance, Fungal; Female; Male; Mycoses; Random Allocation; Saccharomycetales; Treatment Outcome

Talaromyces marneffei infection is a major cause of human immunodeficiency virus (HIV)-related death in South and Southeast Asia. Guidelines recommend initial treatment with amphotericin B deoxycholate, but this drug has substantial side effects, a high cost, and limited availability. Itraconazole is available in oral form, is associated with fewer unacceptable side effects than amphotericin, and is widely used in place of amphotericin; however, clinical trials comparing these two treatments are lacking.. In this open-label, noninferiority trial, we randomly assigned 440 HIV-infected adults who had talaromycosis, confirmed by either microscopy or culture, to receive either intravenous amphotericin B deoxycholate (amphotericin) (219 patients), at a dose of 0.7 to 1.0 mg per kilogram of body weight per day, or itraconazole capsules (221 patients), at a dose of 600 mg per day for 3 days, followed by 400 mg per day, for 11 days; thereafter, all the patients received maintenance therapy with itraconazole. The primary outcome was all-cause mortality at week 2. Secondary outcomes included all-cause mortality at week 24, the time to clinical resolution of talaromycosis, early fungicidal activity, relapse of talaromycosis, development of the immune reconstitution inflammatory syndrome (IRIS), and the side-effect profile.. The risk of death at week 2 was 6.5% in the amphotericin group and 7.4% in the itraconazole group (absolute risk difference, 0.9 percentage points; 95% confidence interval [CI], -3.9 to 5.6; P<0.001 for noninferiority); however, the risk of death at week 24 was 11.3% in the amphotericin group and 21.0% in the itraconazole group (absolute risk difference, 9.7 percentage points; 95% CI, 2.8 to 16.6; P=0.006). Treatment with amphotericin was associated with significantly faster clinical resolution and fungal clearance and significantly lower rates of relapse and IRIS than itraconazole. The patients who received amphotericin had significantly higher rates of infusion-related reactions, renal failure, hypokalemia, hypomagnesemia, and anemia than patients in the itraconazole group.. Amphotericin was superior to itraconazole as initial treatment for talaromycosis with respect to 6-month mortality, clinical response, and fungicidal activity. (Funded by the Medical Research Council and others; IVAP Current Controlled Trials number, ISRCTN59144167 .).

Topics: Administration, Oral; Adult; AIDS-Related Opportunistic Infections; Amphotericin B; Antifungal Agents; Creatinine; Deoxycholic Acid; Drug Combinations; Female; Humans; Induction Chemotherapy; Infusions, Intravenous; Itraconazole; Male; Mycoses; Talaromyces

Macrorhabdus ornithogaster, avian gastric yeast, is a common cause of gastrointestinal disease in budgerigars ( Melopsittacus undulatus). To better understand the clinical disease in budgerigars presented in a practice population, we reviewed the occurrence, clinical signs, and treatment success of M ornithogaster disease in budgerigars during a 2.5-year period at the Clinic for Birds and Reptiles, University of Leipzig (Leipzig, Germany). The yeast was diagnosed by microscopic examination of fresh fecal samples. Male budgerigars of all ages were most affected. Most clinical signs in birds with confirmed positive results were nonspecific, except for the occurrence of undigested seeds in the feces. Although radiographic appearance of a dilated proventriculus is indicative of a M ornithogaster infection, it is difficult to recognize because of the small size of the budgerigars. Birds with positive results were treated with amphotericin B (100 mg/kg PO q12h) for 4 weeks. Treatment was stressful for the birds because of the handling required and the long treatment duration, and therapeutic results were unsatisfactory. Therefore, the indications for treatment with amphotericin B should be carefully considered in birds with positive M ornithogaster results. An increased occurrence of the infection in association with other pathogens was detected.

Topics: Amphotericin B; Animals; Antifungal Agents; Bird Diseases; Feces; Female; Gastrointestinal Diseases; Hospitals, Animal; Incidence; Male; Melopsittacus; Mycoses; Saccharomycetales; Treatment Outcome

Invasive fungal infection (IFI) is a major life-threatening problem encountered by patients with hematological malignancies receiving intensive chemotherapy. Empirical antifungal agents are therefore important. Despite the availability of antifungal agents for such situations, the optimal agents and administration methods remain unclear. We conducted a prospective phase 2 study of empirical 1 mg/kg/day liposomal amphotericin B (L-AMB) in 80 patients receiving intensive chemotherapy for hematological malignancies. All enrolled patients were high-risk and had recurrent prolonged febrile neutropenia despite having received broad-spectrum antibacterial therapy for at least 72 hours. Fifty-three patients (66.3 %) achieved the primary endpoint of successful treatment, thus exceeding the predefined threshold success rate. No patients developed IFI. The treatment completion rate was 73.8 %, and only two cases ceased treatment because of adverse events. The most frequent events were reversible electrolyte abnormalities. We consider low-dose L-AMB to provide comparable efficacy and improved safety and cost-effectiveness when compared with other empirical antifungal therapies. Additional large-scale randomized studies are needed to determine the clinical usefulness of L-AMB relative to other empirical antifungal therapies.

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; Febrile Neutropenia; Female; Hematologic Neoplasms; Humans; Male; Middle Aged; Mycoses; Prospective Studies; Young Adult

To assess the safety and tolerability of high-dose weekly (10 mg/kg) liposomal amphotericin B (LamB) for antifungal prophylaxis in liver transplantation (LT) recipients with predefined risk factors for invasive fungal infection (IFI), a prospective phase II noncomparative trial was performed at our center over a 4-year period.. In the selected LT recipients, LamB was administered weekly until hospital discharge after LT for minimum 2 weeks. Criteria for early discontinuing prophylaxis were: (i) any adverse event (AE); (ii) suspicion of IFI. Safety and tolerability were assessed according to the incidence of grades 3 to 4 AEs based on Common Toxicity Criteria (CTC) classification. Post-LT follow-up was of 180 days.. Overall, 76 patients were included. Liposomal amphotericin B was started within a median of 1 (interquartile range, 1-4) day after LT. Overall, 66 of 76 (86.8%) patients completed the prophylaxis, 10 discontinued the study protocol: 6 for infusion-related AE, 4 for suspected IFI. Adverse events consisted of five cases of lumbar pain and one case of thoracic pain which occurred after a median of 1.5 (interquartile range, 1-2) LamB infusions. None of the patients reported CTC grades 3 to 4 hypokalemia, three reported CTC grade 3 acute renal injury, none of which were deemed directly attributable to LamB. No drug-drug interactions with immunosuppressive drugs were reported, and no episode of rejection occurred during the prophylaxis. In only two of the four patients with suspected IFI was the diagnosis of invasive candidiasis confirmed.. Our results suggest high-dose weekly LamB may be a safe prophylactic strategy for high-risk LT recipients.

Topics: Adult; Amphotericin B; Antifungal Agents; Drug Administration Schedule; Female; Humans; Italy; Liver Transplantation; Male; Middle Aged; Mycoses; Prospective Studies; Risk Factors; Time Factors; Treatment Outcome

Children with hematologic malignancies are at an increased risk of invasive fungal infections and a greater risk has been seen with exposure to building construction. Prophylaxis with high-dose (IV) liposomal amphotericin B (L-AmB) 10 mg/kg once weekly was initiated in our high risk children based on previous pharmacokinetic studies. This treatment regimen was associated with a 26% incidence of adverse infusion reactions.

Topics: Adolescent; Amphotericin B; Antibiotic Prophylaxis; Antifungal Agents; Child; Child, Preschool; Female; Humans; Leukemia, Lymphoid; Male; Mycoses; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma

Some preclinical and pharmacokinetic studies suggested the variable safety and the potential efficacy of an antifungal prophylaxis with a single high dose of liposomal amphotericin B (L-AmB) in high-risk patients. An open-label, prospective study was conducted with 48 adults receiving induction chemotherapy for acute myeloid leukemia (AML). Patients received a single infusion of 15 mg/kg of body weight L-AmB and, eventually, a second dose after 15 days of persistent neutropenia. The primary objective was tolerability and safety. Efficacy was also evaluated as a secondary endpoint. A pharmacokinetic study was performed with 34 patients in order to evaluate any association of plasma L-AmB levels with toxicity and efficacy. Overall, only 6 patients (12.5%) reported Common Toxicity Criteria (CTC) grade 3 hypokalemia, which was corrected with potassium supplementation in all cases, and no patient developed clinically relevant nephrotoxicity. Mild infusion-related adverse events occurred after 6 of 53 (11.3%) total infusions, with permanent drug discontinuation in only one case. Proven invasive fungal disease (IFD) was diagnosed in 4 (8.3%) patients. The mean AmB plasma levels at 6 h, 24 h, and 7 days after L-AmB administration were 160, 49.5, and 1 mg/liter, respectively. The plasma AmB levels were higher than the mean values of the overall population in 3 patients who developed CTC grade 3 hypokalemia and did not significantly differ from the mean values of the overall population in 3 patients who developed IFD. Our experience demonstrates the feasibility and safety of a single 15-mg/kg L-AmB dose as antifungal prophylaxis in AML patients undergoing induction chemotherapy.

Topics: Adult; Aged; Amphotericin B; Antibiotic Prophylaxis; Antifungal Agents; Drug Administration Schedule; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Mycoses; Prospective Studies; Treatment Outcome

A multicenter, uncontrolled clinical study has been conducted to evaluate the safety, efficacy, and pharmacokinetics of liposomal amphotericin B (L-AMB) in children. In this article, the safety and efficacy of L-AMB are discussed. Subjects were diagnosed with invasive fungal infection (definitely diagnosed cases), possible fungal infection (clinically diagnosed cases), and febrile neutropenia with suspected fungal infection (febrile neutropenia cases). Of the 39 subjects treated with L-AMB, 18 received a definite (11) or clinical (7) diagnosis of invasive fungal infection. In these subjects, excluding one unevaluable subject, L-AMB was effective in nine out of 17 subjects(52.9%). Of 12 febrile neutropenia cases, improvement in clinical symptoms, etc., was observed for six but these were excluded from the efficacy analysis because they concomitantly used medications that may have affected efficacy. The causative fungus was identified in four out of 39 subjects and confirmed to be eliminated by treatment with L-AMB in one subject. Adverse events possibly related to L-AMB (adverse drug reactions) were reported in 36 out of 39 subjects (92.3%). The most commonad verse drug reaction was decreased potassium in 20 out of 39 subjects (51.3%), but all these subjects recovered with appropriate treatment, for example potassium supplementation.In a Japanese Phase II clinical study of adult patients, the incidence of adverse drug reactions was 95.3%(82/86 subjects) and the efficacy was 63.6% (42/66). Taken together, these data indicate that the safety and efficacy of L-AMB are almost the same in pediatric and adult patients.

Topics: Amphotericin B; Antifungal Agents; Child; Child, Preschool; Creatinine; Female; Humans; Hypokalemia; Male; Mycoses; Neutropenia

Given that the rationale for empirical antifungal therapy in neutropenic children is limited and based on adult patient data, we performed a prospective, randomized, controlled trial that evaluated 110 neutropenic children with persistent fever. Those at high risk for invasive fungal infections (IFI) received caspofungin (Arm C) or liposomal amphotericinB (Arm B); those with a lower risk were randomized to receive Arm B, C, or no antifungal treatment (Arm A). Complete response to empirical antifungal therapy was achieved in 90/104 patients (86·5%): 48/56 at high risk (85·7%) [88·0% in Arm B; 83·9% in Arm C (P = 0·72)], and 42/48 at low risk (87·5%) [87·5% in control Arm A, 80·0% Arm B, 94·1% Arm C; (P = 0·41)]. None of the variables tested by multiple logistic regression analysis showed a significant effect on the probability to achieve complete response. IFI was diagnosed in nine patients (8·2%, 95% confidence interval, 3·8-15·0). This randomized controlled study showed that empirical antifungal therapy was of no advantage in terms of survival without fever and IFI in patients aged <18 years and defined with low risk of IFI. Higher risk patients, including those with relapsed cancer, appear to be the target for empirical antifungal therapy during protracted febrile neutropenia.

Topics: Amphotericin B; Antifungal Agents; Antineoplastic Agents; Caspofungin; Child; Child, Preschool; Echinocandins; Female; Fever of Unknown Origin; Hospitalization; Humans; Infant; Length of Stay; Lipopeptides; Male; Mycoses; Neutropenia; Opportunistic Infections; Patient Selection; Prospective Studies; Treatment Outcome

Pediatric patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) often receive intravenous liposomal amphotericin B (L-AmB) as antifungal prophylaxis. There are no guidelines for antifungal prophylaxis in children in this situation. Caspofungin (CAS), a broad-spectrum echinocandin, could be an effective alternative with lower nephrotoxicity than L-AmB.. We retrospectively analyzed the safety, feasibility, and efficacy of CAS in our center, and compared the results with L-AmB as antifungal monoprophylaxis in pediatric patients undergoing HSCT. 60 pediatric patients received L-AmB (1 or 3 mg/kg bw/day) and another 60 patients received CAS (50 mg/m2/day) as antifungal monoprophylaxis starting on day one after HSCT. The median ages of patients receiving L-AmB and CAS were 7.5 years and 9.5 years, respectively.. No proven breakthrough fungal infection occurred in either group during the median treatment period of 23 days in the L-AmB group and 24 days in the CAS group. One patient receiving CAS developed probable invasive aspergillosis. During L-AmB treatment, potassium levels significantly decreased below normal values. Patients treated with L-AmB had more drug-related side effects and an increased need for oral supplementation with potassium, sodium bicarbonate and calcium upon discharge as compared with the CAS group. CAS was well-tolerated and safe in this cohort of immunocompromised pediatric patients, who underwent high-dose chemotherapy and HSCT.. Prophylactic CAS and L-AmB showed similar efficacy in this biggest cohort of pediatric patients after allogeneic HSCT reported, so far. A prospective randomized trial in children is warranted to allow for standardized guidelines.

Topics: Adolescent; Amphotericin B; Antifungal Agents; Caspofungin; Chemoprevention; Child; Child, Preschool; Echinocandins; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Infant; Lipopeptides; Male; Mycoses; Retrospective Studies; Transplantation, Homologous

Antifungal prophylaxis is shown to decrease the risk of invasive fungal infection (IFI) after hematopoietic stem-cell transplantation (HSCT). Posaconazole has been approved for prophylaxis in HSCT. However, it is only available orally given three times per day. We evaluated once weekly intravenous amphotericin B lipid complex (ABLC), given its broad-spectrum antifungal activity and prolonged half-life (172 hr), as an alternative prophylaxis in HSCT.. We prospectively randomized allogeneic HSCT patients to receive 7.5 mg/kg of intravenous ABLC weekly or 200 mg of posaconazole orally three times per day as prophylaxis for up to 6 weeks. Endpoints were the incidence of IFI and drug-related toxicities. ABLC was discontinued if creatinine level increased to two times the baseline or greater.. A total of 46 patients were randomized; 40 received at least one dose of the drug and were included in the analysis: 19 received ABLC and 21 received posaconazole. All patients received tacrolimus. Apache II score, neutropenia, and creatinine, bilirubin, and alanine aminotransferase levels were similar in both groups at baseline. One patient in the ABLC arm and none in posaconazole arm developed IFI (5% vs. 0%, P=0.48). More patients in the ABLC arm doubled their serum creatinine (53% vs. 5%, P=0.001) necessitating discontinuation of the study drug.. High-dose prophylactic ABLC in HSCT was associated with nephrotoxicity that could be aggravated by the concomitant use of other nephrotoxic agents. Further studies are needed to evaluate the role of weekly high-dose ABLC as antifungal prophylaxis in patients at lower risk for nephrotoxicity.

Topics: Administration, Oral; Adult; Aged; Amphotericin B; Antifungal Agents; Female; Hematopoietic Stem Cell Transplantation; Humans; Infusions, Intravenous; Leukemia; Lipids; Lymphoma; Male; Middle Aged; Mycoses; Prospective Studies; Risk; Tacrolimus; Time Factors; Transplantation, Homologous; Triazoles

Topics: Adolescent; Amphotericin B; Antibiotic Prophylaxis; Antifungal Agents; Child; Child, Preschool; Early Termination of Clinical Trials; Female; Hospitals, Pediatric; Humans; Immunocompromised Host; Liposomes; Lung Diseases, Fungal; Male; Mycoses; Time Factors

In 2008, the European Organisation for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) published revised definitions for diagnosing invasive fungal disease. A previous prospective trial of liposomal amphotericin B for invasive mould disease (AmBiLoad) used modified EORTC/MSG 2002 criteria. We wished to re-evaluate the response and survival based on the revised definitions to compare the outcomes of early vs. late treatment. Patients who had received an allogeneic haematopoietic stem cell transplant or who were neutropaenic (absolute neutrophil count <500 μl(-1) within 14 days of study entry) had been recruited on the basis of a halo or air crescent sign on chest computerised tomography. Originally classified as probable invasive mould disease, they were categorised as possible invasive mould disease using 2008 criteria. Patients had received liposomal amphotericin B at either 3 or 10 mg kg(-1) QD for 14 days, followed by 3 mg kg(-1) QD. Response at end of treatment and the 12-week survival were re-calculated according to 2008 definitions. Six-week survival was estimated by Kaplan-Meier analysis. Of 201 patients with invasive mould disease, 118 (59%) had a diagnosis based on halo signs (possible cases). Mycological evidence was present in 83 (41%) cases (probable/proven cases). Survival rates at 12 weeks for possible vs. probable/proven cases in the 3 mg kg(-1) QD group were 82% vs. 58% (P = 0.006), and 65% vs. 50% (P = 0.15) in the 10 mg kg(-1) QD group. At 6 weeks, rates were 87% vs. 69% in the 3 mg kg(-1) QD group (P = 0.009), and 75% vs. 61% in the 10 mg kg(-1) QD group (P = 0.01). Patients with possible invasive mould disease based on EORTC/MSG 2008 criteria had improved survival rates compared with those treated for probable/proven invasive mould disease. As possible invasive mould disease probably reflects an early-stage of disease, a better outcome might be expected when treatment with liposomal amphotericin B is started preemptively.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Child; Child, Preschool; Female; Humans; Immunocompromised Host; Infant; Infant, Newborn; Male; Middle Aged; Mycoses; Survival Analysis; Treatment Outcome

Patients with neutropenic fever after 4-7 days of broad-spectrum antibiotics are given antifungals empirically. This strategy may lead to over-treatment.. Patients with hematological malignancies undergoing intensive chemotherapy or hematopoietic stem cell transplantation were randomized to two arms. Patients in the 'preemptive' arm had regular galactomannan (GM) assays, and received caspofungin, amphotericin or voriconazole (CAV) for persistent febrile neutropenia if they had two positive GM results, or a positive GM result and a computed tomography (CT) of the thorax suggestive of invasive pulmonary aspergillosis (IPA). Patients in the 'empirical' arm received CAV in accordance with established guidelines.. Of 27 episodes in the preemptive arm, two cases of IPA were picked up by monitoring. In six episodes, CAV was started despite persistently negative GM readings. One additional patient received CAV for a false-positive GM. Of 25 episodes in the empirical arm, CAV was started empirically in 10, one of whom had CT features of IPA. By intent-to-treat and evaluable-episode analyses, respectively, the preemptive approach saved 11% and 14% of patients from empirical antifungals. Twelve-week survival was 85.2% in the preemptive arm and 84% in the empirical arm.. A preemptive approach may reduce empirical antifungal use without compromising survival in persistently febrile neutropenic patients.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Caspofungin; Drug Therapy, Combination; Echinocandins; Female; Fever; Galactose; Humans; Immunocompromised Host; Invasive Pulmonary Aspergillosis; Lipopeptides; Male; Mannans; Middle Aged; Mycoses; Neutropenia; Opportunistic Infections; Prospective Studies; Pyrimidines; Radiography, Thoracic; Risk Factors; Singapore; Tomography, X-Ray Computed; Treatment Outcome; Triazoles; Voriconazole

Invasive fungal infections (IFI) are a major cause of infection-related mortality during induction chemotherapy of acute leukemia (AL) patients. Data on antifungal prophylaxis (AFP) in children are limited by retrospective design, small sample size, and variability of chemotherapy phases having different risk of IFI. There are no data comparing voriconazole versus amphotericin B (AmB) as AFP in either adult/pediatric AL. The objectives of this study were to compare efficacy and toxicity of AmB and voriconazole as AFP in pediatric AL patients.. As a pilot study, total 100 children (≤15 y) with denovo acute myeloid leukemia and acute lymphoblastic leukemia were randomized to either oral voriconazole or low dose intravenous AmB as AFP during induction chemotherapy.. Failure of prophylaxis occurred in 14/50 patients in voriconazole arm (1 proven mucormycosis, 1 possible IFI, 11 empirical antifungal therapy, and 1 withdrawal owing to hepatotoxicity) and 17/50 patients in AmB arm (3 possible IFI, 13 empirical antifungal therapy, and 1 withdrawal owing to difficult venous access) (P=0.66). Of the 29 patients who had failure of prophylaxis unrelated to drug toxicity, computed tomography of the chest showed infiltrates in 10 patients with 3/12 in voriconazole arm and 7/16 in AmB arm (P=0.43). Drug-related serious adverse events were 6% versus 30% in voriconazole and AmB arms, respectively (P<0.01). Further, total number of toxicities per patient in AmB arm were significantly higher as compared with voriconazole arm (P<0.0001).. This is the first randomized study comparing voriconazole with AmB in pediatric AL patients as AFP during induction chemotherapy; our results showed that oral voriconazole seems to be comparable with AmB with less toxicity and more convenience. (ClinicalTrials.gov identifier: NCT00624143).

Topics: Administration, Oral; Adolescent; Amphotericin B; Antifungal Agents; Antineoplastic Agents; Child; Child, Preschool; Female; Humans; Infant; Infusions, Intravenous; Leukemia, Myeloid, Acute; Male; Mycoses; Pilot Projects; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Pyrimidines; Treatment Outcome; Triazoles; Voriconazole

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Caspofungin; Child; Child, Preschool; Drug Therapy, Combination; Echinocandins; Female; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Lipopeptides; Male; Middle Aged; Mycoses; Neutropenia; Prospective Studies; Pyrimidines; Transplantation Conditioning; Triazoles; Voriconazole; Young Adult

To analyse the potential antagonism between azoles, which inhibit ergosterol synthesis, and polyenes, which bind directly to ergosterol in cell membranes, in patients receiving sequential azole-polyene treatment.. In an earlier randomized, double blind study of liposomal amphotericin as initial therapy for invasive filamentous fungal infection (IFFI), a 3 mg/kg/day dose had a favourable overall response rate of 50% and 12 week survival rate of 72%. No improved outcome was seen with 10 mg/kg/day for the first 14 days. The study population was further analysed for the effect of prior azole exposure on treatment responses to liposomal amphotericin B. The protocol allowed prior treatment with azoles for prophylaxis or empirical therapy, and for up to 4 days for the confirmed IFFI before starting liposomal amphotericin B. Outcomes were compared for subsets of patients based on receipt of any azole and receipt of voriconazole during the 30 day screening period prior to study treatment.. Of 201 patients with data review board-confirmed IFFI, 116 (57.7%) received prior azoles and 36 (17.9%) received prior voriconazole. Favourable responses were achieved in 57 (49.1%) patients with prior azole exposure, in 39 (45.9%) without prior azole and in 13 (36.1%) with prior voriconazole. Numbers of patients alive at 12 weeks were 74 (63.8%) with any prior azole, 56 (65.9%) without prior azole and 26 (72.2%) after prior voriconazole. No differences were statistically significant.. Prior treatment with any azole or specifically with voriconazole did not seem to impact on overall response or survival in patients treated with liposomal amphotericin B for confirmed IFFI.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Azoles; Child; Child, Preschool; Double-Blind Method; Drug Interactions; Female; Humans; Infant; Male; Middle Aged; Mycoses; Treatment Outcome; Young Adult

Invasive fungal infections (IFIs) are major complications after allogeneic hematopoietic SCT (HSCT). PCR-based assays able to detect fungal DNA have been reported to precede clinical diagnosis of IFI. We performed a prospective study to evaluate a PCR-based pre-emptive approach. Ninety-nine patients undergoing reduced-intensity conditioning (RIC) HSCT were followed with fungal PCR during the first 100 days post transplantation. Patients who tested positive were randomized to receive liposomal amphotericin B, or to no intervention. After day 100, PCR tests were performed only on clinical suspicion of IFI. A single positive PCR test was not associated with IFI, irrespective of treatment. After day 100, PCR tests for Aspergillus did not contribute to diagnosis of invasive aspergillosis (IA). The cumulative incidence rates of proven or probable IA during the first year after transplantation were 9%. GVHD grades II-IV (P=0.0014), CMV-seronegative recipient with CMV-seropositive donor (P0.001), and conditioning with alemtuzumab (P=0.014) were significant risk factors for developing IA in a multivariate model. In this study, PCR on peripheral blood was a poor indicator of IFI early after RIC HSCT. Aspergillus PCR tests performed on clinical suspicion after day 100 were insufficiently sensitive to be diagnostically useful.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus; Candida; Candidiasis; Child; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Middle Aged; Mycoses; Polymerase Chain Reaction; Prospective Studies; Risk Factors; Treatment Outcome; Young Adult

The objective of this study was to assess the costs and effectiveness (avoided invasive fungal infections - IFIs; overall mortality) of prophylaxis with posaconazole 200 mg per os TID and standard azoles (fluconazole 400 mg per os OD, itraconazole 200 mg per os BID) in neutropenic patients with acute myelogenous leukaemia or myelodysplastic syndromes. A 100-day cost-effectiveness model was developed following the Italian hospital perspective. The probability of IFIs, death from IFIs, and death from other causes was obtained from the literature. Health care sector resources (type, volume, unit cost) are given in Euros and refer to 2009. The robustness of the cost-effectiveness model was tested via one-way and probabilistic sensitivity analyses. Total costs for posaconazole (standard azoles) was estimated at Euros 3365.26 (Euros 2339.96). Posaconazole is consistently more effective than standard azoles. The incremental cost-effectiveness ratio for avoided IFI (avoided overall mortality) with posaconazole is Euros 15,850.51 (Euros 18,038.43). Sensitivity analyses confirmed the robustness of such findings. In conclusion, posaconazole as a prophylaxis in neutropenic patients with AML or MDS who are at risk of IFI is good value for money for Italian hospitals.

Topics: Administration, Oral; Amphotericin B; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Cost-Benefit Analysis; Deoxycholic Acid; Drug Combinations; Drug Costs; Equipment and Supplies; Fluconazole; Follow-Up Studies; Hospital Costs; Humans; Immunocompromised Host; Infusions, Intravenous; Italy; Itraconazole; Leukemia, Myeloid, Acute; Mycoses; Myelodysplastic Syndromes; Neutropenia; Oncology Nursing; Treatment Outcome; Triazoles

The combination of liposomal amphotericin B (LAMB) and caspofungin (CAS) holds promise to improve the outcome of opportunistic invasive mycoses with poor prognosis. Little is known, however, about the safety and pharmacokinetics of the combination in patients at high risk for these infections. The safety and pharmacokinetics of the combination of LAMB and CAS were investigated in a risk-stratified, randomized, multicenter phase II clinical trial in 55 adult allogeneic hematopoietic stem cell recipients (aHSCT) with granulocytopenia and refractory fever. The patients received either CAS (50 mg/day; day 1, 70 mg), LAMB (3 mg/kg of body weight/day), or the combination of both (CASLAMB) until defervescence and granulocyte recovery. Safety, development of invasive fungal infections, and survival were assessed through day 14 after the end of therapy. Pharmacokinetic sampling and analysis were performed on days 1 and 4. All three regimens were well tolerated. Premature study drug discontinuations due to grade III/IV adverse events occurred in 1/18, 2/20, and 0/17 patients randomized to CAS, LAMB, and CASLAMB, respectively. Adverse events not leading to study drug discontinuation were frequent but similar across cohorts, except for a higher frequency of hypokalemia with CASLAMB (P < 0.05). Drug exposures were similar for patients receiving combination therapy and those randomized to monotherapy. There was no apparent difference in the occurrence of proven/probable invasive fungal infections and survival through day 14 after the end of therapy. CASLAMB combination therapy in immunocompromised aHSCT patients was as safe as monotherapy with CAS or LAMB and had similar plasma pharmacokinetics, lending support to further investigations of the combination in the management of patients with invasive opportunistic mycoses.

Topics: Adolescent; Adult; Agranulocytosis; Amphotericin B; Antifungal Agents; Caspofungin; Child; Child, Preschool; Drug Therapy, Combination; Echinocandins; Female; Hematopoietic Stem Cell Transplantation; Humans; Lipopeptides; Male; Middle Aged; Mycoses; Transplantation, Homologous; Treatment Outcome; Young Adult

A major randomized clinical trial, evaluating voriconazole versus liposomal amphotericin B (LAMB) as empirical therapy in febrile neutropenia, recommended voriconazole as a suitable alternative to LAMB. The current study sought to investigate the health economic impact of using voriconazole and LAMB for febrile neutropenia in Australia.. A decision analytic model was constructed to capture downstream consequences of empirical antifungal therapy with each agent. The main outcomes were: success, breakthrough fungal infection, persistent baseline fungal infection, persistent fever, premature discontinuation and death. Underlying transition probabilities and treatment patterns were derived directly from trial data. Resource use was estimated using an expert panel. Cost inputs were obtained from the latest Australian representative published sources. The perspective adopted was that of the Australian hospital. Uncertainty and sensitivity analyses were undertaken via the Monte Carlo simulation.. Compared with voriconazole, LAMB was associated with a net cost saving of AU$1422 (2.9%) per patient. A similar trend was observed with the cost per death prevented and successful treatment. LAMB dominated voriconazole as it resulted in higher efficacy and lower costs when compared with voriconazole. The results were most sensitive to the duration of therapy and the alternative therapy used post discontinuations. In uncertainty analysis, LAMB had 99.8% chance of costing less than voriconazole.. In this study, which used the current standard five component endpoint to assess the impact of empirical antifungal therapy, LAMB was associated with cost savings relative to voriconazole.

Topics: Amphotericin B; Australia; Cost-Benefit Analysis; Fever; Humans; Mycoses; Neutropenia; Pyrimidines; Treatment Outcome; Triazoles; Voriconazole

We compared the efficacy and safety of empirical plus PCR-based vs empirical liposomal amphotericin B treatment after Allo-SCT. Allo-SCT recipients were randomized to receive either PCR-based preemptive therapy (group A; n=198) or empirical antifungal therapy (group B; n=211) with liposomal amphotericin B. In group A, therapy was started after one positive PCR result or after 120 h of febrile neutropenia refractory to broad-spectrum antibacterial therapy. In group B, liposomal amphotericin B was started after 120 h of refractory febrile neutropenia. Demographic and clinical characteristics were well balanced. A total of 112 (57.1%) patients in group A and 76 (36.7%) patients in group B received antifungal therapy (P<0.0001). Twelve patients in group A and 16 patients in group B developed proven invasive fungal infection (IFI). Survival curves showed better survival until day 30 when close PCR monitoring was performed (mortality 1.5 vs 6.3%; P=0.015), but there was no difference at day 100. At day 100, no difference was observed in the incidence of IFI (primary end point) and survival between the two arms. Further studies are required to assess the benefit of using PCR in patients after SCT.

Topics: Adolescent; Adult; Aged; Amphotericin B; Child; Child, Preschool; Female; Humans; Infant; Liposomes; Male; Middle Aged; Mycoses; Polymerase Chain Reaction; Stem Cell Transplantation; Survival Analysis; Transplantation, Homologous

Antifungal prophylaxis for liver transplant recipients (LTRs) is common among patients considered at high risk of infection, but optimal prophylaxis duration and drug has not been defined. This study aimed to assess the effects of 14 days of antifungal therapy prophylaxis in reducing proven invasive fungal infections (IFI) in high-risk subjects. Eligible subjects who met 2 or more risk criteria were randomized 1:1 to the treatment arms (liposomal amphotericin B or fluconazole) and were followed for 100 days post transplantation for evidence of IFI. The study was designed to enroll 300 subjects, but was closed early for insufficient enrollment. A total of 71 subjects were enrolled and randomized. Two-thirds of subjects completed 14 days of study therapy. Ten subjects developed proven or probable IFI with Candida species (9 subjects) and Cryptococcus neoformans (1 subject); rates were similar in the 2 treatment arms. Eleven subjects died, but no death was attributed to study drug or IFI. In summary, high-risk LTRs tolerated antifungal prophylaxis well, and rates of IFI were lower than previously reported in untreated high-risk LTRs.

Topics: Adult; Amphotericin B; Antibiotic Prophylaxis; Antifungal Agents; Candida; Candidiasis; Cryptococcosis; Cryptococcus neoformans; Double-Blind Method; Female; Humans; Incidence; Liver Transplantation; Male; Middle Aged; Mycoses; Treatment Outcome

Empirical antifungal therapy is the standard of care for neutropenic patients with hematological malignancies who remain febrile despite broad-spectrum antibacterial treatment. Recent diagnostic improvements may ensure the early diagnosis of potentially invasive fungal disease. Reserving antifungals for this stage may achieve similar survival rates and reduce treatment toxicity and costs.. In this multicenter, open-label, randomized noninferiority trial, we compared an empirical antifungal strategy with a preemptive one. Empirical treatment was defined as antibacterial treatment of patients who have persistent or recurrent fever. Preemptive treatment was defined as treatment of patients who have clinical, imaging, or galactomannan-antigen-assay evidence suggesting fungal disease. First-line antifungal treatment was amphotericin B deoxycholate (1 mg/kg/day) or liposomal amphotericin (3 mg/kg/day), depending on daily renal function. The primary efficacy outcome was the proportion of patients alive at 14 days after recovery from neutropenia.. The median duration of neutropenia (neutrophil count, <500 cells/mm3) for the 293 patients enrolled was 18 days (range, 5-69 days). By intention-to-treat analysis, survival was 97.3% with empirical treatment and 95.1% with preemptive treatment. The lower 95% confidence limit for the difference in mortality was -5.9%, which was within the noninferiority margin of -8%. Probable or proven invasive fungal infections were more common among patients who received preemptive treatment than among patients who received empirical treatment (13 of 143 vs. 4 of 150; P < .05), and most infections occurred during induction therapy (12 of 73 patients in the preemptive treatment group vs. 3 of 78 patients in the empirical treatment group were infected during induction therapy; P < .01). Preemptive treatment did not decrease nephrotoxicity but decreased costs of antifungal therapy by 35%.. Preemptive treatment increased the incidence of invasive fungal disease, without increasing mortality, and decreased the costs of antifungal drugs. Empirical treatment may provide better survival rates for patients receiving induction chemotherapy.

Topics: Adult; Aged; Amphotericin B; Antibiotic Prophylaxis; Antifungal Agents; Chi-Square Distribution; Deoxycholic Acid; Drug Combinations; Female; Fever; Humans; Male; Middle Aged; Multicenter Studies as Topic; Mycoses; Neutropenia; Opportunistic Infections; Risk Factors; Statistics, Nonparametric

A high intermittent dose regimen (group A: 10 mg kg(-1) on day 1, 5 mg kg(-1) on days 3 and 6) was compared with standard dosing (group B: 3 mg kg(-1) per day for 14 days) of liposomal amphotericin B (LAB) for empirical treatment of persistent febrile neutropenia. A total cumulative dose of 1275 mg (group A) and 2800 mg (group B) was administered. Infusion-related adverse drug events, mainly rigors/chills, occurred more frequently with group A (11/45, 24 % infusions) than with group B (12/201, 6 % infusions) (P=0.002), which extended the mean infusion time by 20 min (P=0.001). Creatinine levels were similar in the two regimens: the A : B ratio of the area under the curve for creatinine (AUC(CREATININE)) for days 2-7 was 1.09 (P=0.27) and for days 2-14 was 1.05 (P=0.51). Rises in creatinine were mild (clinical toxicity criteria 1) in all patients with elevations. Hypokalaemia tended to be less severe in group A with a lower proportion of hypokalaemic days [57/143 (39 %) vs 80/137 (58 %), P=0.21], a higher AUC(POTASSIUM) (A : B ratio of 1.06, P=0.12), a lower proportion of patients with hypokalaemia at the end of study (10 vs 61 %, P=0.01) and fewer potassium-supplemented days [12/210 (6 %) vs 41/210 (19.5 %), P<0.1]. There were mildly elevated median levels of serum bilirubin, alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase, which were similar for the two regimens and were usually associated with other co-existing co-morbid conditions. The AUC for these enzymes was also similar in the two groups. No patient had discontinuation of the study drug due to toxicity. Composite success was identical for each regimen (11/15 patients, 73 %). Three of the fifteen patients in group B and none in group A developed invasive fungal infections (IFIs). Beta-D-Glucan levels were similar in both groups for patients without an IFI [AUC(GLUCAN) of 362 and 683 (P=0.36) for groups A and B, respectively]. The rate of defervescence was similar for each regimen (P=0.75). This feasibility study suggests that a short intermittent high-dose course of 10/5/5 mg LAB kg(-1) on days 1, 3 and 6 may be as safe and effective as a standard 14 day course of 3 mg kg(-1) per day, with drug-acquisition cost savings and reduced drug exposure. A larger study is indicated for confirmation of this.

Topics: Adolescent; Adult; Amphotericin B; Antibiotic Prophylaxis; Antifungal Agents; Drug Administration Schedule; Feasibility Studies; Female; Fever; Humans; Kidney; Liver; Male; Middle Aged; Mycoses; Neutropenia; Treatment Outcome; Young Adult

To observe the efficacy and safety of amphotericin B for treatment of invasive fungal infections (IFI) in patients with hematologic diseases.. 121 patients were given amphotericin B 5 -50 mg/d for 5 - 101 d with a median of 19 d.. The clinical efficacy rate was 67.3%, and fungal elimination rate 66.7%. The adverse events included rigor and fever, hypokalaemia, hepatic damage, nephrotoxicity, nausea and vomiting, phlebitis and teeter.. Amphotericin B is still a high-efficiency drug in the treatment of IFI, although it has many side effects. With monitoring of hepatic and renal function, it is still a relatively safe and effective drug.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Female; Humans; Male; Middle Aged; Mycoses; Treatment Outcome; Young Adult

As antifungal agents are frequently used in hematology and oncology, economic data on the empirical therapy of suspected systemic fungal infection are pivotal. Data were analyzed according to: (1) the rate of nephrotoxicity related to treatment with caspofungin in comparison to liposomal amphotericin B (L-AmB) from a randomized clinical trial, (2) the effect of nephrotoxicity on length of hospital stay from a European observational study, and (3) an example of total bottom-up cost in a department of hematology in Germany. All estimates include 95% confidence intervals (CI) using two-stage Monte Carlo simulation on binominal and Gaussian random variables from separate studies with comparable populations. Overall, 8.9 (95% CI 5.9-12.1) fewer patients (of 100 randomized) experienced worsening of renal function with caspofungin vs L-AmB, giving a number needed to treat for one patient to be harmed by L-AmB of 12 (95% CI 8-17). This was estimated to translate into 5.3 extra days in hospital (95% CI 1.6-9.1) per event or 0.48 days (95% CI 0.14-0.88) worth 298 euro (95% CI 89-554) per patient receiving L-AmB rather than caspofungin. From the hospital perspective, use of caspofungin was estimated to be cost-neutral compared to L-AmB at a per diem total hospital cost of 428 euro with, and 1284 euro without, consideration of supplementary reimbursement (Zusatzentgelt) of both L-AmB and caspofungin. The data presented in this scenario show that use of caspofungin in hematology-oncology departments in Germany results in shorter hospital stays and is at least cost-neutral compared to use of L-AmB.

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Costs and Cost Analysis; Double-Blind Method; Echinocandins; Germany; Humans; Lipopeptides; Liposomes; Longitudinal Studies; Mycoses; Prospective Studies

The authors had for aim to define the threshold of nephrotoxicity before switching to other antifungal treatment in hematological patients treated by conventional amphotericin B (AmB) as an empiric antifungal treatment.. A prospective randomised multicenter study was made on 32 neutropenic hematological patients receiving conventional AmB for empirical antifungal treatment. The patients were randomised after a greater than or equal to 30% increase of serum creatinine (sCr). Patients in the early-switch group received liposomal AmB just after randomisation and patients in the late-switch group received liposomal AmB only when serum creatinine increase was greater or equal to 100% or sCr reached 170mumol/L.. Thirty-one patients were analysed: 16 patients in the early-switch group and 15 patients in the late-switch group (seven switched to liposomal AmB and eight continued conventional AmB treatment). The mean age of patients was 48 years and 68% were men. The most frequent underlying haematological malignancy was acute leukemia (94%). In the late-switch group, the degradation of renal function continued after randomisation contrary to the early-switch group: median variations of calculated sCr clearance in early- and late-switch groups were -16.8 and -1.5%, respectively (P=0.03). Moreover, an early switch was cost-effective with a sCr lower duration of hospitalisation in comparison with a late switch.. This randomised trial suggests that an early switch to Liposomal AmB improves and preserves renal function in comparison with a late switch.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Chemistry, Pharmaceutical; Creatinine; Drug Hypersensitivity; Female; Humans; Kidney; Kidney Function Tests; Liposomes; Male; Middle Aged; Mycoses

The use of high-dose corticosteroids for graft-versus-host disease (GVHD) treatment represents a major risk factor for long-term invasive fungal infections. The aim of this study was to investigate the safety and tolerance of weekly prophylactic administration of once-weekly high-dose (7.5 mg/kg) of liposomal amphotericin B (L-AmB) therapy in 21 adult patients receiving high-dose prednisone (2 mg/kg/day) for acute GVHD therapy after reduced intensity conditioning (RIC) allogeneic stem cell transplantation (allo-SCT). Patients received a median of 4 (range, 1-8) infusions of L-AmB. Seven patients (33%; 95% confidence intervals (CI), 13-53%) discontinued taking the study drug owing to study drug-related adverse events, including elevated serum creatinine (>1.5 times from baseline values; n=5), hypotension and pain (n=1), and violent chest pain and arrhythmia (n=1). The overall frequency of infusion-related reactions was 29% (n=6; 95% CI, 10-48%), but these reactions were always transient and relieved by stopping the infusion. This safety data provide support for an efficacy study of this prophylaxis strategy, because this may help further improving the outcome of RIC or nonmyeloablative allo-SCT.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Female; Graft vs Host Disease; Hematologic Neoplasms; Humans; Male; Middle Aged; Mycoses; Stem Cell Transplantation; Transplantation Conditioning; Transplantation, Homologous

In this study, rational dosing guidelines for amphotericin B-deoxycholate (AmB) are proposed for children. AmB steady-state trough concentrations (C(ss,trough)) and plasma creatinine concentrations (C(creat)) were measured in 83 children (age: 10 months to 18 years) receiving prophylactic AmB therapy (1 mg/kg/day). Maximum tolerable AmB C(ss,trough) were identified by determining the probability of large (>24%, 75th percentile) increases in C(creat) after 6 days of AmB for a series of C(ss,trough) ranges. Dose requirements were determined using a concentration-targeting approach. The 0.76-1.05 mg/l C(ss,trough) range provided the maximum concentrations that still had a low probability (p < 0.29) of adverse renal effects. 1 mg/kg/day AmB produces C(ss,trough) within this range for children weighing 25-45 kg. Lighter children (10-25 kg) require higher AmB doses (1.25-1.5 mg/kg/day) to achieve target C(ss,trough), while heavier children (45-55 kg) require lower doses (0.75 mg/kg/day). These starting dose guidelines may require individualization and prospective evaluation.

Topics: Adolescent; Amphotericin B; Antifungal Agents; Body Weight; Child; Child, Preschool; Computer Simulation; Creatinine; Cyclosporine; Deoxycholic Acid; Drug Combinations; gamma-Glutamyltransferase; Humans; Immunosuppressive Agents; Infant; Kidney Diseases; Microbial Sensitivity Tests; Models, Biological; Mycoses; Neoplasms; Risk Factors; Urea

Safety, tolerability and efficacy of itraconazole and amphotericin B (AMB) were compared for empirical antifungal treatment of febrile neutropenic cancer patients.. In an open, randomised study, 162 patients with at least 72 h of antimicrobial treatment received either intravenous followed by oral itraconazole suspension or intravenous AMB for a maximum of 28 days. Permanent discontinuation of study medication due to any adverse event was the primary safety parameter. Efficacy parameters included response and success rate for both treatment groups.. Significantly fewer itraconazole patients discontinued treatment due to any adverse event (22.2 vs. 56.8% AMB; p < 0.0001). The main reason for discontinuation was a rise in serum creatinine (1.2% itraconazole vs. 23.5% AMB). Renal toxicity was significantly higher and more drug-related adverse events occurred in the AMB group. Intention-to-treat (ITT) analysis showed favourable efficacy for itraconazole: response and success rate were both significantly higher than for AMB (61.7 vs. 42% and 70.4 vs. 49.3%, both p < 0.0001). Treatment failure was markedly reduced in itraconazole patients (25.9 vs. 43.2%), largely due to the better tolerability.. Itraconazole was tolerated significantly better than conventional AMB and also showed advantages regarding efficacy. This study confirms the role of itraconazole as a useful and safe agent in empirical antifungal therapy of febrile neutropenic cancer patients.

Topics: Administration, Oral; Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Cross-Over Studies; Empiricism; Female; Fever of Unknown Origin; Germany; Hematologic Neoplasms; Humans; Infusions, Intravenous; Itraconazole; Male; Middle Aged; Mycoses; Neutropenia; Opportunistic Infections; Patient Dropouts; Treatment Outcome

To evaluate the cost-effectiveness of caspofungin vs. liposomal amphotericin B in the treatment of suspected fungal infections in the UK.. The cost-effectiveness of caspofungin vs. liposomal amphotericin B was evaluated using a decision-tree model. The decision tree was populated using both data and clinical definitions from published clinical studies. Model outcomes included success in terms of resolution of fever, baseline infection, absence of breakthrough infection, survival and quality adjusted life years (QALYs) saved. Discontinuation due to nephrotoxicity or other adverse events were included in the model. Efficacy and safety data were based on additional analyses of a randomised, double blind, multinational trial of caspofungin compared with liposomal amphotericin B. Information on life expectancy, quality of life, medical resource consumption and costs were obtained from peer-reviewed published data.. The caspofungin mean total treatment cost was 9762 pounds (95% uncertainty interval 6955-12,577), which was 2033 pounds (-2489; 6779) less than liposomal amphotericin B. Treatment with caspofungin resulted in 0.40 (-0.12; 0.94) additional QALYs saved in comparison with liposomal amphotericin B. Probabilistic sensitivity analysis found a 95% probability of the incremental cost per QALY saved being within the generally accepted threshold for cost-effectiveness (30,000 pounds). Additional analyses with varying dose of caspofungin and liposomal amphotericin B confirmed these findings.. Given the underlying assumptions, caspofungin is cost-effective compared with liposomal amphotericin B in the treatment of suspected fungal infections in the UK.

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Cost-Benefit Analysis; Double-Blind Method; Echinocandins; Humans; Length of Stay; Lipopeptides; Liposomes; Mycoses; Peptides, Cyclic; Quality-Adjusted Life Years; United Kingdom

Despite improved supportive care, and the introduction of less toxic lipid-formulations of amphotericin B deoxycholate and other new antifungal agents the mortality from invasive fungal infection (IFI) in hematology patients remains high. New management strategies are therefore required to improve outcome.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Child; Female; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Kidney Diseases; Liposomes; Male; Middle Aged; Mycoses; Postoperative Complications; Treatment Outcome

Topics: Aged; Amphotericin B; Antifungal Agents; Drug Carriers; Female; Humans; Kidney; Kidney Diseases; Male; Middle Aged; Mycoses; Neutropenia

In a recently reported randomized trial, low-dose intravenous liposomal amphotericin B (L-AmB) reduced the incidence of invasive fungal infections (20.2 vs. 4.6%, p < 0.001) in high-risk patients with hematological malignancies and prolonged neutropenia.. In the present study, we performed a retrospective cost-benefit analysis of L-AmB prophylaxis from the hospital perspective.. Ninety-nine patients were eligible; baseline characteristics were balanced for age, sex, underlying disease, and duration of neutropenia. The mean duration of hospitalization was 42.9 days and 52.3 days in the prophylaxis arm and in patients without antifungal prophylaxis, respectively (p = 0.096). The L-AmB prophylaxis was associated with additional costs of approximately EUR 630 per patient. However, total medication costs (including L-AmB prophylaxis) were EUR 1,219 and EUR 2,815 in patients with L-AmB prophylaxis and in patients in the control arm, respectively (p < 0.001). When involving also costs for medical procedures, the L-AmB prophylaxis reaches a positive net benefit of EUR 1,094 per patient.. Our data shows that antifungal prophylaxis, e.g. with L-AmB, can be a safe and effective strategy to reduce the frequency of invasive fungal infections in selected high-risk patients and to obtain significant cost savings for the hospital.

Topics: Amphotericin B; Antifungal Agents; Comorbidity; Cost of Illness; Cost-Benefit Analysis; Female; Germany; Hematologic Neoplasms; Humans; Incidence; Male; Middle Aged; Mycoses; Neutropenia; Risk Assessment; Risk Factors; Treatment Outcome

Disseminated fungal infection causes significant morbidity and mortality in children undergoing hematopoietic stem cell transplantation (HSCT). The widespread use of prophylactic oral triazoles has limitations of poor absorption, interindividual variability in metabolism, and hepatic toxicity. AmBisome (amphotericin B liposomal complex) has a better safety profile than the parent drug amphotericin B and produces higher plasma and tissue concentrations. We hypothesized that once-weekly high-dose AmBisome therapy could provide adequate fungal prophylaxis for immunocompromised children undergoing HSCT. We performed a pharmacokinetic pilot study to determine whether once-weekly high-dose AmBisome administration would result in effective concentrations throughout the dosing interval. A total of 14 children (median age, 3 years, 1 month; range, 4.5 months-9 years, 9 months) undergoing HSCT received once-weekly intravenous AmBisome prophylaxis (10 mg/kg as a 2-hour infusion). Blood samples for pharmacokinetic measurements were drawn around the first and the fourth weekly doses. The concentration of non-lipid-complexed amphotericin in plasma was determined by a validated bioassay. Pharmacokinetic parameters after single doses and during steady state were calculated using standard noncompartmental methods. AmBisome was well tolerated at this dose. Complete pharmacokinetic profiles for weeks 1 and 4 were obtained in 12 patients. The half-life calculated in this pediatric population was shorter on average than reported in adults (45 hours vs 152 hours). The volume of distribution correlated best with body weight (R(2) = .55), and clearance was best predicted by initial serum creatinine level (R(2) = .19). Mean (+/- standard deviation) individual plasma trough concentrations were 0.23 (0.13) mg/L after single doses and 0.47 (0.41) mg/L after multiple doses. Mean steady-state area under the curve was higher at week 4 than after a single dose (P < .05). Single-dose and steady-state pharmacokinetic profiles were similar in 8 patients, whereas in 4 patients the week 4 profile showed nonlinear elimination. However, plasma concentrations at 7 days (Cmin) were not significantly different after the first and fourth doses, suggesting no significant accumulation over the course of therapy. Our data show measurable amphotericin B plasma concentrations 7 days after high-dose infusion of AmBisome. This suggests that once-weekly dosing, as described in this study, may provide usef

Topics: Amphotericin B; Antifungal Agents; Child; Child, Preschool; Female; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Humans; Infant; Male; Mycoses; Prospective Studies; Time Factors

Conventional amphotericin B-based antifungal therapy for invasive fusariosis in patients with a hematologic malignancy results in a > or = 70% failure rate. Posaconazole is a broad-spectrum antifungal agent with in vitro and in vivo activity against Fusarium species.. In this retrospective analysis of patients from 3 open-label clinical trials, we evaluated posaconazole for the treatment of invasive fusariosis. Twenty-one patients with proven or probable invasive fusariosis who had disease refractory to or who were intolerant of standard antifungal therapy received oral posaconazole suspension (800 mg per day in divided doses) as salvage therapy.. Successful outcome occurred in 10 (48%) of all 21 patients. Among patients with leukemia who received posaconazole therapy for >3 days, the overall success rate was 50%; for patients who recovered from myelosuppression, the success rate was 67%, compared with 20% for those with persistent neutropenia.. These results suggest that posaconazole is useful for the treatment of invasive fusariosis.

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; Female; Fusarium; Humans; Leukemia; Male; Middle Aged; Mycoses; Retrospective Studies; Salvage Therapy; Treatment Outcome; Triazoles

Allogeneic hematopoietic stem cell transplant (HSCT) recipients are at increased risk for invasive fungal infections (IFIs) over prolonged periods of time. Aerosolized amphotericin B lipid complex (ABLC) has shown promise in lung transplant recipients as a convenient means of delivering protective drug to the upper airways avoiding systemic toxicities. The safety and tolerability of aerosolized ABLC in 40 subjects undergoing allogeneic HSCT was prospectively investigated in an open-labeled, non-comparative study. Subjects received aerosolized ABLC treatment once daily for 4 days, then once weekly for 13 weeks; fluconazole was administered daily as standard of care through post-transplant day 100. Pulmonary mechanics were measured before and after each dose of inhaled ABLC; adverse events (AEs) and the development of IFI were also monitored. Cough, nausea, taste disturbance, or vomiting followed 2.2% of 458 total inhaled ABLC administrations; 5.2% of inhaled ABLC administrations were associated with >or=20% decrease in pulmonary function measurements (forced expiratory volume in 1 second or forced vital capacity) and none required treatment with bronchodilators or withdrawal from study. Four mild AEs were considered possibly or probably related to study treatment; no deaths or withdrawals from treatment were attributed to study drug. Of 3 proven IFIs occurring during the study period, only 1, a catheter-related case of disseminated fusariosis, occurred while the subject was receiving study medication. Aerosolized ABLC was well tolerated in allogeneic HSCT recipients. With only 1 of 40 subjects developing IFI while receiving treatment, the combination of fluconazole and inhaled ABLC warrants further study as antifungal prophylaxis following allogeneic HSCT.

Topics: Adolescent; Adult; Aerosols; Amphotericin B; Antifungal Agents; Drug Combinations; Drug Therapy, Combination; Female; Fluconazole; Hematopoietic Stem Cell Transplantation; Humans; Male; Middle Aged; Mycoses; Phosphatidylcholines; Phosphatidylglycerols; Safety; Transplantation, Homologous; Treatment Outcome

Sensitivity analyses were incorporated in a Phase III study of caspofungin vs. liposomal amphotericin B as empirical antifungal therapy for febrile neutropenic patients to determine the impact of varying definitions of fever resolution on response rates.. The primary analysis used a 5-part composite endpoint: resolution of any baseline invasive fungal infection, no breakthrough invasive fungal infection, survival, no premature discontinuation of study drug, and fever resolution for 48 h during the period of neutropenia. Pre-specified analyses used 3 other definitions for fever resolution: afebrile for 24 h during the period of neutropenia, afebrile at 7 days post therapy, and eliminating fever resolution altogether from the composite endpoint. Patients were stratified on entry by use of antifungal prophylaxis and risk of infection. Allogeneic hematopoietic stem cell transplants or relapsed acute leukemia defined high-risk patients.. In the primary analysis, 41% of patients in each treatment group met the fever-resolution criteria. Low-risk patients had shorter durations of neutropenia but failed fever-resolution criteria more often than high-risk patients. In each exploratory analysis, response rates increased in both treatment groups compared to the primary analysis, particularly in low-risk patients.. Response rates for the primary composite endpoint for both treatment groups in this study were driven by low rates of fever resolution. Requiring fever resolution during neutropenia in a composite endpoint can mask more clinically relevant outcomes.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Caspofungin; Double-Blind Method; Echinocandins; Female; Fever; Hematopoietic Stem Cell Transplantation; Humans; Lipopeptides; Male; Middle Aged; Mycoses; Neutropenia; Peptides, Cyclic; Risk Factors; Time Factors; Transplantation, Homologous; Treatment Outcome

Fungal infection may be secondary to nasal polyposis or represent a real etiopathogenic factor in the infection itself.. The aim of this study was to evaluate the effectiveness of a combined treatment with lysine acetylsalicylate (LAS) and amphotericin B in preventing recurrence in patients with nasal polyposis with accompanying mycotic infection in comparison with a control group with nasal polyposis and fungal infection who did not receive antifungal therapy.. A total of 115 patients with nasal polyposis were randomly assigned to 4 different groups and treated as follows: (1) group A, 25 patients were first surgically treated and then treated with LAS; (2) group B, 25 patients received 40 mg of triamcinolone retard intramuscularly 3 times every 10 days (total dose 120 mg) and then they were treated with LAS; (3) group C, 16 patients were surgically treated and then treated with LAS and amphotericin B; (4) group D: 23 patients were treated with a medical polypectomy and steroids (as in the group B) and then with LAS and amphotericin B.. We found no significant differences between groups C and D, groups C and A, or groups B and D. However, the recurrence of nasal polyps in the groups treated with amphotericin B plus LAS (C and D) was significantly lower (P = .018) than in the 2 groups treated only with LAS (A and B).. Our results indicate that long term topical treatment with LAS and amphotericin B may be clinically effective in the treatment of patients with nasal polyposis associated with fungal infection.

Topics: Administration, Intranasal; Amphotericin B; Antifungal Agents; Aspirin; Dose-Response Relationship, Drug; Drug Therapy, Combination; Fungi; Humans; Kaplan-Meier Estimate; Lysine; Mycoses; Nasal Polyps; Treatment Outcome

Invasive fungal infections (IFI) are frequent causes of mortality after allogeneic stem-cell transplantation (SCT). A very important risk factor for IFI is the use of steroids. We used a risk-based chemoprevention in an open-labelled pilot study. All patients received oral fluconazole or itraconazole (200-400 mg day(-1)) during their neutropenic episode. Starting on day +30, patients receiving prednisone > or =30 mg day(-1) were switched to twice weekly Amphotericin-B-lipid-complex (ABLC) in a dose of 4 mg kg(-1). Patients receiving lower steroid doses continued on the fluconazole/itraconazole prophylaxis. Between 1999 and 2002, 100 patients were enrolled and followed for IFI for 1 year. Seven patients were started on therapeutic daily ABLC treatment before day +30 because of documented or suspected IFI; four had definite or probable aspergillosis, and two had candidaemia. Thirty patients did not need prophylactic ABLC; only one developed candidaemia. Sixty-three patients received ABLC prophylaxis for a median of 52 days (range: 1-289). Seven of these patients developed IFI; one definite and two probable cases of aspergillosis, one case of probable Trichosporon beigelii infection, and three cases of candidaemia. The twice weekly ABLC was well tolerated. This risk-based chemoprevention appears to be effective and might diminish the role of steroids as risk factor for IFI after allogeneic SCT. The relatively high incidence of early IFI suggests that additional prophylaxis for IFI may be indicated for poor-risk patients prior to day +30.

Topics: Administration, Oral; Adolescent; Adult; Aged; Amphotericin B; Anti-Inflammatory Agents; Antifungal Agents; Child; Drug Administration Schedule; Drug Combinations; Female; Humans; Injections, Intravenous; Male; Middle Aged; Mycoses; Phosphatidylcholines; Phosphatidylglycerols; Pilot Projects; Postoperative Complications; Prednisone; Stem Cell Transplantation; Steroids; Time Factors; Treatment Outcome

Fungal infections are a major cause of morbidity and mortality in patients with hematological malignancies. Candida and Aspergillus species are the most important opportunistic fungal pathogens in this patient population. Amphotericin B is the treatment of choice, but its administration is often hampered by severe side-effects, which may be reduced by continuous infusion of this drug. We describe 17 consecutive patients with hematological malignancies, suffering from fever of unknown origin with possible fungal infections, treated with amphotericin B as continuous infusion compared with a control group of 10 patients treated with conventional rapid infusion of amphotericin B over 2 - 6 h. No acute side-effects or severe nephrotoxicity were observed during continuous infusion of amphotericin B. Target doses were reached faster in patients with continuous infusion of amphotericin B than in patients with rapid infusion. We conclude that continuous infusion of amphotericin B is safe in neutropenic patients with hematological malignancies.

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; C-Reactive Protein; Deoxycholic Acid; Dose-Response Relationship, Drug; Drug Combinations; Female; Fever; Hematologic Neoplasms; Humans; Infusions, Intravenous; Male; Middle Aged; Mycoses; Neutropenia; Treatment Outcome

We treated 74 adults with a hematological malignancy and documented or suspected invasive fungal infection (IFI) with amphotericin B lipid complex (ABLC) at 3 mg/kg/day. Forty-five patients (61%) received upfront therapy and 29 patients (39%) received salvage therapy for their IFI. Forty-eight of 71 evaluable patients responded [complete responses in 40 (56%) and partial responses in 8 (11%)] and 15 (21%) died as a consequence of the IFI. Response rates in invasive aspergillosis were 33 out of 49 (67%) for probable/definite cases and 6 out of 11 (55%) for invasive candidiasis. In 40 patients with neutropenia-associated IFI, rapid neutropenic recovery ( < 10 days from study entry) was essential for response to therapy (90% vs. 32%, P < 0.01). Treatment was well tolerated, with 15% infusions followed by infusion-related adverse events, nephrotoxicity in 7% of patients and 11% of withdrawals due to toxicity. These data suggest that intermediate-doses of ABLC may be of similar efficacy than higher doses with less toxicity, making it a cost-effective alternative worthy of study in future trials.

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; Female; Hematologic Neoplasms; Humans; Lipids; Male; Middle Aged; Mycoses; Salvage Therapy

Invasive fungal infections are a life-threatening complication in transplant recipients. The prevalence of fungal infection after orthotopic liver transplantation (OLT) is 5% to 42%. The most common isolated pathogens are Candida and Aspergillus species. High-risk liver transplant recipients are more susceptible to the development of invasive fungal infections, with prevalence >40% and mortality rates of 78% to 100%. The strategy for fungal prophylaxis in this population has not been defined.. Among 100 consecutive OLT followed for 28 months, 21 recipients (15 men, overall mean age of 48.5 years, range 23-65 years) were considered to be high risk for the development of fungal infections when they presented at least one of the following criteria: acute liver failure, assisted ventilation >7 days, retransplantation, relaparotomy, antibiotic therapy >14 days, transfusion requirements >20 red blood cells units, and/or biliary leakage. This group received intravenous liposomal amphotericin B (1 mg/kg/d for 7-10 days).. One-year survival in the high-risk group was 80%. Prevalence of invasive fungal infection was 9.5%. No Candida infection was observed. Two patients developed Aspergillus infection: an abdominal aspergillosis treated with percutaneous drainage and liposomal amphotericin B (5 mg/kg/d) showed a favorable clinical outcome. The other patient who developed brain aspergillosis died 25 days after OLT. Adverse events related to the drug were hypokalemia (n = 2), back pain (n = 3), and renal dysfunction (n = 2). None of these events required withdrawal of the prophylaxis regimen.. In our series, prophylaxis with liposomal amphotericin B in high-risk liver graft recipients showed a low rate of severe fungal infections. More studies are needed in order to determine the highest risk population and the best drug dosage.

Topics: Amphotericin B; Antifungal Agents; Disease Susceptibility; Humans; Liver Transplantation; Mycoses; Postoperative Complications; Survival Analysis

Aerosolized administrations of amphotericin B deoxycholate (AmBd) and amphotericin B lipid complex (ABLC) in lung transplant recipients were compared for safety and tolerability. The incidence of invasive fungal infections in patients receiving aerosolized amphotericin B formulations as sole prophylaxis was determined.. A prospective, randomized (1:1), double-blinded trial was conducted with 100 subjects. AmBd and ABLC were administered postoperatively by nebulizer at doses of 25 mg and 50 mg, respectively, which were doubled in mechanically ventilated patients. The planned treatment was once every day for 4 days, then once per week for 7 weeks. Treatment-related adverse events and invasive fungal infections were quantitated for 2 months after study drug initiation.. Intent-to-treat analysis revealed study drug was discontinued for intolerance in 6 of 49 (12.2%) and 3 of 51 (5.9%) patients in the AmBd- and ABLC-treated groups, respectively (p=0.313). Subjects receiving AmBd were more likely to have experienced an adverse event (odds ratio 2.16, 95% confidence interval 1.10, 4.24, p=0.02). Primary prophylaxis failure within 2 months of study drug initiation was observed in 7 of 49 (14.3%) AmBd-treated patients and 6 of 51 (11.8%) ABLC-treated patients. No fungal pneumonias were observed. Only two (2%) patients experienced documented primary prophylaxis failure with Aspergillus infections within the follow-up period.. Both aerosol AmBd and ABLC appear to be associated with a low rate of invasive pulmonary fungal infection in the early posttransplant period. Patients receiving ABLC were less likely to experience a treatment-related adverse event.

Topics: Adolescent; Adult; Aerosols; Aged; Amphotericin B; Deoxycholic Acid; Double-Blind Method; Drug Combinations; Female; Heart-Lung Transplantation; Humans; Lung Diseases; Lung Transplantation; Male; Middle Aged; Mycoses; Phosphatidylcholines; Phosphatidylglycerols; Postoperative Complications; Racial Groups; Retrospective Studies

Conventional amphotericin B (c-AmB) remains the empirical antifungal treatment of choice for neutropenic patients with persistent fever of unknown origin (FUO). Unfortunately, empirical treatment with c-AmB is hampered by its safety profile, with frequent infusion-related adverse events (IRAEs) and renal toxicity. Amphotericin B lipid complex (ABLC) has been investigated for this indication due to its low toxicity profile. The recommended dose of ABLC is 5 mg/kg/d, which is five to seven times higher than the recommended dose of c-AmB.. This randomized, controlled trial includes 105 adult patients with hematologic malignancies and with FUO after receiving chemotherapy or autologous stem cell transplantation. Patients were randomly allocated to receive ABLC at 1 mg/kg/d or c-AmB at 0.6 mg/kg/d for empirical antifungal therapy.. The incidence of renal toxicity was significantly lower in the ABLC group, compared with c-AmB group: 8% vs. 32%, respectively (P = 0.003). The rates of IRAEs were similar in both groups (73% for ABLC vs. 77% for c-AmB). The overall response rate was 72% for ABLC compared with 48% for c-AmB (P = 0.018). This difference was mainly due to the significantly higher renal toxicity in the c-AmB group. The number of emergent fungal infections and overall mortality were similar in both groups.. This randomized trial suggests that ABLC at 1 mg/kg/d produces less nephrotoxicity than c-AmB, without differences in the incidence of IRAEs and with similar efficacy.

Topics: Adult; Amphotericin B; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Chemical and Drug Induced Liver Injury; Combined Modality Therapy; Drug Combinations; Female; Fever of Unknown Origin; Hematologic Neoplasms; Humans; Hypokalemia; Immunocompromised Host; Incidence; Kidney Diseases; Male; Middle Aged; Mycoses; Neutropenia; Peripheral Blood Stem Cell Transplantation; Phosphatidylcholines; Phosphatidylglycerols; Treatment Outcome

This study assessed the risk of haematological, renal and hepatic toxicity associated with amphotericin B lipid complex (ABLC; Abelcet) in a multicentre, open-label, non-comparative study of 93 patients from 17 different hospitals who received ABLC because of proven or suspected systemic fungal infection or leishmaniasis. Most (66%) patients had onco-haematological diseases. Optimum treatment with ABLC comprised a slow (2-h) infusion dose of 5 mg/kg/day for a minimum period of 14 days. Biochemical and haematological parameters were measured pre-, during and post-treatment. In the overall patient group, the mean serum creatinine concentration was similar pre- and post-study (1.00 +/- 1.14 mg/dL vs. 1.20 +/- 1.19 mg/dL; p > 0.05). There were no significant changes pre- and post-treatment in concentrations of haemoglobin, potassium, transaminases and bilirubin. There was no significant correlation between the dose administered and the concentrations of serum creatinine (Spearmann 0.22). There was no greater nephrotoxicity in the patients with previous renal failure, or in those who had received amphotericin B previously. There were serious adverse events in five patients, but other alternative causes that could explain these events were present in three of these patients. Fevers or chills were experienced by 23% of the patients during the ABLC infusion, but only in one case did this necessitate the suspension of treatment. It was concluded that ABLC is a drug with low nephrotoxicity, even when administered to patients with pre-existing renal insufficiency. Adverse events were generally slight or moderate, and were managed easily with appropriate pre-medication.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Child; Child, Preschool; Drug Combinations; Female; Humans; Incidence; Infant; Kidney Diseases; Leishmaniasis, Visceral; Male; Middle Aged; Mycoses; Phosphatidylcholines; Phosphatidylglycerols; Treatment Outcome

Patients with persistent fever and neutropenia often receive empirical therapy with conventional or liposomal amphotericin B for the prevention and early treatment of invasive fungal infections. Caspofungin, a member of the new echinocandin class of compounds, may be an effective alternative that is better tolerated than amphotericin B.. In this randomized, double-blind, multinational trial, we assessed the efficacy and safety of caspofungin as compared with liposomal amphotericin B as empirical antifungal therapy. At study entry, patients were stratified according to risk and according to whether they had previously received antifungal prophylaxis. A successful outcome was defined as the fulfillment of all components of a five-part composite end point.. Efficacy was evaluated in 1095 patients (556 receiving caspofungin and 539 receiving liposomal amphotericin B). After adjustment for strata, the overall success rates were 33.9 percent for caspofungin and 33.7 percent for liposomal amphotericin B (95.2 percent confidence interval for the difference, -5.6 to 6.0 percent), fulfilling statistical criteria for the noninferiority of caspofungin. Among patients with baseline fungal infections, a higher proportion of those treated with caspofungin had a successful outcome (51.9 percent vs. 25.9 percent, P=0.04). The proportion of patients who survived at least seven days after therapy was greater in the caspofungin group (92.6 percent vs. 89.2 percent, P=0.05). Premature study discontinuation occurred less often in the caspofungin group than in the amphotericin B group (10.3 percent vs. 14.5 percent, P=0.03). The rates of breakthrough fungal infections and resolution of fever during neutropenia were similar in the two groups. Fewer patients who received caspofungin sustained a nephrotoxic effect (2.6 percent vs. 11.5 percent, P<0.001), an infusion-related event (35.1 percent vs. 51.6 percent, P<0.001), or a drug-related adverse event or discontinued therapy because of drug-related adverse events.. Caspofungin is as effective as and generally better tolerated than liposomal amphotericin B when given as empirical antifungal therapy in patients with persistent fever and neutropenia.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Caspofungin; Double-Blind Method; Echinocandins; Female; Fever; Humans; Kidney Diseases; Lipopeptides; Liposomes; Male; Middle Aged; Mycoses; Neoplasms; Neutropenia; Peptides; Peptides, Cyclic; Survival Rate; Treatment Outcome

The incidence of fungal infections and the role of liposomal amphotericin B (Ambisome) in proven and probable infections were evaluated in acute leukemic patients, intolerant to conventional amphotericin B. During 1999-2002, 307 febrile episodes occurred in 231 patients. Fungi were responsible for 3% of bloodstream infections. Ambisome was employed in 5 fungal sepsis (1 Candida albicans, 1 C. famata, 1 C. tropicalis, 1 C. krusei, 1 Geotrichum capitatum) 2 Aspergillosis, 2 probable fungal pneumonia cases. A favorable response was achieved in 78% of patients (4 fungemia, 2 aspergillosis, 1 probable), an unfavorable response in 1 C. krusei fungemia and in 1 probable pneumonia. Our antimicrobial pattern documented a high resistance rate to azoles. We concluded that Ambisome is an effective and well tolerated agent and its introduction has changed the outcome for many patients, although in some refractory diseases other strategies must be considered.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Diagnosis, Differential; Drug Resistance, Fungal; Female; Fever; Humans; Leukemia, Myeloid, Acute; Liposomes; Male; Middle Aged; Mycoses; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Risk Factors; Treatment Outcome

Although chronic rhinosinusitis (CRS) is one of the most frequently reported chronic diseases its etiology is not well understood. Recently, fungi have been proposed to influence the chronicity of rhinosinusitis. If fungi do play an important role then topical antifungal treatment may improve the inflammatory process of CRS. Therefore, in this study we measured inflammatory cytokine levels in nasal polyps after intranasal antifungal irrigation.. Nasal polyps were collected before and 4 weeks after treatment with 100 mg/l topical amphotericin B (n = 16), 50 mg/l topical amphotericin B (n = 14) or normal saline (n = 11). The cytokine--IL-5, IL-8, interferon-gamma, RANTES--protein content of polyp homogenates were determined by means of ELISA.. Nasal polyps were found to contain large amounts of cytokines (IL-5, IL-8 and RANTES) compared with normal inferior turbinates. After 4 weeks of treatment with topical agents, IL-5 levels tended to decrease in comparison with those of the other cytokines, but this difference was not statistically significant.. Topical amphotericin B treatment and nasal saline irrigation both influence the expression of nasal polyp cytokines. Topical nasal irrigation may influence the inflammatory process of CRS.

Topics: Administration, Intranasal; Administration, Topical; Adult; Amphotericin B; Antifungal Agents; Chemokine CCL5; Cytokines; Female; Humans; Interferon-gamma; Interleukin-5; Interleukin-8; Male; Mycoses; Nasal Polyps; Sodium Chloride; Therapeutic Irrigation

Fungal infections are a major cause of morbidity and mortality in patients undergoing induction chemotherapy for acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). The authors evaluated the efficacy and toxicity of liposomal amphotericin B (L-AmB) compared with a combination of fluconazole plus itraconazole (F+I) as prophylaxis in this setting.. Patients with newly diagnosed AML or high-risk MDS who were undergoing initial induction chemotherapy were randomized to receive either F+I (fluconazole 200 mg orally every 12 hours plus itraconazole tablets 200 mg orally every 12 hours) or L-AmB (3 mg/kg intravenously 3 times per week) in this prospective, open-label study.. Seventy-two L-AmB-treated patients and 67 F+I-treated patients were enrolled in the study. Of these, 47% of patients completed antifungal prophylaxis without a change in therapy for proven or suspected fungal infection. Three patients in each arm developed a proven fungal infection. Twenty-three percent of the L-AmB-treated patients and 24% of the F+I-treated patients were changed to alternative antifungal therapy because of persistent fever (P value not significant). Nine percent of the L-AmB-treated patients developed pneumonia of unknown etiology compared with 16% of the F+I-treated patients (P value not significant). Increases in serum creatinine levels to > 2 mg/dL (20% for the L-AmB arm vs. 6% for the F+I arm; P = 0.012) and increases in serum bilirubin levels to > 2 mg/dL (43% vs. 22%, respectively; P = 0.021) were more common with L-AmB. Infusion-related reactions were noted in five L-AmB-treated patients. Responses to chemotherapy and induction mortality rates were similar for the two arms.. L-AmB and F+I appear similar in their efficacy as antifungal prophylaxis during induction chemotherapy for patients with AML and MDS. L-AmB was associated with higher rates of increased serum bilirubin and creatinine levels.

Topics: Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Antineoplastic Agents; Drug Therapy, Combination; Female; Fluconazole; Humans; Itraconazole; Leukemia, Myeloid, Acute; Liposomes; Male; Middle Aged; Mycoses; Myelodysplastic Syndromes; Opportunistic Infections; Prospective Studies; Survival Analysis

To investigate the prevention and therapy of fungal infection in patients with severe acute pancreatitis (SAP).. Seventy patients with SAP admitted from Jan. 1998 to Dec. 2002 were randomly divided into garlicin prevention group, fluconazole (low dosage) prevention group and control group. The incidence of fungal infection, the fungal clearance and mortality after treatment were compared.. The incidence of fungal infection in garlicin group and fluconazole group was lower than that in control group (16% vs 30%, P<0.05 and 9% vs 30%, P<0.01, respectively). Amphotericin B or therapy-dose fluconazole had effects on patients with fungal infection in garlicin group and control group, but had no effects on patients with fungal infection in fluconzole group.. Prophylactic dosage of antifungal agents (garlicin or low dosage fluconazole) can reduce the incidence of fungal infection in patients with SAP. But once fungal infection occurs, amphotericin B should be used as early as possible if fluconazole is not effective.

Topics: Acute Disease; Adult; Aged; Allyl Compounds; Amphotericin B; Antifungal Agents; Disulfides; Female; Fluconazole; Humans; Incidence; Male; Middle Aged; Mycoses; Pancreatitis; Prospective Studies; Treatment Outcome

The aim of this study was to evaluate the efficacy of two antifungal prophylaxis regimens in liver transplant recipients. One hundred and twenty-nine consecutive recipients were randomized to receive sequential treatment with intravenous liposomal amphotericin B + oral itraconazole, intravenous fluconazole + oral itraconazole, or intravenous and oral placebo. Frequency and incidence of mycotic colonization, local and systemic infection of mycotic origin, causes of death, and possible risk factors for mycotic infection were evaluated. The incidence of mycotic colonization was higher in the placebo group ( P<0.01), but there was no significant difference in the incidence of infection between the three groups. Pre-transplant colonization, severity of liver disease, and graft rejection were all risk factors for the development of fungal infection. The routine use of antifungal prophylaxis for all liver transplant recipients does not seem to be justified.

Topics: Adult; Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluconazole; Humans; Immunosuppressive Agents; Itraconazole; Liver Diseases; Liver Transplantation; Male; Middle Aged; Mycoses; Placebos; Postoperative Complications; Survival Analysis

To compare conventional amphotericin B (c-amp B) and liposomal amphotericin B (L-AMP-LRC-1-India) in patients with systemic fungal infection in open, randomized, comparative, laboratory blind, phase III safety and efficacy study.. Formulation of liposomal amphotericin B - L-AMP-LRC-1, containing natural phospholipids, was prepared and tested at the Department of Clinical Pharmacology, Seth GS Medical College and KEM Hospital, Mumbai, India. Patients suffering from proven systemic fungal infection, were treated with c-amp B or L-AMP-LRC-1 with 17 patients in each group. Data was compared for the safety and efficacy.. L-AMP-LRC-1 was better tolerated than c-amp B. Out of the 695 infusions of c-amp B fever occurred on 25.04% occasions in 68.42% patients, while it occurred on 2.09% occasions out of 767 infusions (in 30.43% patients of L-AMP-LRC-1. Chills occurred on 16.83% and 1.17% occasions after c-amp B and liposomal amphotericin B respectively. Other adverse effects observed on 0.2-5% of occasions were: headache, nausea, vomiting, palpitation and dizziness occurring more frequently in c-amp B group. The L-AMP-LRC-1 did not cause bronchospasm at 1 mg/kg dose in a patient who developed bronchospasm to 0.1 mg/kg dose of c-amp B. The L-AMP-LRC-1 was found to be less nephrotoxic than c-amp B and could be administered to patients who had renal problems or had undergone renal transplant. L-AMP-LRC-1 caused less hypokalemia than c-amp B. Effficacy: 17/17 patients in L-AMP-LRC-1 group and 14/17 in c-amp B group had complete response (100% and 82.35% response rate). The number of infusions and dose of amphotericin B and L-AMP-LRC-1 used were similar and required individualization of duration of treatment (in cases where response to fixed duration was not observed). All the patients were treated with 0.5 to 1.0 mg/kg/day dose of L-AMP-LRC-1 (except one patient required 2 mg/kg dose). This is markedly different from other marketed liposome and lipid formulations, which are recommended at higher (3-5 mg/kg) doses every day. At the same time L-AMP-LRC-1 being prepared from naturally occurring lipids is expected to cost at least one-third of the marketed formulation. Thus cost of every day treatment would be very much less compared to other delivery systems. Thus L-AMP-LRC-1 will be an economical and safe treatment option available to the physicians for the treatment of systemic fungal infection.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Child; Child, Preschool; Female; Humans; Infant; Infant, Newborn; Male; Middle Aged; Mycoses; Single-Blind Method; Treatment Outcome

Over the past decade, invasive fungal infections have become an increasingly important problem in patients undergoing hematopoietic stem cell transplantation (HSCT). The optimal approach for prophylactic antifungal therapy has yet to be determined. To resolve this issue, we performed a prospective randomized study to compare the efficacy of fluconazole (FL) versus low-dose amphotericin B (AmB) in preventing fungal infections during the first 100 days after HSCT. Patients undergoing allogenic or autologous HSCT were randomized to receive fluconazole 200 mg/day PO or amphotericin B 0.2 mg/kg/day IV beginning 1 day prior to commencement of conditioning regimen and continuing until engraftment, drug-associated toxicity was suspected, or systemic fungal infection was suspected or proven. High-dose amphotericin B (0.5-1.0 mg/kg/day) was started for patients with suspected or proven fungal infections. From January 1993 to December 1998, a total of 186 patients were enrolled into the trial, with 100 receiving FL and 86 receiving AmB. Eighty (43%) patients were removed from prophylaxis for persistent fever despite broad-spectrum antibacterial therapy or suspected fungal infections (FL 46 vs. AmB 34, P > 0.05). The incidence of proven fungal infections (FL 12% vs. AmB 12.8%), suspected fungal infections (FL 4% vs. AmB 2.3%), superficial fungal infections (FL 1% vs. AmB 4.6%) did not show any significant difference. The survival at 100 days post transplant was similar between the 2 groups (FL 78% vs. AmB 70%, P = 0.254). Death attributable to fungal infections was similar in both groups (6% vs. 7%, P > 0.05). We conclude that fluconazole is as effective as low-dose amphotericin B in prophylaxis against fungal infections in patients undergoing hematopoietic cell transplantation.

Topics: Adolescent; Adult; Amphotericin B; Antifungal Agents; Aspergillosis; Bone Marrow Transplantation; Candidiasis; Child; Child, Preschool; Female; Fluconazole; Humans; Infant; Male; Middle Aged; Mycoses; Postoperative Complications; Stem Cell Transplantation; Time Factors; Transplantation, Autologous; Transplantation, Homologous

Patients with neutropenia and persistent fever are often treated empirically with amphotericin B or liposomal amphotericin B to prevent invasive fungal infections. Antifungal triazoles offer a potentially safer and effective alternative.. In a randomized, international, multicenter trial, we compared voriconazole, a new second-generation triazole, with liposomal amphotericin B for empirical antifungal therapy.. A total of 837 patients (415 assigned to voriconazole and 422 to liposomal amphotericin B) were evaluated for success of treatment. The overall success rates were 26.0 percent with voriconazole and 30.6 percent with liposomal amphotericin B (95 percent confidence interval for the difference, -10.6 to 1.6 percentage points); these rates were independent of the administration of antifungal prophylaxis or the use of colony-stimulating factors. There were fewer documented breakthrough fungal infections in patients treated with voriconazole than in those treated with liposomal amphotericin B (8 [1.9 percent] vs. 21 [5.0 percent], P=0.02). The voriconazole group had fewer cases of severe infusion-related reactions (P<0.01) and of nephrotoxicity (P<0.001). The incidence of hepatotoxicity was similar in the two groups. Patients receiving voriconazole had more episodes of transient visual changes than those receiving liposomal amphotericin B (22 percent vs. 1 percent, P<0.001) and more hallucinations (4.3 percent vs. 0.5 percent, P<0.001). Parenteral voriconazole was changed to the oral formulation in 22 percent of the voriconazole group, with a reduction in the mean duration of hospitalization by one day in all patients (P=0.17) but by two days in patients at high risk (P=0.03).. Voriconazole is a suitable alternative to amphotericin B preparations for empirical antifungal therapy in patients with neutropenia and persistent fever.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Chemical and Drug Induced Liver Injury; Child; Chronic Disease; Female; Fever; Humans; Infusions, Intravenous; Male; Middle Aged; Mycoses; Neoplasms; Neutropenia; Prospective Studies; Pyrimidines; Triazoles; Voriconazole

Bronchopulmonary fungal infections continue to be a major cause of morbidity and mortality in lung transplant recipients, and amphotericin B remains the drug of choice for prophylaxis of most fungal infections. Unfortunately, intravenous amphotericin B has numerous serious adverse effects; thus, nebulized amphotericin B could decrease the incidence of adverse effects seen with the intravenous formulation and provide high local concentrations in the lung tissue. We performed a prospective pilot study to characterize the bronchoalveolar lavage (BAL), lung tissue, and plasma concentrations of amphotericin B following inhalation administration to lung transplant recipients.. Amphotericin B 30 mg was administered by nebulizer prior to a routine bronchoscopy. Amphotericin B concentrations in BAL samples from the upper and lower lobes, transbronchial biopsies, and plasma (obtained by drawing a blood sample 30 min after the amphotericin B inhalation) were analyzed by HPLC.. Eight patients were enrolled in the study (mean age 50.0 +/- 16.1 y; number of years posttransplant 3.0 +/- 1.9; type of transplant 5 double-lung, 3 single-lung). The mean amphotericin B concentration in the upper and lower lobe BAL samples were 0.68 +/- 0.36 and 0.50 +/- 0.31 microgram/mL, respectively. Amphotericin B concentrations, detected in only 2 of 5 biopsy samples, were 0.118 and 0.03 microgram/g. Amphotericin B was detected in the plasma of only 1 patient (0.19 mg/L).. This pilot study demonstrated that detectable concentrations of amphotericin B can be attained in both the upper and lower BAL samples following aerosol administration. However, the frequency of the dose and duration of treatment still need to be determined in a larger study.

Topics: Administration, Inhalation; Adult; Aerosols; Aged; Amphotericin B; Antifungal Agents; Bronchoalveolar Lavage Fluid; Chromatography, High Pressure Liquid; Female; Humans; Lung; Lung Transplantation; Male; Middle Aged; Mycoses; Nebulizers and Vaporizers; Pilot Projects; Prospective Studies

Nephrotoxicity is the major adverse effect of amphotericin B (AmB), often limiting administration of full dosage. Selective distal tubular epithelial toxicity seems to be responsible for the profound potassium wasting that is a major clinical side effect of treatment with AmB. Potassium depletion also potentiates the tubular toxicity of AmB. This study was designed to assess the ability of spironolactone to reduce potassium requirements and to prevent hypokalemia in neutropenic patients on AmB treatment.. In this study 26 patients with various hematological disorders were randomized to receive either intravenous AmB alone or AmB and oral spironolactone 100 mg twice daily when developing a proven or suspected fungal infection.. Patients receiving concomitant AmB and spironolactone had significantly higher plasma potassium levels than those receiving AmB alone (P = 0.0027). Those patients receiving AmB and spironolactone required significantly less potassium supplementation to maintain their plasma potassium within the normal range (P = 0.022). Moreover, urinary potassium losses were significantly less in patients receiving AmB and spironolactone than those receiving AmB alone (P = 0.040).. This study showed that spironolactone can reduce potassium requirements and prevent hypokalemia by reducing urinary potassium loss in neutropenic patients on AmB treatment.

Topics: Amphotericin B; Antifungal Agents; Humans; Hypokalemia; Kidney Function Tests; Mineralocorticoid Receptor Antagonists; Mycoses; Neoplasms; Neutropenia; Potassium; Spironolactone

To determine the efficacy of selective decontamination of the digestive tract (SDD) in patients undergoing elective transplantation of the liver.. Randomized, double-blind, placebo-controlled study.. Two academic teaching hospitals.. Adult patients undergoing elective liver transplantation: 26 patients receiving SDD and 29 patients receiving a placebo.. Patients undergoing SDD were administered 400 mg of norfloxacin once daily as soon as they were accepted for transplantation. Postoperative treatment for this group consisted of 2 mg of colistin, 1.8 mg of tobramycin, and 10 mg of amphotericin B, four times daily, combined with an oral paste containing a 2% solution of the same drugs until postoperative day 30. Prophylactic intravenous administration of antibiotics was not part of the SDD regimen in this study. Control patients were given a similar regimen with placebo drugs.. The mean number of postoperative bacterial and fungal infections in the first 30 days after transplantation was the primary efficacy end point. Days on a ventilator, days spent in the intensive care unit, and medical costs were registered as secondary outcome variables.. Of the 26 patients undergoing SDD, 22 (84.5%) developed an infection in the postoperative study period; in the placebo group (n = 29), these numbers were not significantly different (25 patients, 86%). The mean number of postoperative infectious episodes per patient was also not significantly different: 1.77 (SDD) vs. 1.93 (placebo). Infections involving Gram-negative aerobic bacteria and Candida species were significantly less frequent in patients receiving SDD (p <.001 and p <.05). Total costs were higher in the group receiving SDD.. Selective decontamination of the digestive tract does not prevent infection in patients undergoing elective liver transplantation and increases the cost of their care. It does, however, affect the type of infection. Infections with Gram-negative bacilli and with Candida species are replaced by infections with Gram-positive cocci.

Topics: Adult; Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Bacterial Infections; Decontamination; Digestive System; Double-Blind Method; Female; Humans; Liver Transplantation; Male; Mycoses; Norfloxacin; Postoperative Complications; Tobramycin

To test the hypothesis that amphotericin B deoxycholate is less toxic when given by continuous infusion than by conventional rapid infusion.. Randomised, controlled, non-blinded, single centre study.. University hospital providing tertiary clinical care.. 80 mostly neutropenic patients with refractory fever and suspected or proved invasive fungal infections.. Patients were randomised to receive 0.97 mg/kg amphotericin B by continuous infusion over 24 hours or 0.95 mg/kg by rapid infusion over four hours.. Patients were evaluated for side effects related to infusion, nephrotoxicity, and mortality up to three months after treatment. Analysis was on an intention to treat basis.. Patients in the continuous infusion group had fewer side effects and significantly reduced nephrotoxicity than those in the rapid infusion group. Overall mortality was higher during treatment and after three months' follow up in the rapid infusion than in the continuous infusion group.. Continuous infusions of amphotericin B reduce nephrotoxicity and side effects related to infusion without increasing mortality.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Deoxycholic Acid; Drug Administration Schedule; Drug Combinations; Female; Follow-Up Studies; Humans; Kidney Diseases; Male; Middle Aged; Mycoses; Neutropenia; Opportunistic Infections; Prospective Studies; Survival Rate

The efficacy and safety of itraconazole oral solution and a combination of amphotericin B capsules plus nystatin oral suspension were compared in the prophylaxis of fungal infections in neutropenic patients. In an open, randomized, multicentre trial, 144 patients received itraconazole oral solution 100 mg bd, and 133 patients received amphotericin B 500 mg tds plus nystatin 2 MU qds. Overall, 65% of itraconazole-treated patients were considered to have had successful prophylaxis, compared with 53% in the polyene group. Proven deep fungal infections occurred in 5% of patients in each group. Fewer patients receiving itraconazole than amphotericin plus nystatin had superficial infections (3 versus 8%; P = 0.066). This trend in favour of itraconazole was seen in patients with profound neutropenia (neutrophil count <0.1 x 10(9) cells/L at least once) or prolonged neutropenia (neutrophil count <1.0 x 10(9) cells/L for >14 days). The median time to prophylactic failure was longer in the itraconazole group (37 days) than in the polyene group (34 days). The number of patients with fungal colonization (nose, sputum, stool) changed more favourably from baseline to endpoint in the itraconazole group than in the polyene group. Both treatments were safe and well tolerated; however, patients receiving amphotericin plus nystatin had a higher incidence of nausea and rash. In conclusion, itraconazole oral solution at doses of 100 mg bd and oral amphotericin B plus nystatin have similar prophylactic efficacy against fungal infections in neutropenic patients. On the basis of reduced incidence of superficial fungal infections, fungal colonization and specific adverse events, itraconazole may be the preferred treatment.

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; Female; Humans; Itraconazole; Male; Middle Aged; Mycoses; Neoplasms; Neutropenia; Nystatin

Fungal infections remain a major cause of treatment failure and death in acute leukemia. New liposomal preparations of amphotericin B are now available. While less toxic, their comparative efficacy and toxicity profiles are unknown. In this study the comparative efficacy and safety of ABLC vs. AmBisome was evaluated in seventy-five patients with leukemia who developed 82 episodes of suspected or documented mycosis, and were treated (1:1) with either ABLC (n=43) or AmBisome (n=39). Both drugs were dosed accordingly from 3 to 5 mg/kg/day. Using an intent-to-treat analysis, the overall response to therapy was 27/43 (63%) for ABLC and 15/39 (39%) for AmBisome (p=0.03). Median dose and duration of treatment was 10 days at 3 mg/kg for ABLC and 15 days at 4 mg/kg for AmBisome. Acute, not dose-limiting infusion side effects were seen in 70% vs. 36% (p=0.002), ABLC vs. AmBisome. Increase of bilirubin > 1.5 times from baseline was 38% vs. 59%, ABLC vs. AmBisome (p=0.05). ABLC and AmBisome were equally effective for the treatment of suspected or documented fungal infections. While, acute infusion-toxicity was greater with ABLC, infusion toxicity requiring discontinuation was similar for both drugs. AmBisome was better tolerated than ABLC but was associated with mild abnormalities in liver function tests at the end of therapy.

Topics: Acute Disease; Amphotericin B; Antifungal Agents; Antineoplastic Agents; Drug Combinations; Humans; Leukemia; Mycoses; Phosphatidylcholines; Phosphatidylglycerols

Amphotericin B deoxycholate is currently the standard empirical antifungal therapy in neutropenic patients with cancer who have persistent fever that does not respond to antibiotic therapy. However, this treatment often causes infusion-related and metabolic toxicities, which may be dose limiting.. To compare the efficacy and safety of itraconazole with those of amphotericin B as empirical antifungal therapy.. An open randomized, controlled, multicenter trial, powered for equivalence.. 60 oncology centers in 10 countries.. 384 neutropenic patients with cancer who had persistent fever that did not respond to antibiotic therapy.. Intravenous amphotericin B or intravenous itraconazole followed by oral itraconazole solution.. Defervescence, breakthrough fungal infection, drug-related adverse events, and death.. For itraconazole and amphotericin B, the median duration of therapy was 8.5 and 7 days and the median time to defervescence was 7 and 6 days, respectively. The intention-to-treat efficacy analysis of data from 360 patients showed response rates of 47% and 38% for itraconazole and amphotericin B, respectively (difference, 9.0 percentage points [95% CI, -0.8 to 19.5 percentage points]). Fewer drug-related adverse events occurred in the itraconazole group than the amphotericin B group (5% vs. 54% of patients; P = 0.001), and the rate of withdrawal because of toxicity was significantly lower with itraconazole (19% vs. 38%; P = 0.001). Significantly more amphotericin B recipients had nephrotoxicity (P < 0.001). Breakthrough fungal infections (5 patients in each group) and mortality rates (19 deaths in the itraconazole group and 25 deaths in the amphotericin B group) were similar. Sixty-five patients switched to oral itraconazole solution after receiving the intravenous formulation for a median of 9 days.. Itraconazole and amphotericin B have at least equivalent efficacy as empirical antifungal therapy in neutropenic patients with cancer. However, itraconazole is associated with significantly less toxicity.

Topics: Administration, Oral; Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Antineoplastic Agents; Deoxycholic Acid; Drug Combinations; Fever; Humans; Infusions, Intravenous; Itraconazole; Mycoses; Neoplasms; Neutropenia; Opportunistic Infections; Risk Factors; Treatment Failure

Invasive fungal infections (IFI) are a major cause of morbidity and mortality in patients with cancer. A retrospective analysis of children with cancer at high risk for IFI treated at Münster University Hospital showed that the incidence (7.4% vs. 1.8%) and lethality (28.1% vs. 0) of documented IFI were lower in patients receiving systemic antifungal prophylaxis with liposomal amphotericin B (l-AmB) in comparison to a historical control group. To determine whether this decline in incidence and lethality was due to antifungal prophylaxis or was produced by advances in diagnostic procedures and early empirical antifungal therapy, a prospective study was initiated. Patients in the prophylaxis arm received thrice-weekly 1 mg kg(-1) body weight l-AmB, whilst patients in the early intervention arm received no prophylaxis. Diagnostic procedures and antifungal therapy for suspected or proven IFI were initiated as clinically indicated for all patients. The primary endpoint of the study was the incidence of IFI. Secondary endpoints were the use of therapeutic doses of l-AmB, the safety of prophylactic l-AmB, and the total consumption of l-AmB for antifungal therapy. The interim analysis after 1 year showed no differences between the two approaches with respect to the incidence of IFI and to safety issues.

Topics: Adolescent; Adult; Amphotericin B; Antifungal Agents; Child; Child, Preschool; Female; Humans; Incidence; Infant; Infant, Newborn; Liposomes; Male; Mycoses; Neutropenia; Prospective Studies

To observe the therapeutic effect and side effects of amphotericin B for fungal infections in patients with malignant hematologic diseases.. 40 patients (male 27, female 13; average age 35.5 years) with malignant hematologic diseases were given amphotericin B, 5-50 mg/d per day for 5-85 days (average time 21 days).. The clinical efficacy rate of amphotericin B was 52.5%, and the fungal elimination rate was 56.2%. Among the side effects, rigor and fever were present in 2.5% of the patients. Hypokalaemia was found in 12.5%, hepatotoxicity in 15.0% and nephrotoxicity in 15.0%.. As amphotericin B has a broad anti-fungal spectrum and relatively good efficacy, it is still a high-efficiency drug in treatment of systematical fungal infections. However, the use of drug is limited because of its many side effects. Our study indicates that if it is used properly and hepatic and renal function tests are carried out regularly, amphotericin B is a relatively safe and effective drug.

Topics: Adolescent; Adult; Aged; Amphotericin B; Child; Child, Preschool; Female; Hematologic Neoplasms; Humans; Kidney; Liver; Male; Middle Aged; Mycoses; Treatment Outcome

Systemic fungal infections are a major problem in bone marrow transplant recipients who have prolonged neutropenia or who receive high-dose corticosteroids. Prophylaxis with Fluconazole or low-dose amphotericin B reduces, but does not eliminate these infections. To determine which prophylactic agent is better, we performed a prospective randomized study. Patients undergoing allogeneic (related or unrelated) or autologous marrow or peripheral stem cell transplantation were randomized to receive Fluconazole (400 mg/day p. o. or i.v.) or amphotericin B (0.2 mg/kg/day i.v.) beginning 1 day prior to stem cell transplantation and continuing until recovery of neutrophils to >500/microl. Patients were removed from their study drug for drug-associated toxicity, invasive fungal infection or suspected fungal infection (defined as the presence of fever >38 degrees C without positive culture while on broad-spectrum anti-bacterial antibiotics). Proven or suspected fungal infections were treated with high-dose amphotericin B (0.5-0.7 mg/kg/day). Patients were randomized at each institution and stratified for the type of transplant. The primary end-point of the study was prevention of documented fungal infection; secondary endpoints included fungal colonization, drug toxicity, duration of hospitalization, duration of fever, duration of neutropenia, duration and total dose of high-dose amphotericin B and overall survival to hospital discharge. From July 1992 to October 1994, a total of 355 patients entered into the trial with 159 patients randomized to amphotericin B and 196 to Fluconazole. Patient groups were comparable for diagnosis, age, sex, prior antibiotic or antifungal therapy, use of corticosteroids prior to transplantation and total duration of neutropenia. Amphotericin B was significantly more toxic than Fluconazole especially in related allogeneic transplantation where 19% of patients developed toxicity vs 0% of Fluconazole recipients (p < 0.05). Approximately 44% of all patients were removed from prophylaxis for presumed fungal infection. Proven fungal infections occurred in 4.1% and 7.5% of Fluconazole and amphotericin-treated patients, respectively. Proven fungal infections occurred in 9.1% and 14.3% of related allogeneic marrow recipients receiving Fluconazole or amphotericin B, respectively, and 2.1% and 5.6% of autologous marrow recipients receiving Fluconazole or amphotericin B, respectively (P > 0.05). In this prospective trial, low-dose amphotericin B

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; Bone Marrow Transplantation; Chemical and Drug Induced Liver Injury; Confidence Intervals; Female; Fever; Fluconazole; Humans; Male; Middle Aged; Mycoses; Neutropenia; North America; Prospective Studies; Renal Insufficiency; Survival

We conducted an open label, randomised clinical trial to compare amphotericin B colloidal dispersion (ABCD, Amphocil) 2 mg/kg/day intravenously with fluconazole 200 mg/day orally, for the prevention of fungal disease in neutropenic patients with haematological malignancies. In the event of unresolved fever after 4 days of empirical antibacterial therapy, patients in both treatment groups were to receive ABCD, 4 mg/kg/day. However, the study had to be stopped in an early phase, due to severe side-effects of ABCD. A total of 24 patients were enrolled, 12 patients were randomly assigned to receive prophylactic ABCD, which was administered for a mean of 13.9 days. Fluconazole prophylaxis was given to 12 patients for a mean of 21.2 days. Therapeutic ABCD, 4 mg/kg, was initiated in four patients because of suspected fungal infection, all of whom had initially received fluconazole. A high rate of infusion-related toxicity of ABCD was observed. Chills occurred in 15/16 ABCD recipients (94%), accompanied by a temperature rise of >/=2 degrees C in 4/16 patients and of >/=1 degrees C but <2 degrees C in 10/16 patients. Other ABCD-related adverse events were hypotension (4/16), nausea with vomiting (5/16), tachycardia (7/16), headache (3/16) and dyspnoea (3/16). For premedication patients received: antihistamines (12/16), hydrocortisone (9/16) and/or morphine (6/16). ABCD was discontinued in 8/16 patients (50%) due to side-effects, which ultimately dictated early termination of the study. We conclude that ABCD is not suitable for antifungal prophylaxis in neutropenic patients due to severe infusion-related side-effects. Subject numbers were too low for conclusions on variables of antifungal efficacy.

Topics: Adolescent; Adult; Aged; Amphotericin B; Bilirubin; Consumer Product Safety; Contraindications; Female; Fluconazole; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Infusions, Intravenous; Male; Middle Aged; Morphine; Mycoses; Neutropenia; Respiratory Tract Diseases; Shivering; Survival; Time Factors; Transaminases

This study describes a pharmacokinetic evaluation of amphotericin B (AMB) lipid complex injection (ABLC or Abelcet) in 17 patients with systemic fungal infection administered 5 mg/kg of body weight/day by infusion for 10 to 17 days. The results showed that AMB exhibited multiexponential disposition with high clearance, large volume of distribution at steady state, and long apparent elimination half-life but no evidence of accumulation in the blood after multiple daily doses. The results confirm previous observations and further reinforce the suggestion that ABLC may exist as a depot in the tissues from which free AMB is slowly released to limit exposure.

Topics: Adult; Amphotericin B; Antifungal Agents; Area Under Curve; Drug Combinations; Female; Half-Life; Humans; Infusions, Intravenous; Male; Middle Aged; Mycoses; Phosphatidylcholines; Phosphatidylglycerols

To compare the efficacy and safety of fluconazole and amphotericin B as empiric antifungal therapy of febrile neutropenic patients with cancer.. A total of 317 neutropenic patients (<500 cells/mm3) with persistent or recrudescent fever despite 4 or more days of antibacterial therapy were randomly assigned to receive either fluconazole (400 mg intravenously once daily) or amphotericin B (0.5 mg/kg once daily). Patients were evaluated for the efficacy and safety of each drug by clinical criteria, frequent cultures and radiological procedures, and laboratory values. A response was classified as satisfactory at the end of therapy if the patient was afebrile, had no clinical or microbiological evidence of fungal infection, and did not require study termination due to lack of efficacy, drug toxicity, or death.. A satisfactory response occurred in 68% of the patients treated with fluconazole (107 of 158 patients) and in 67% of patients treated with amphotericin B (106 of 159 patients). Progressive or new fungal infections during therapy occurred in 13 (8%) patients treated with fluconazole (8 with Candida, 5 with Aspergillus) and in 10 (6%) patients treated with amphotericin B (5 with Candida, 3 with Aspergillus, 2 with other fungi). Adverse events related to study drug (especially fever, chills, renal insufficiency, electrolyte disturbances, and respiratory distress) occurred more often in patients treated with amphotericin B (128 [81%] of 159 patients) than patients treated with fluconazole (20 [13%] of 158 patients, P = 0.001). Eleven (7%) patients treated with amphotericin B but only 1 (1%) patient treated with fluconazole were terminated from the study owing to an adverse event (P = 0.005). Overall mortality (27 [17%] patients treated with fluconazole versus 34 [21%] patients treated with amphotericin B) and mortality from fungal infection (7 [4%] patients treated with fluconazole versus 5 [3%] patients treated with amphotericin B) were similar in each study group.. Intravenous fluconazole can be an effective and safe alternative to amphotericin B for empiric antifungal therapy in many febrile neutropenic patients. However, because fluconazole may be ineffective in the treatment of Aspergillus, patients at risk for that infection should be evaluated by chest radiograph, computed tomographic scanning, and cultures before the use of empiric fluconazole therapy.

Topics: Amphotericin B; Antifungal Agents; Cause of Death; Female; Fever; Fluconazole; Humans; Infusions, Intravenous; Male; Middle Aged; Mycoses; Neoplasms; Neutropenia; Treatment Outcome

In this double-blind study to compare safety of 2 lipid formulations of amphotericin B, neutropenic patients with unresolved fever after 3 days of antibacterial therapy were randomized (1:1:1) to receive amphotericin B lipid complex (ABLC) at a dose of 5 mg/kg/d (n=78), liposomal amphotericin B (L Amph) at a dose of 3 mg/kg/d (n=85), or L Amph at a dose of 5 mg/kg/d (n=81). L Amph (3 mg/kg/d and 5 mg/kg/d) had lower rates of fever (23.5% and 19.8% vs. 57.7% on day 1; P<.001), chills/rigors (18.8% and 23.5% vs. 79.5% on day 1; P<.001), nephrotoxicity (14.1% and 14.8% vs. 42.3%; P<.01), and toxicity-related discontinuations of therapy (12.9% and 12.3% vs. 32.1%; P=.004). After day 1, infusional reactions were less frequent with ABLC, but chills/rigors were still higher (21.0% and 24.3% vs. 50.7%; P<.001). Therapeutic success was similar in all 3 groups.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Child; Child, Preschool; Chills; Double-Blind Method; Drug Carriers; Female; Fever; Humans; Infusions, Intravenous; Liposomes; Male; Middle Aged; Mycoses; Nausea; Neutropenia; Survival Rate; Vomiting

Fungal infections are an important cause of morbidity and mortality in immunocompromised patients. Treatment with amphotericin B is the main therapeutic approach. However, this treatment is limited by the substantial toxicity. We present the data of the first randomized prospective comparative trial in adults (134 patients with fever of unknown origin) with conventional amphotericin B and a liposomal formulation of amphotericin B (AmBisome, published in 1997 by Prentice et al. (Br. J. Haematol. 98, 711-718) and the data of adults with documented fungal infections (59 patients), treated in this trial. Patients received either conventional amphotericin B 1 mg kg-1 per day, liposomal amphotericin B 1 mg kg-1 per day or liposomal amphotericin B 3 mg kg-1 per day. Patients were entered if they had fever of unknown origin (FUO), defined as temperature of 38 degrees C or more, not responding to 96 h of systemic broad-spectrum antibiotic treatment, and neutropenia (< 0.5 x 10(9) l-1). Efficacy of treatment was assessed, with success defined as resolution of fever for three consecutive days (< 38 degrees C) in the group of patients with FUO and the freedom of clinical signs and/or the elimination of fungus in the group of patients with documented fungal infections. The safety of treatment and renal and hepatic toxicity of liposomal and conventional amphotericin B were compared. No statistically significant difference was found in the treatment efficacy in the three study arms. However, there is a tendency of better treatment results in the two groups of patients, who received liposomal amphotericin B. Thirty-five per cent of patients with documented fungal infections and 46% of patients with FUO responded to amphotericin B. In the patients group, that received 1 mg kg-1 liposomal amphotericin B it was 63 and 49%, in the group of patients that received 3 mg kg-1 liposomal amphotericin B it was 47 and 64%. Evidence of toxicity due to amphotericin B was seen in 50 patients (83%), toxicity due to liposomal amphotericin B, 1 mg kg-1, was seen in 35 patients (50%), and due to liposomal amphotericin B 3 mg kg-1 in 34 patients (54%). This was a statistically significant difference (P = 0.001). It was concluded that liposomal amphotericin B was safer than conventional amphotericin B, but both formulations are equivalent in treatment efficacy. The prophylactic use of amphotericin B in these immunocompromised patients is discussed.

Topics: Adult; Amphotericin B; Child; Female; Fever of Unknown Origin; Humans; Liposomes; Male; Middle Aged; Mycoses; Neutropenia

In patients with persistent fever and neutropenia, amphotericin B is administered empirically for the early treatment and prevention of clinically occult invasive fungal infections. However, breakthrough fungal infections can develop despite treatment, and amphotericin B has substantial toxicity.. We conducted a randomized, double-blind, multicenter trial comparing liposomal amphotericin B with conventional amphotericin B as empirical antifungal therapy.. The mean duration of therapy was 10.8 days for liposomal amphotericin B (343 patients) and 10.3 days for conventional amphotericin B (344 patients). The composite rates of successful treatment were similar (50 percent for liposomal amphotericin B and 49 percent for conventional amphotericin B) and were independent of the use of antifungal prophylaxis or colony-stimulating factors. The outcomes were similar with liposomal amphotericin B and conventional amphotericin B with respect to survival (93 percent and 90 percent, respectively), resolution of fever (58 percent and 58 percent), and discontinuation of the study drug because of toxic effects or lack of efficacy (14 percent and 19 percent). There were fewer proved breakthrough fungal infections among patients treated with liposomal amphotericin B (11 patients [3.2 percent]) than among those treated with conventional amphotericin B (27 patients [7.8 percent], P=0.009). With the liposomal preparation significantly fewer patients had infusion-related fever (17 percent vs. 44 percent), chills or rigors (18 percent vs. 54 percent), and other reactions, including hypotension, hypertension, and hypoxia. Nephrotoxic effects (defined by a serum creatinine level two times the upper limit of normal) were significantly less frequent among patients treated with liposomal amphotericin B (19 percent) than among those treated with conventional amphotericin B (34 percent, P<0.001).. Liposomal amphotericin B is as effective as conventional amphotericin B for empirical antifungal therapy in patients with fever and neutropenia, and it is associated with fewer breakthrough fungal infections, less infusion-related toxicity, and less nephrotoxicity.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Antibiotic Prophylaxis; Antifungal Agents; Child; Child, Preschool; Double-Blind Method; Drug Carriers; Female; Fever; Humans; Infusions, Intravenous; Kidney; Liposomes; Male; Middle Aged; Mycoses; Neutropenia; Treatment Outcome

Liposomal amphotericin (AmBisome) 2 mg/kg three times weekly was compared with placebo as prophylaxis against fungal infection in patients undergoing chemotherapy or bone marrow transplantation (BMT) for haematological malignancies. Prophylaxis began on day 1 of chemotherapy and continued until neutrophils regenerated or infection was suspected. Of 161 evaluable patients, 74 received AmBisome and 87 received placebo. Proven fungal infections developed in no patients on AmBisome and in three on placebo (3.4%) (P = NS). Suspected fungal infections requiring intervention with systemic antifungal therapy (usually amphotericin B) occurred in 31 patients on AmBisome (42%) and in 40 on placebo (46%) (P = NS). Suspected deep-seated infections developed in 21 (28.3%) and 31 (35.6%) patients, respectively (P = NS). Time to develop a suspected or proven deep-seated infection showed a trend in favour of AmBisome (P = 0.11). Fifty patients had fungal colonisation (48 with Candida spp, two with Aspergillus spp) of at least one body site during prophylaxis; 15 patients while receiving AmBisome (20%) and 35 while on placebo (40%) (P < 0.01). Time to colonisation was significantly delayed in the group receiving AmBisome (P < 0.05). Treatment-related toxicity was modest and no additional toxicity was observed in patients receiving AmBisome. AmBisome 2 mg/kg three times weekly is safe and reduces fungal colonisation in patients receiving intensive chemotherapy or BMT. However, despite encouraging trends, prophylactic AmBisome did not lead to a significant reduction in fungal infection or in requirement for systemic antifungal therapy.

Topics: Adult; Amphotericin B; Antifungal Agents; Antigens, Fungal; Aspergillus; Candida; Double-Blind Method; Female; Humans; Liposomes; Lung Diseases, Fungal; Male; Middle Aged; Mycoses; Neutropenia; Placebos

The efficacy of amphotericin B bladder irrigation at two concentrations was studied. Patients with funguria (> or =15,000 colony-forming units of yeast per milliliter of urine), an indwelling urinary catheter, and a physician order for amphotericin B continuous bladder irrigation were randomly assigned to receive 10 or 50 mg of amphotericin B per liter of sterile water as a continuous irrigation for 72 hours at the rate of 42 mL/hr. Before the bladder irrigation began, the indwelling catheter was changed to a three-way catheter. Repeat urine cultures were performed 24 hours after the irrigation was discontinued. A total of 28 patients were enrolled from November 1993 to May 1995. The rate of eradication of the infection was 100% in the 50-mg/L group and 67% in the 10-mg/ L group. Subject enrollment was stopped prematurely because all the treatment failures occurred in the 10-mg/L group. Dose was the only variable significantly associated with outcome. Bladder irrigation with amphotericin B was more effective when the drug concentration was 50 mg/L rather than 10 mg/L.

Topics: Administration, Intravesical; Adult; Aged; Amphotericin B; Antifungal Agents; Catheters, Indwelling; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Mycoses; Therapeutic Irrigation; Urinary Bladder Diseases; Urine

Amphotericin B is the agent of choice for most invasive fungal infections in critically ill patients. It is associated with at least a 50% incidence of nephrotoxicity, despite prophylactic measures such as sodium loading. Newer formulations of amphotericin B are available but are costly and have unknown bioavailability in critically ill patients. Previous trials in neutropenic and critically ill patients have demonstrated that mixing amphotericin B with 20% lipid solution (Intralipid; Clintec Nutrition, Deerfield, III) may decrease nephrotoxicity.. In this randomized, prospective clinical trial, patients with positive fungal blood cultures, tracheal/sputum cultures or peritoneal cavity cultures were randomized to receive either 0.5 mg/kg per day of amphotericin B dextrose or 1.0 mg/kg per day of amphotericin B lipid emulsion. Duration of therapy was determined by the primary care team. Weekly 24-hour creatinine clearance was measured until 2 weeks after amphotericin B therapy was completed.. The two groups were similar based on age, white blood cell count, serum creatinine, and creatinine clearance at the beginning of therapy. The group receiving amphotericin B lipid emulsion had significantly less decrease in creatinine clearance compared with controls, despite receiving significantly more amphotericin B.. Amphotericin B lipid emulsion can be given at a higher total cumulative dose than amphotericin B dextrose with less nephrotoxicity.

Topics: Adult; Amphotericin B; Antifungal Agents; Colloids; Creatinine; Fat Emulsions, Intravenous; Glucose; Humans; Intensive Care Units; Middle Aged; Mycoses; Prospective Studies; Solutions

Lipid formulations of amphotericin B have been recently introduced for treatment of invasive fungal infections. However, little is known about their role in pediatric populations.. We studied the safety and antifungal efficacy of amphotericin B lipid complex (ABLC, Abelcet) in 111 treatment episodes in pediatric patients through an open label, emergency use multicenter study. Patients with invasive fungal infections were enrolled if they had mycoses refractory to conventional antifungal therapy, if they were intolerant of previous systemic antifungal agents or concomitant nephrotoxic drugs or if they had preexisting renal disease.. All 111 treatment episodes were evaluable for safety and 54 were evaluable for efficacy. The mean serum creatinine for the study population did not significantly change between baseline (1.23 +/- 0.11 mg/dl) and cessation of ABLC therapy (1.32 +/- 0.12 mg/dl) during 6 weeks. There were no significant differences observed between initial and end-of-therapy levels of serum potassium, magnesium, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and hemoglobin. However, there was an increase in mean total bilirubin (3.66 +/- 0.73 to 5.31 +/- 1.09 mg/dl) at the end of therapy (P = 0.054). Among 54 cases fulfilling criteria for evaluation of antifungal efficacy, a complete or partial therapeutic response was obtained in 38 patients (70%) after ABLC therapy. Complete or partial therapeutic response was documented in 56% of cases with aspergillosis (n = 25) and in 81% (n = 27) with candidiasis. Among premature infants (n = 8) and allogeneic marrow recipients (n = 14), response rates were 88 and 57%, respectively. Response was similar in those patients enrolled because of intolerance to previous antifungal therapy or because of progressive infection.. These data support the use of ABLC for treatment of invasive fungal infections in pediatric patients who are intolerant of or refractory to conventional antifungal therapy.

Topics: Adolescent; Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis; Child; Child, Preschool; Creatinine; Drug Combinations; Female; Humans; Infant; Infant, Newborn; Male; Mycoses; Phosphatidylcholines; Phosphatidylglycerols; Zygomycosis

To assess the economic impact of adding granulocyte colony-stimulating factor (G-CSF) to amphotericin B to treat a presumed deep-seated fungal infection in neutropenic patients. This study was conducted from the perspective of the National Health Service (NHS) hospital sector.. We used our previously reported trial as the clinical basis for the analysis (see Participants and interventions). These data were combined with resource utilisation data, enabling us to construct a decision tree model of the treatment paths attributable to managing patients in each arm of the trial. The model was used to calculate the cost effectiveness of using amphotericin B plus G-CSF compared to amphotericin B monotherapy in neutropenic patients with a presumed deep-seated fungal infection.. An adult leukaemia/bone marrow transplant (BMT) unit in a large UK teaching hospital.. Patients with a neutrophil count of < 0.5 x 10(9)/L and having a presumed deep-seated fungal infection after either chemotherapy or stem cell/bone marrow transplantation for haematological malignancy.. 29 patients received intravenous amphotericin B (1 mg/kg daily) plus subcutaneous G-CSF (3 to 5 micrograms/kg daily) and 30 patients received intravenous amphotericin B (1 mg/kg daily) monotherapy. The clinical trial showed that 62% of patients responded to antifungal treatment with amphotericin B plus G-CSF compared to 33% of patients who responded to amphotericin B monotherapy (p = 0.027). Nonresponders went on to receive a lipid formulation of amphotericin B.. The mean cost per patient treated with amphotericin B plus G-CSF was 11,247 Pounds and the corresponding cost for amphotericin B monotherapy was 14,317 Pounds (1996/1997 values)--a cost reduction of 3070 Pounds per patient. Sensitivity analyses demonstrated that the addition of G-CSF to conventional amphotericin B in the treatment of a presumed deep-seated fungal infection offers not only clinical benefits, but cost benefits which are robust to changes in clinical and economic parameters.. From a UK hospital perspective, amphotericin B plus G-CSF is cost effective compared with amphotericin B monotherapy in managing a presumed deep-seated fungal infection in neutropenic patients. This result should provide strong arguments to clinicians and policy-makers for the adoption of this treatment strategy in such patients.

Topics: Adult; Amphotericin B; Antifungal Agents; Cost-Benefit Analysis; Decision Trees; Drug Therapy, Combination; Granulocyte Colony-Stimulating Factor; Humans; Mycoses; Neutropenia; United Kingdom

We compared the efficacy and tolerability of fluconazole (FCA) with amphotericin B/flucytosine (ABF) in neutropenic patients with haematological malignancies. Antifungal therapy started on day 4 when fever was unresponsive to antibiotics or on day 1 together with the antibiotics, if there was evidence of mycosis. If patients did not respond to FCA after 7 days they switched to ABF. 98 patients, 51 FCA and 47 ABF were included in the study. Response to fever was achieved in 28/51 FCA patients and in another 16 after switching to ABF. So in overall 44/51 (86.2%) of the FCA and 37/47 (78.8%) of the ABF group defervescence was observed. 46 patients (21 FCA, 25 ABF) developed radiological signs of pneumonia. Resolution of infiltrates was achieved in 5/21 FCA and 20/25 ABF patients, and another 10 of 15 initially not responding patients showed regression when switched to ABF, 5 of these had highly suspected aspergillosis. Adverse events occurred in 19.6% of FCA and 97.9% of ABF patients. In conclusion fluconazole and amphotericin B/flucytosine seem to be equally effective. In view of its lower toxicity fluconazole may be preferred as first line empiric antifungal agent, but in case of nonresponse, pneumonia or aspergillosis it may be replaced by amphotericin B combined with flucytosine.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Drug Therapy, Combination; Female; Fluconazole; Flucytosine; Humans; Male; Middle Aged; Mycoses; Neutropenia

Disseminated fungal infections are a major problem in high risk neonates. Conventional antifungal agents are often unsatisfactory and have a high incidence of severe adverse effects.. We administered liposomal encapsulated amphotericin B (AmBisome), which is an alternative to conventional amphotericin B, to 40 preterm (mean birth weight, 1090 +/- 313.6 g; mean gestational age, 28.35 +/- 2.13 weeks) and 4 full term (mean birth weight, 3080 +/- 118 g; mean gestational age, 39 +/- 0.7 weeks) newborn infants with a severe fungal infection.. Candida albicans was the most frequent fungus isolated (70%). The duration of intravenous AmBisome therapy ranged from 7 to 49 days; the cumulative dose ranged from 7 to 138.8 mg/kg (median, 45.2 mg/kg). Administration of AmBisome was effective in 72.7% of patients; 5 of 6 cases of meningitis also recovered; 63.6% of 33 very low birth weight infants survived. No side effects were observed.. To our knowledge this is the largest study of the treatment of neonates with liposomal amphotericin B, and the results confirm its effectiveness and safety. However, randomized clinical trials are required to establish the most effective administration protocol for AmBisome, i.e. the starting dosage, the maximum effective dosage and the cumulative dosage, and to verify whether the preparation should be associated with another antifungal agent.

Topics: Amphotericin B; Antifungal Agents; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Liposomes; Mycoses

Amphotericin B colloidal dispersion (ABCD) is a new formulation of conventional amphotericin B designed to minimize drug distribution in the kidney and reduce nephrotoxicity. We studied the safety and efficacy of ABCD in 133 renally compromised patients with invasive fungal infections. Patients had either nephrotoxicity from amphotericin B or preexisting renal disease. Intravenous treatment with ABCD (4 mg/kg of body weight daily) was administered for up to 6 weeks. Evaluations included clinical response to treatment and adverse events, with emphasis on changes in serum creatinine levels. ABCD did not appear to have an adverse effect on renal function: mean serum creatinine level tended to decrease slightly with days on therapy, and increases were not dose related. Complete or partial response to treatment was reported for 50% of the 133 intent-to-treat patients and 67% of the 58 evaluable patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Child; Child, Preschool; Female; Follow-Up Studies; Humans; Infant; Kidney; Male; Middle Aged; Mycoses; Prospective Studies; Renal Insufficiency; Treatment Outcome

A study was conducted to compare the renal effects of amphotericin B lipid complex (ABLC), a lipid formulation of the widely used antifungal medication, with conventional amphotericin B (AmB) in the treatment of serious fungal infections, including invasive candidiasis, cryptococcal meningitis, and aspergillosis. The clinical experience of ABLC includes two types of open-label studies: randomized comparative (ABLC 5 mg/kg/d compared with AmB 0.6 to 1 mg/kg) and emergency use. In the comparative studies, changes in serum creatinine were evaluated three ways: doubling of the baseline value, an increase from < or = 1.5 mg/dL at baseline to > or = 1.5 mg/dL, and an increase from < or = 1.5 mg/dL at baseline to > or = 2.0 mg/dL. More patients in the AmB group reached these end points than in the ABLC group (P < or = 0.007), and the time needed to reach each of these end points was significantly shorter for the AmB group (P < or = 0.02). Increased serum creatinine was reported as an adverse event more frequently by patients receiving AmB than by patients receiving ABLC. In the emergency use study, a steady and statistically significant decrease in serum creatinine was observed among patients who started ABLC treatment with serum creatinine greater than 2.5 mg/dL due to prior AmB treatment. ABLC offers the physician a valuable, less-nephrotoxic alternative to AmB for the treatment of patients with severe, invasive fungal infections.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis; Creatinine; Drug Combinations; Female; Humans; Kidney; Male; Meningitis, Cryptococcal; Middle Aged; Mycoses; Phosphatidylcholines; Phosphatidylglycerols

Disseminated infection with Penicillium marneffei is common in patients infected with human immunodeficiency virus (HIV) in Southeast Asia. Treatment with amphotericin B alone is effective but requires a prolonged hospital stay. We conducted an open-label nonrandomized study to evaluate the efficacy and safety of treatment with amphotericin B at a dosage of 0.6 mg/(kg.d) intraveneously for 2 weeks, followed by a 400-mg/d dosage of oral itraconazole for 10 weeks. Of the 74 HIV-infected patients we studied who had disseminated P. marneffei infection, diagnosed by positive fungal culture and clinical evidence of infection, 72 (97.3%) responded to the treatment. There were no serious adverse drug effects. It was concluded that the regimen was effective and safe for treatment of disseminated P. marneffei infection in HIV-infected patients.

Topics: Adult; AIDS-Related Opportunistic Infections; Amphotericin B; Antifungal Agents; Female; Humans; Itraconazole; Male; Middle Aged; Mycoses; Penicillium; Thailand; Treatment Outcome

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Child; Female; Humans; Immunosuppressive Agents; Liposomes; Liver Transplantation; Male; Middle Aged; Mycoses; Postoperative Complications

The safety and antifungal efficacy of amphotericin B lipid complex (ABLC) were evaluated in 556 cases of invasive fungal infection treated through an open-label, single-patient, emergency-use study of patients who were refractory to or intolerant of conventional antifungal therapy. All 556 treatment episodes were evaluable for safety. During the course of ABLC therapy, serum creatinine levels significantly decreased from baseline (P < .02). Among 162 patients with serum creatinine values > or = 2.5 mg/dL at the start of ABLC therapy (baseline), the mean serum creatinine value decreased significantly from the first week through the sixth week (P < or = .0003). Among the 291 mycologically confirmed cases evaluable for therapeutic response, there was a complete or partial response to ABLC in 167 (57%), including 42% (55) of 130 cases of aspergillosis, 67% (28) of 42 cases of disseminated candidiasis, 71% (17) of 24 cases of zygomycosis, and 82% (9) of 11 cases of fusariosis. Response rates varied according to the pattern of invasive fungal infection, underlying condition, and reason for enrollment (intolerance versus progressive infection). These findings support the use of ABLC in the treatment of invasive fungal infections in patients who are intolerant of or refractory to conventional antifungal therapy.

Topics: Adult; Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis; Creatinine; Cryptococcosis; Drug Combinations; Female; Humans; Male; Mycoses; Phosphatidylcholines; Phosphatidylglycerols

Invasive fungal infections have increasingly become a matter of concern with regard to patients receiving intensive myelosuppressive therapy for hematologic malignancies. Such infections, especially prolonged neutropenia systemic fungal infections, may contribute substantially to infectious complications and early death. Measures for early detection and effective prophylactic strategies using active and nontoxic antifungal agents are therefore urgently needed.. The current randomized study was initiated to assess the efficacy of oral fluconazole as systemic antifungal prophylaxis for high risk patients with recurrent acute myeloid leukemia undergoing intensive salvage therapy.. Of 68 fully evaluable patients, 36 were randomized to fluconazole in addition to standard prophylaxis with oral co-trimoxazol, colistin sulphate, and amphotericin B suspension, and 32 were randomized to standard prophylaxis only. No major differences between the two groups were observed in the number of episodes of fever of unknown origin (61% vs. 50%) or clinically defined infections (56% vs. 50%). Microbiologically defined infections were more frequent in the fluconazole group (50% vs. 31%), mainly due to a higher incidence of bacteremias (42% vs. 22%). There were two cases of proven invasive fungal infections in each group. Systemic amphotericin B was administered more frequently to patients receiving fluconazole prophylaxis (56% vs. 28%). Fluconazole prophylaxis had no impact on the rate of early death or overall survival.. For patients with high risk recurrent acute myeloid leukemia undergoing intensive salvage therapy, antifungal prophylaxis with fluconazole was not superior to standard prophylaxis only.

Topics: Acute Disease; Administration, Oral; Adolescent; Adult; Aged; Amphotericin B; Antibiotic Prophylaxis; Antifungal Agents; Female; Fluconazole; Humans; Immunocompromised Host; Leukemia, Myeloid; Male; Middle Aged; Mycoses; Prospective Studies; Recurrence; Risk Factors; Salvage Therapy

The purpose of this study was to test the comparative efficacy and toxicity of empiric gentamicin and ciprofloxacin, in combination with piperacillin, in febrile patients with treatment-induced neutropenia. Fifty patients were prospectively randomized to receive piperacillin plus gentamicin (PG), and 46 were randomized to receive piperacillin plus ciprofloxacin (PC). The groups were similar in age, sex, diagnosis, duration of neutropenia, and incidence of positive cultures. The two antibiotic regimens were associated with comparable rates of defervescence in the patients with gram-positive bacteremia. In the patients with gram-negative bacteremia and those with negative cultures, however, defervescence was more prompt in the PC group. In particular, 27% of the culture-negative patients on PC, compared to only 5% of those on PG, defervesced within 72 hr (P = 0.015). Because of the more prompt defervescence in the PC group, amphotericin B was used less frequently; 78% of the patients on PG compared with only 56% of those on PC were started on amphotericin B (P = 0.025). PC is an effective alternative to the more traditional PG for treatment of febrile neutropenic hosts who have not been given prophylactic quinolones. More important, PC appears to hasten defervescence compared with PG, especially in culture-negative patients and those with gram-negative bacteremia, and may decrease the necessity of additional antimicrobial agents such as amphotericin B.

Topics: Adult; Amphotericin B; Bacterial Infections; Ciprofloxacin; Drug Therapy, Combination; Female; Fever; Gentamicins; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Mycoses; Neutropenia; Piperacillin; Prospective Studies; Time Factors; Vancomycin

We conducted a prospective, randomized, double-blind study comparing amphotericin B colloidal dispersion (ABCD) with amphotericin B in the empirical treatment of fever and neutropenia. Patients with neutropenia and unresolved fever after > or = 3 days of empirical antibiotic therapy were stratified by age and concomitant use of cyclosporine or tacrolimus. Patients were then randomized to receive therapy with ABCD (4 mg/[kg.d]) or amphotericin B (0.8 mg/[kg.d]) for < or = 14 days. A total of 213 patients were enrolled, of whom 196 were evaluable for efficacy. Fifty percent of ABCD-treated patients and 43.2% of amphotericin B-treated patients had a therapeutic response (P = .31). Renal dysfunction was less likely to develop and occurred later in ABCD recipients than in amphotericin B recipients (P < .001 for both parameters). Infusion-related hypoxia and chills were more common in ABCD recipients than in amphotericin B recipients (P = .013 and P = .018, respectively). ABCD appeared comparable in efficacy with amphotericin B, and renal dysfunction associated with ABCD was significantly less than that associated with amphotericin B. However, infusion-related events were more common with ABCD treatment than with amphotericin B treatment.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Child; Child, Preschool; Colloids; Cyclosporine; Double-Blind Method; Female; Fever; Humans; Immunosuppressive Agents; Infant; Infusions, Intravenous; Kidney Function Tests; Male; Middle Aged; Mycoses; Neutropenia; Opportunistic Infections; Pilot Projects; Prospective Studies; Tacrolimus; Treatment Outcome

It has been suggested that a better outcome of neutropenia-associated invasive fungal infections can be achieved when high doses of lipid formulations of amphotericin B are used. We now report a randomized multicentre study comparing liposomal amphotericin B (AmBisome, 5 mg/kg/d) to amphotericin B deoxycholate (AmB, 1 mg/kg/d) in the treatment of these infections. Of 106 possible patients, 66 were enrolled and analysed for efficacy: nine had documented fungaemia, 17 had other invasive mould infections and 40 had suspected pulmonary aspergillosis. After completion of the course medication, in the AmBisome group (n = 32) 14 patients had achieved complete response, seven a partial response and 11 were failures as compared to 6, 13 and 15 patients (n = 34) treated with AmB (P=0.09); P=0.03 for complete responders. A favourable trend for AmBisome was found at day 14, in patients with documented infections and in patients with pulmonary aspergillosis (P=0.05 and P=0.096 respectively). Mortality rates were lower in patients treated with AmBisome (adjusted for malignancy status, P=0.03). More patients on AmB had a >100% increase of their baseline serum creatinine (P<0.001). The results indicate that, in neutropenic patients with documented or suspected invasive fungal infections AmBisome 5 mg/kg/d was superior to AmB 1 mg/kg/d with respect to efficacy and safety.

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; Deoxycholic Acid; Drug Combinations; Female; Humans; Male; Middle Aged; Mycoses; Neutropenia; Opportunistic Infections; Survival Analysis; Treatment Outcome

This study evaluated the efficacy of low-dose dopamine for prevention of amphotericin B-induced nephrotoxicity in autologous bone marrow transplant and leukemia patients. Seventy-one patients undergoing cytoreductive therapy who required amphotericin B were randomly assigned in an unblinded fashion to a group receiving continuous-infusion low-dose dopamine (3 microgram/kg/min) or a group receiving no dopamine. Amphotericin B was dosed at 0.5 or 1.0 mg/kg/day based on computerized tomography scan results or presence of positive blood cultures. No patient received saline boluses. The rate of nephrotoxicity, severity as graded by Southwest Oncology Group toxicity criteria, and time to each grade of nephrotoxicity were compared between the two groups. Eighty percent of the no-dopamine group and 66.7% of the dopamine group developed nephrotoxicity, defined as a 1.5-fold or greater increase in baseline serum creatinine level (P = 0.20). No statistical difference was noted at any grade of nephrotoxicity between the two groups. Thirty-four percent of patients in the no-dopamine group versus 17.6% in the dopamine group had a 2.5-fold or greater increase in serum creatinine level, which was not statistically significant (P = 0.0888). Ten patients developed grade IV nephrotoxicity and were withdrawn from the study, 7 in the no-dopamine group and 3 in the dopamine group (P = 0.19). The time to each grade of nephrotoxicity was also not significantly different for the two groups. Eleven adverse drug reactions were reported in the dopamine group in comparison to one in the no-dopamine group. Thus, dopamine offers little in the way of prevention of nephrotoxicity associated with amphotericin B therapy. Although the significance of drug reactions in the dopamine group is not clearly established due to lack of cardiac monitoring in the no-dopamine group, dopamine therapy is not without complications.

Topics: Adolescent; Adult; Amphotericin B; Antifungal Agents; Bone Marrow Transplantation; Dopamine; Female; Humans; Kidney Diseases; Leukemia; Male; Middle Aged; Mycoses; Prospective Studies

Several studies have documented the efficacy of amphotericin B as empiric antifungal therapy in cancer patients with prolonged fever and neutropenia. Amphotericin, however, is a toxic drug. Fluconazole has broad-spectrum antifungal activity with an excellent safety profile. Although prophylactic use of fluconazole is widespread, its efficacy as an empiric antifungal agent has not been extensively investigated.. We randomly assigned 106 patients with absolute neutropenia (< or = 500 cells microL) and persistent fever of undetermined origin (> 38 degrees C) despite 1 week of broad-spectrum antibiotic therapy to receive either fluconazole 400 mg orally daily or amphotericin B 0.5 mg/kg/day. Patients with obvious invasive fungal infections were excluded, as were those with abnormal renal or hepatic function. Success was defined as defervescence with the initially assigned antifungal regimen without development of clinically evident invasive fungal infection.. Six patients were excluded from the analysis, mostly because they did not have severe neutropenia. Forty-eight patients received amphotericin B, and 52 received fluconazole. Baseline clinical characteristics and laboratory parameters as well as duration of neutropenia (7.7 versus 6.9 days), duration of fever (7.8 versus 8.1 days), and duration of hospitalization (10.4 versus 8.3 days) were similar between those receiving amphotericin and fluconazole. Treatment success rates and mortality rates were similar in the two groups: 22 (46%) patients in the amphotericin group and 29 (56%) patients in the fluconazole group responded successfully to therapy (P = 0.3), whereas 16 (33%) patients in the amphotericin group and 14 (27%) patients in the fluconazole group died during hospitalization (P = 0.5). Adverse events such as chills and fever (4 versus 1), bronchospasm (2 versus none), severe hypokalemia (25 versus 12) and nephrotoxicity (9 versus 3) were more frequently observed in patients receiving amphotericin. Adverse prognostic factors included prolonged duration of neutropenia and pneumonia.. These results suggest that fluconazole is an equally effective but less toxic alternative to amphotericin B as empiric antifungal therapy in cancer patients with prolonged fever and neutropenia.

Topics: Adolescent; Adult; Amphotericin B; Antifungal Agents; Female; Fever; Fluconazole; Humans; Male; Middle Aged; Mycoses; Neoplasms; Neutropenia; Treatment Outcome

115 patients undergoing allogeneic or autologous bone marrow or peripheral blood stem cell transplantation were treated empirically or for documented fungal infection with liposomal amphotericin-B in doses up to 10mg/kg bodyweight for a duration up to 61 days. The therapy was excellent tolerated and clinical side effects occurred in only eight patients. The drug had to be withdrawn in one episode. A significant influence of liposomal amphotericin-B on laboratory parameters was not observed. Creatinine increased under therapy from a median base point of 1,0 (0,2-3,5) mg/dl to the upper normal value of 1,4 (0,4-4,2) mg/dl. Heavy increases of creatinine as well as of bilirubin, OT and PT were mostly associated with GvHD or regimen related toxicity. Considering the high-risk state of the patients the overall response rate was favourable with 62,9%. However, despite administration of liposomal amphotericin-B culture-proven mycoses were associated with a high morbidity (93,3%). Only one of fourteen patients was cured from Candida lambica septicaemia. We conclude that the antimycotic therapy with liposomal amphotericin-B has a low incidence of side effects. This should, considering the high mortality of fungal infections in BMT recipients, encourage investigators to perform dose escalating studies against the conventional formulation.

Topics: Adolescent; Adult; Amphotericin B; Antifungal Agents; Child; Child, Preschool; Female; Hematopoietic Stem Cell Transplantation; Humans; Infant; Leukemia; Male; Middle Aged; Mycoses

Topics: Amphotericin B; Antifungal Agents; Double-Blind Method; Humans; Immunocompromised Host; Liposomes; Mycoses

Bone marrow transplant (BMT) recipients are at increased risk of invasive fungal disease as a result of the profound neutropenia associated with transplantation. Amphotericin B lipid complex injection (ABLC, ABELCET) was developed to preserve the broad spectrum and fungicidal activity of conventional amphotericin B while avoiding its associated nephrotoxicity. ABLC was made available to physicians in an emergency-use program to treat seriously ill patients with advanced fungal infections who had failed to respond to previous systemic antifungal therapy (mostly amphotericin B), had experienced nephrotoxicity or severe acute toxicity due to amphotericin B or other drugs, or had pre-existing renal disease. Of 59 clinically evaluable BMT recipients with presumed or confirmed fungal infections, 31 (53%) responded to treatment: 23 (39%) were cured and eight (14%) improved. For 38 mycologically evaluable patients, pathogens were eradicated in 19 (50%). For 30 patients who began ABLC treatment with a serum creatinine > 221 mumol/l, significant reductions were observed at weeks 1 to 3 (P < 0.01) and 6 (P < 0.001). Trends in serum creatinine during ABLC therapy between autologous and allogeneic transplant recipients were similar. In summary, the results of this evaluation indicate that ABLC appears to be less nephrotoxic than conventional amphotericin B as well as an effective treatment for BMT recipients with presumed or confirmed fungal infections.

Topics: Adolescent; Adult; Amphotericin B; Antifungal Agents; Bone Marrow Transplantation; Child; Child, Preschool; Creatinine; Drug Combinations; Female; Humans; Male; Middle Aged; Mycoses; Neutropenia; Phosphatidylcholines; Phosphatidylglycerols

The safety of amphotericin B colloidal dispersion (ABCD) was tested in five open-label Phase I/II clinical trials in 572 selected patients who had a fungal infection secondary to a severe underlying disease. In 442 cases ABCD was administered after therapy with amphotericin B, which had been withdrawn in 192 of them because of toxicity. One hundred and forty patients had pre-existing nephrotoxicity. ABCD doses of up to 6 mg/kg/day resulted in no differences in serum creatinine levels, even in patients with pre-existing renal failure. ABCD therapy resulted in no difference in liver function as measured by SGOT, alkaline phosphatase and total bilirubin levels in serum. Apart from thrombocytopenia, there was no significant alteration in hematological or other biochemical parameters in the blood. Adverse events attributable to ABCD requiring discontinuation of therapy occurred in 70 patients (12.2%). The most frequent of these were infusion-related adverse events, which occurred in 5.4% of patients. As a consequence, the maximum tolerated dose was set at 7.5 mg/kg/day. These studies show clearly that ABCD can be administered safely to patients without the risk of renal toxicity, even when renal impairment has already developed following therapy with conventional amphotericin B deoxycholate.

Topics: Amphotericin B; Antifungal Agents; Colloids; Creatinine; Drug Delivery Systems; Humans; Immunocompromised Host; Kidney; Mycoses

Suspected deep or systemic mycosis in patients undergoing high-dose therapy and autologous or allogeneic bone marrow transplantation (BMT) requires an immediate systemic antimycotic therapy. Intravenous therapy with the standard drug conventional amphotericin-B is associated with severe adverse effects like nephrotoxicity and chills. Furthermore, BMT patients often receive other potential nephrotoxic drugs such as CsA or virustatics. In this study, we report 74 BMT-patients treated with liposomal amphotericin-B for culture-documented aspergillosis (n = 5) or candidiasis (n = 6), or for serologically (n = 35) or clinically suspected mycosis or as prophylaxis (n = 2). Therapy was initiated with a median dose of 2.8 (0.64-5.09) mg/kg body-weight and continued for 13 (1-55) days. The drug was excellently tolerated and only in one was therapy stopped due to severe chills and fever. Severe organ impairment was not observed under therapy with liposomal amphotericin-B. Creatinine decreased in five patients after an increase under preceding therapy with the conventional formulation. Influence of liposomal amphotericin-B on bilirubin and transaminases was difficult to evaluate due to therapy-related toxicity, veno-occlusive disease (VOD), and graft-versus-host disease (GvHD). 10/11 culture-positive patients died from aspergillosis (5/5) or candidiasis (5/6), but in 9/11 of these subjects the immunity was additionally compromised by GvHD, steroid therapy, and VOD. Liposomal amphotericin-B was effective in preventing relapse of systemic mycosis in 10/12 patients with a history of aspergillosis (n = 11) or candidiasis (n = 1). We conclude, that favourable toxicity of liposomal amphotericin-B should encourage dose escalation studies of liposomal amphotericin-B randomised against the conventional formulation and that the comparison of patients undergoing BMT with patients under standard chemotherapy might be difficult because of additional risk factors of the BMT-patients.

Topics: Adolescent; Adult; Amphotericin B; Antifungal Agents; Antineoplastic Agents; Bone Marrow Transplantation; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Carriers; Female; Hematopoietic Stem Cell Transplantation; Humans; Infant; Liposomes; Male; Middle Aged; Mycoses

Shivering is experienced by up to 70% of patients undergoing amphotericin B therapy. Treatment with meperidine hydrochloride, currently the most widely used medication for controlling amphotericin B-induced shivering, was compared with nefopam hydrochloride, which has been successfully used to treat post-operative shivering.. Forty-five patients with cancer and systemic fungal infections randomly received nefopam hydrochloride, 0.3 mg/kg, meperidine hydrochloride, 0.7 mg/kg, or saline solution intravenously 15 minutes before the cessation of amphotericin B infusion (1 mg/kg for 45 minutes). If shivering persisted, patients in the control (saline solution) group received either nefopam hydrochloride, 0.3 mg/kg, or meperidine hydrochloride, 0.7 mg/kg.. Occurrence of shivering 15 minutes after the cessation of amphotericin B infusion was significantly less frequent in the nefopam (6.6%) and meperidine (40%) groups compared with the control group (66.6%). The incidence of shivering in the nefopam group with respect to the meperidine group was also significantly reduced. Moreover, nefopam administration to 5 persistently shivering patients in the control group definitively stopped the shivering in all of them (100%) in a mean (+/- SD) time of 29.1 +/- 4.8 seconds, while meperidine terminated shivering in 4 (80%) of 5 patients in a mean (+/- SD) time of 200.0 +/- 30.2 seconds. The adverse reactions that can be ascribed to nefopam or meperidine use were nausea and sedation, respectively, and may be considered negligible.. Nefopam seems to be more effective than meperidine in preventing and quickly suppressing amphotericin B-induced shivering.

Topics: Adult; Aged; Amphotericin B; Analgesics, Non-Narcotic; Analgesics, Opioid; Antifungal Agents; Antineoplastic Agents; Female; Humans; Male; Meperidine; Middle Aged; Mycoses; Nefopam; Neoplasms; Shivering; Treatment Outcome

Neutropenia-related fungal infections can be life-threatening despite antifungal therapy. We evaluated the role of recombinant granulocyte colony-stimulating factor (rG-CSF)-elicited white blood cell (WBC) transfusions in patients with neutropenia-related fungal infections. Adult patients with hematologic malignancies, absolute neutrophil counts (ANC) <500/microl and fungal infections refractory to amphotericin B, received daily transfusions of rG-CSF-elicited and irradiated WBC transfusions from related donors. Donors received 5 microg/kg/day of rG-CSF subcutaneously. Donors achieved a mean ANC of 29.4 x 10(3) per microliter. The mean yield of neutrophils per transfusion was 41 x 10(9) (range, 10-116). Fifteen patients received a median of eight transfusions (range, 3-16). Fourteen patients had received rG-CSF for a median of 12 days. The median ANC baseline was 20/microl. Eleven patients had favorable responses and eight of them remained free of infection 3 weeks after therapy. Favorable responses occurred among patients with better Zubrod performance status (median, 3 vs 4) and shorter duration of both profound neutropenia (median, 15 vs 25 days) and active infection (median, 8 vs 17 days). The mean 1- and 24-h post-transfusion ANCs were 594/microl (range, 98-1472/microl) and 396/microl (range, 50-1475/microl), respectively. Adverse reactions were observed in nine of 35 donors and in the recipients of six of 130 transfusions. rG-CSF-elicited WBC transfusions may be a safe and promising approach for treating neutropenia-related fungal infections.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Blood Donors; Female; Granulocyte Colony-Stimulating Factor; Humans; Leukocyte Transfusion; Male; Middle Aged; Mycoses; Neutropenia; Pilot Projects; Prospective Studies

One hundred and thirty-four adults and 204 children were randomized in two prospective, parallel comparative multicentre trials to receive either conventional amphotericin B 1 mg/kg/d (c-AMB), liposomal amphotericin B 1 mg/kg/d(L-AMB1) or liposomal amphotericin B 3 mg/ kg/d (L-AMB3). Patients were entered if they had a pyrexia of unknown origin (PUO) defined as temperature of 38 degrees C or more, not responding to 96 h of systemic broad-spectrum antibiotic treatment, and neutropenia (< 0.5 x 10(9)/l). The safety and toxicity of liposomal amphotericin B was compared with that of conventional amphotericin B. Efficacy of treatment was assessed, with success defined as resolution of fever for 3 consecutive days (< 38 degrees C) without the development of any new fungal infection. Clinical and laboratory parameters were collected for safety analysis. In both the paediatric and adult populations, L-AMB treated patients had a 2-6-fold decrease in the incidence (P < or = 0.01) of test-drug-related side-effects, compared to c-AMB. Severe trial-drug-related side-effects were seen in 1% of L-AMB treated patients, in contrast to 12% of patients on c-AMB (P < 0.01). Nephrotoxicity, in the patient subset not receiving concomitant nephrotoxic agents, defined as a doubling from the patients baseline serum creatinine level, was not observed in the L-AMB1 arm whereas the incidence was 3% in patients on L-AMB3 and 23% in those on c-AMB (P < 0.01). Moreover, time to develop nephrotoxicity was longer in both L-AMB arms than c-AMB (P < 0.01). Severe hypokalaemia was observed less frequently in both L-AMB arms (P < 0.01). Analysis was by intention-to-treat and included all patients randomized. Success was defined by a minimum of 3 consecutive days with fever (< 38 degrees C) continuing to study end indicated by recovery of neutrophils to 0.5 x 10(9)/l. Addition of systemic antifungal therapy or development of systemic fungal infection were failures as was persistent fever to study end. Efficacy assessments indicated success in 49% of the total group treated with c-AMB, 58% of patients responded to L-AMB1 and 64% to L-AMB3. A statistically significant difference was found between c-AMB and L-AMB3 (P = 0.03) but a Kaplan-Meier analysis of time to differvescence of fever showed there was no significant difference between the arms. It was concluded that liposomal amphotericin at either 1 or 3 mg/kg/d was significantly safer than conventional amphotericin B in children and adults.

Topics: Adult; Amphotericin B; Antifungal Agents; Child; Female; Fever of Unknown Origin; Humans; Male; Mycoses; Neutropenia; Prospective Studies

Amphotericin B (AmB) has been the most effective systemic antifungal agent, but its use is limited by the dose-limiting toxicity of the conventional micellar dispersion formulation (Fungizone). New formulations with better and improved safety profiles are being developed and include ABELCET (formerly ABLC), but their dispositions have not been well characterized; hence, the reason for their improved profiles remains unclear. This report details the pharmacokinetics of ABELCET examined in various pharmacokinetic and efficacy studies by using whole-blood measurements of AmB concentration performed by high-pressure liquid chromatography. The data indicated that the disposition of AmB after administration of ABELCET is different from that after administration of Fungizone, with a faster clearance and a larger volume of distribution. It exhibits complex and nonlinear pharmacokinetics with wide interindividual variability, extensive distribution, and low clearance. The pharmacokinetics were unusual. Clearance and volume of distribution were increased with dose, peak and trough concentrations after multiple dosings increased less than proportionately with dose, steady state appeared to have been attained in 2 to 3 days, despite an estimated half-life of up to 5 days, and there was no evidence of significant accumulation in the blood. The data are internally consistent, even though they were gathered under different conditions and circumstances. The pharmacokinetics of ABELCET suggest that lower concentrations in blood due to higher clearance and greater distribution may be responsible for its improved toxicity profile compared to those of conventional formulations.

Topics: Amphotericin B; Antifungal Agents; Antineoplastic Agents; Area Under Curve; Chromatography, High Pressure Liquid; Drug Combinations; Drug Interactions; Half-Life; HIV Infections; Humans; Kidney Diseases; Leishmaniasis, Mucocutaneous; Mycoses; Neutropenia; Phosphatidylcholines; Phosphatidylglycerols; Reference Values

Topics: Adult; Amphotericin B; Antifungal Agents; Child; Drug Carriers; Fever of Unknown Origin; Humans; Liposomes; Mycoses; Neutropenia; Randomized Controlled Trials as Topic

Amphotericin B colloidal dispersion (ABCD; Amphocil) was evaluated in a phase I dose-escalation study in 75 marrow transplant patients with invasive fungal infections (primarily Aspergillus or Candida species) to determine the toxicity profile, maximum tolerated dose, and clinical response. Escalating doses of 0.5-8.0 mg/kg in 0.5-mg/kg/patient increments were given up to 6 weeks. No infusion-related toxicities were observed in 32% of the patients; 52% had grade 2 and 5% had grade 3 toxicity. No appreciable renal toxicity was observed at any dose level. The estimated maximum tolerated dose was 7.5 mg/kg, defined by rigors and chills and hypotension in 3 of 5 patients at 8.0 mg/kg. The complete or partial response rate across dose levels and infection types was 52%. For specific types of infections, 53% of patients with fungemia had complete responses, and 52% of patients with pneumonia had complete or partial responses. ABCD was safe at doses to 7.5 mg/kg and had tolerable-infusion-related toxicity and demonstrable antifungal activity.

Topics: Adult; Amphotericin B; Antifungal Agents; Aspartate Aminotransferases; Aspergillosis; Bone Marrow Transplantation; Candidiasis; Chemical and Drug Induced Liver Injury; Cholesterol Esters; Creatinine; Humans; Kidney Diseases; Mycoses

To evaluate the safety, tolerance and pharmacokinetics of a new formulation of amphotericin B (AmB; CAS 1397-89-3) 18 AIDS patients treated for different kinds of mycoses were studied: oropharingeal and/or esophageal azole-resistant candidiasis (9), CNS cryptococcosis (7) or aspergillosis (2). Amphotericin B daily dose was infused in 100 ml of a lipid emulsion. The patients aged from 26 to 54 years with body weight ranging from 42 to 89 kg. Blood samples were collected at fixed intervals and plasma stored at -20 degrees C until tested by a specific HPLC assay. The individual kinetic analysis of plasma drug levels was performed by a two-compartment open model. The data were analyzed using P-Pharm, a computer program designed for population pharmacokinetic analysis that allows pooling of data. The effect of a variety of demographic factors on clearance and volume of distribution was investigated. The clearance and the apparent volume of distribution were, respectively, (mean +/- SD): 0.037 +/- 0.015 l/h/kg and 0.45 +/- 0.32 l/kg. The interindividual variability in AmB clearance and volume of distribution was modelled with proportional error with an estimated coefficient of variation of 40.6% and 70.9%, respectively. Clinical and biological tolerance was very good and no patient experience infusion-related adverse effects or hematologic and hepatic toxicity; a moderate renal failure occurred in only one patient.

Topics: Acquired Immunodeficiency Syndrome; Adult; Amphotericin B; Antifungal Agents; Chromatography, High Pressure Liquid; Drug Delivery Systems; Female; Humans; Infusions, Intravenous; Lipids; Male; Middle Aged; Mycoses

The pharmacokinetics of amphotericin B administered in a conventional 5% dextrose (glucose) (5% D) solution and in a 20% fat emulsion formulation (Intralipid; 20% IL) were compared in 16 patients (mean age, 42 years [range, 18 to 70 years]) who had been hospitalized for hematological malignancies and with proven or suspected fungal infections. All of the patients received 50 mg (approximately 1 mg/kg of body weight per day) of amphotericin B daily in random order, either as a 50-ml lipid emulsion (20% IL) (group I) or in 500 ml of 5% D (group II). Five serum samples were taken during the 24 h after drug administration, and the levels of amphotericin B were measured by high-pressure liquid chromatography. Serum amphotericin B concentrations declined rapidly during the first 6 h, and subsequent measurements revealed a slow terminal elimination phase in both groups. The maximum serum amphotericin B concentration was significantly lower when the drug was administered in 20% IL (1.46 +/- 0.61 versus 2.83 +/- 1.17 micrograms/ml; P = 0.02). The area under the concentration-time curve from 0 to 24 h was also much lower in group I (17.22 +/- 11.15 versus 28.98 +/- 15.46 micrograms.h/ml). The half-life of the distribution phase was approximately three times longer in group I (2.92 +/- 2.34 h versus 0.64 +/- 0.24 h; P = 0.011). Conversely, the half-lives of the elimination phase were approximately equal in the two groups (11.44 +/- 5.18 versus 15.23 +/- 5.25 h). The mean residence times were also similar in both groups (19.41 +/- 11.13 versus 19.65 +/- 7.86 h). The clearance and the steady-state volume of distribution of amphotericin B in group I were about twice as great as those in group II (62.97 +/- 35.51 versus 33.01 +/- 14.33 ml/kg/h and 1,043.92 +/- 512.10 versus 562.32 +/- 152.05 ml/kg [P = 0.034], respectively). Finally, the volume of distribution in the central compartment was greater in group I than in group II (618.17 +/- 231.80 versus 328.19 +/- 151.71 ml/kg; P = 0.013), but there were no differences in the volume of distribution in the peripheral compartment (425.75 +/- 352.87 versus 234.14 +/- 75.92 ml/kg). These results suggest that amphotericin B has a different pharmacokinetic profile when it is administered in 20% IL than when it is administered in the standard 5% D form and that the main difference is due to a clear-cut difference in the steady-state volume of distribution, especially that in the central compartment.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Fat Emulsions, Intravenous; Female; Half-Life; Humans; Male; Middle Aged; Mycoses; Neutropenia; Prospective Studies; Solutions

Amphotericin B, despite its intrinsic servere toxicity, is the most commonly used empirical antifungal therapy in cancer patients with unexplained fever not responding to empirical antibacterial therapy. The aim of this study was to show whether fluconazole was as effective as, and less toxic than, amphotericin, with no effort made to compare the antifungal activity of the two drugs. A group of 112 persistently febrile (> 38 degrees C) and granulocytopenic (< 1000 cells/mm3) cancer patients, not receiving any absorbable antifungal antibiotic for prophylaxis, with a mean age of 27 years (range 1-73 years), undergoing chemotherapy for a variety of malignancies and with a diagnosis of unexplained fever after at least 96 h of empirical antibacterial therapy, were randomised to receive either fluconazole (6 mg/kg/day up to 400 mg/day) or amphotericin B (0.8 mg/kg/day) as empirical antifungal treatment. Patients were required to have normal chest X-rays at randomisation, no previous history of aspergillosis and negative surveillance cultures for Aspergillus. The intention-to-treat analysis showed defervescence and survival without treatment modification in 42 of 56 patients (75%) in the fluconazole group and in 37 of 56 (66%) in the amphotericin B group (P = 0.4). Duration of therapy was 6 days (95% CI = 4-8 days) in both groups. Death occurred in 3 patients (5%) in the fluconazole and in 2 (4%) in the amphotericin B group. No fungal death was documented in either group. Adverse events developed in 18 of 56 patients (32%) in the fluconazole group and in 46 of 56 (82%) in the amphotericin B group (P < 0.001). In the amphotericin B group, 5 patients had treatment discontinued because of toxicity, versus none in the fluconazole group, a difference which approached statistical significance (P = 0.06). This study shows that fluconazole is by far less toxic than amphotericin B and suggests that it might be as effective as amphotericin B, in pragmatical terms and for this specific indication. However, numbers are too small to allow definitive conclusions about efficacy, and the use of fluconazole for this indication remains experimental. Future studies should try to identify patients more at risk of fungal infections, with the aim of individualising antifungal approaches.

Topics: Adolescent; Adult; Aged; Agranulocytosis; Amphotericin B; Antifungal Agents; Child; Child, Preschool; Female; Fever; Fluconazole; Humans; Immunocompromised Host; Infant; Male; Middle Aged; Mycoses; Neoplasms; Opportunistic Infections; Prospective Studies; Treatment Outcome

Fungal infections are a major problem in patients with hematologic malignancy. Attempts to reduce their frequency with antifungal agents have not been successful. A double-blind, controlled, single-center trial was conducted with 96 consecutive patients undergoing 154 episodes of chemotherapy. Patients received 400 mg of fluconazole or placebo until bone marrow recovery or initiation of intravenous amphotericin B infusions. End points were amphotericin B use, fungal infection, stable neutrophil count > 0.5 x 10(9)/L, toxicity precluding further fluconazole use, and death. By Kaplan-Meier estimation, the time to initiation of amphotericin B therapy was shorter in 76 patients treated with placebo than in 75 treated with fluconazole (P = .003). Also, fluconazole reduced the number of febrile days by 20% (P = .002) and prevented oropharyngeal candidiasis (1/75 vs. 9/76, P = .018). The frequency of deep mycoses (8/76 vs. 8/75) and outcome were unaffected. Fluconazole did not have a favorable effect on infection-related health care costs and was associated with prolonged severe neutropenia (P = .01).

Topics: Adult; Amphotericin B; Antibiotic Prophylaxis; Antifungal Agents; Aspergillosis; Bacteremia; Candidiasis, Oral; Double-Blind Method; Drug Therapy, Combination; Fever; Fluconazole; Humans; Incidence; Infusions, Intravenous; Leukemia; Lymphoma; Middle Aged; Mycoses; Neutropenia; Treatment Outcome

The effects of short-course antifungal regimens on funguria were studied in 180 hospitalized adults who did not have ascending urinary or deep fungal infections but did have > 1,000 cfu of yeast/mL in two consecutive urine cultures. Before treatment, efforts were made to eliminate factors conducive to funguria. No additional interventions were implemented in the management of the control group (group A), whereas five experimental groups received short-course therapy as follows: oral administration of fluconazole (group B); single-dose intravenous administration of amphotericin B (group C); and intermittent bladder irrigation with amphotericin B at low, medium, and high concentrations (groups D, E, and F, respectively). Urine was cultured on days 1 and 7 after antifungal treatment. The rate of spontaneous clearance of funguria in the control group was 40.0%. Rates of clearance in experimental groups B through F were 58.6%, 55.2%, 82.1% (P < .01), 86.7% (P < .001), and 83.3% (P < .001), respectively, on day 1 and 77.3% (P < .01), 72.0% (P < .05), 42.9%, 68.4%, and 68.2% (P < .05), respectively, on day 7. The decrement in yeast count was 60.8% for the control group. Decrements for experimental groups B through F were 80.5%, 74.2%, 94.2% (P < .01), 86.7% (P < .05), and 95.3% (P < .001), respectively, on day 1 and 85.5% (P < .05), 80.7%, 75.7%, 87.9% (P < .05), and 76.4%, respectively, on day 7.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Amphotericin B; Female; Fluconazole; Fungi; Humans; Male; Middle Aged; Mycoses; Prospective Studies; Urine

A pilot exploratory study was undertaken to collect preliminary information relating to safety and overall outcome in using intravenous fluconazole (FLUC) for managing antibiotic resistant neutropenic fever (ARNF), with the objective of assessing feasibility of performing a larger prospective controlled study. Patients who were neutropenic from treatment for leukaemia or bone marrow transplantation, received either fluconazole (FLUC) or amphotericin B (AB). Eight of 16 patients (50%) on FLUC and 21 of 25 patients (84%) on AB defervesced; the mean time to defervescence was 11.0 +/- 10.0 days for FLUC compared to 7.7 +/- 6.3 days for AB, and a similar proportion in each treatment group defervesced within 5 days (50% vs. 52%), respectively. Six of 16 patients (37.5%) on FLUC and three of 25 patients (12%) on AB developed overt invasive fungal disease, including pulmonary aspergillosis (FLUC 4 cases, AB 2 cases) and invasive candidiasis (FLUC 2 cases, AB 0 cases). The mean time to these events was 19.5 +/- 13.4 (FLUC) and 9.0 +/- 3.6 (AB) days. The fungal related mortality rates were higher in the FLUC group: five of 16 patients (31%) vs. two of 25 patients (18%) died respectively; the time to fungal death was 43.2 +/- 18.2 (FLUC) and 25.0 +/- 18.4 (AB) days. This tendency towards a more favourable outcome in patients on AB may have been due to absence of prior fluconazole prophylaxis in patients subsequently receiving IV FLUC. Analysis of a small subgroup of patients who had all received prior prophylaxis with clotrimazole only, indicated that a greater number of patients subsequently receiving IV FLUC died from fungal disease (5/16 vs.0/6, P = 0.09).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Amphotericin B; Aspergillosis, Allergic Bronchopulmonary; Bone Marrow Transplantation; Female; Fever; Fluconazole; Humans; Leukemia; Male; Mycoses; Neutropenia; Pilot Projects; Prospective Studies; Treatment Outcome

Topics: Adolescent; Adult; Aged; Amphotericin B; Aspergillosis; Candidiasis; Child; Child, Preschool; Drug Carriers; Female; Follow-Up Studies; Humans; Infant; Liposomes; Liver Transplantation; Male; Middle Aged; Mycoses; Placebos; Postoperative Complications; Probability; Risk Factors; Time Factors; Tissue Donors

Topics: Adult; Amphotericin B; Antifungal Agents; Aspergillus fumigatus; Colistin; Digestive System; Drug Therapy, Combination; Fluconazole; Humans; Liver Transplantation; Middle Aged; Mycoses; Retrospective Studies; Risk Factors; Sputum; Tobramycin

The purpose of this study was to evaluate the pharmacokinetics of amphotericin B colloidal dispersion and its effect on creatinine clearance in bone marrow transplant patients with systemic fungal infections. Seventy-five patients (42 females and 33 males) with a median age of 34.5 years and a median weight of 70.0 kg were enrolled in the study. Patients received 1 of 15 dose levels (range, 0.5 to 8.0 mg/kg of body weight) daily for a mean duration of 28 days and a mean cumulative dose amount of 8 g. Plasma samples for amphotericin B determination (median number, 4; range, 2 to 30) and daily serum creatinine values were obtained for each patient. Iterative two-stage analysis, one of several approaches to population pharmacokinetic and pharmacodynamic modelling, was employed for the pharmacokinetic analysis. The plasma data were available for 51 of 75 patients and were best described by a two-compartment model. Both plasma clearance and volume of distribution increased with escalating doses; the overall average terminal elimination half-life was 29 h. Of the covariates studied, only body weight and dose size were significant. Serum creatinine values over the duration of therapy were available for 59 of 75 patients. Overall, there was no net change in renal function over the duration of therapy; 12 patients had > 30% increases in creatinine clearance, whereas 13 had > 30% decreases. No measure of amphotericin B colloidal dispersion exposure, demographic values, or concomitant treatment with other medications was related to changes in the creatinine clearance.

Topics: Adolescent; Adult; Amphotericin B; Antifungal Agents; Bone Marrow Transplantation; Child; Creatine; Female; Half-Life; Humans; Kidney Diseases; Kidney Function Tests; Male; Middle Aged; Mycoses; Population

To investigate the influence of infusion duration on infusion-related adverse effects (IRAEs) associated with prophylactic or treatment regimens of amphotericin B in patients with leukemia/bone marrow transplant (BMT).. Randomized, double-blind, 2-arm, complete crossover, prospective clinical trial.. A university-affiliated tertiary care teaching hospital.. The study population consisted of 25 consecutive patients with leukemia/BMT who received 162 prophylactic regimen infusions and 169 treatment regimen infusions of amphotericin B via a central line. Prior to each infusion all patients received a parenteral IRAE prophylaxis regimen of diphenhydramine 25 mg and hydrocortisone 25 mg. No test doses or incremental amphotericin B doses were administered. Patients were monitored closely for IRAEs, which were documented by using a standardized data collection form.. The incidence and nature of IRAEs during a 6-hour monitoring period following the initiation of each infusion was measured. Patients served as their own controls. IRAEs were compared according to infusion duration and therapeutic indication.. Three hundred and thirty-one 2- and 4-hour amphotericin B infusions were administered. We found no difference between 2- and 4-hour infusions in the incidence and severity of IRAEs, including overall events (29% of 166 2-hour infusions vs. 25% of 165 4-hour infusions), chill scores (8% of 166 2-hour infusions vs. 7% of 165 4-hour infusions; highest score 7 vs. 6), nausea and vomiting (7% vs. 12%; highest score 4 in both groups), fever (3% vs. 2%), highest temperature increase (2.4 vs. 1.6 degrees C), systolic hypotension (6% vs. 2%), greatest decrease from baseline (40 vs. 62 mm Hg), diastolic hypotension (5% vs. 3%), and greatest decrease (30 vs. 28 mm Hg) (p > 0.05). Overall, IRAEs were less common in prophylactic treatment regimens (35 events [22%] in 162 infusions) than in treatment regimens (55 events [32%] in 169 infusions) (p < 0.05).. This study demonstrates that patients with leukemia/BMT without myocardial or renal dysfunction who receive hydrocortisone and diphenhydramine as premedications can tolerate 2-hour central line infusions of prophylactic or treatment regimens of amphotericin B as well as 4-hour infusions.

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; Bone Marrow Transplantation; Cross-Over Studies; Double-Blind Method; Drug Tolerance; Female; Hospitals, University; Humans; Immunocompromised Host; Infusions, Intravenous; Leukemia; Male; Middle Aged; Mycoses; Prospective Studies; Time Factors

Amphotericin B colloidal dispersion (ABCD), a novel formulation of amphotericin B and cholesteryl sulfate in a 1:1 ratio, was developed to reduce the toxicity of amphotericin B yet retain its antifungal efficacy. In an open-label trial, ABCD at dosages as high as 6 mg/(kg.d) was administered to 168 patients with documented or presumed systemic mycoses. All patients had responded incompletely to at least 7 days' treatment with conventional amphotericin B (CAB), had experienced CAB-induced nephrotoxic effects, had preexisting renal impairment, or had experienced other CAB-related, treatment-limiting toxic effects. The clinical response to ABCD could be evaluated in 97 patients. Complete clinical response or improvement was noted in 48 (49%) of them after a mean treatment duration of 18.5 days. All 168 enrolled patients were evaluated with regard to safety of the treatment. Even at daily doses as high as 6 mg/kg, and mean and median cumulative doses of 4.0 g and 2.4 g, respectively, ABCD had little renal toxicity: the mean change in serum level of creatinine from baseline to final value was -0.02 mg/dL. Hypokalemia developed in eight patients (5%). This study provides preliminary evidence that ABCD is effective in treating invasive mycoses and lacks the dose-limiting nephrotoxicity of CAB.

Topics: Adult; Amphotericin B; Colloids; Creatinine; Female; Humans; Hypokalemia; Kidney; Male; Mycoses; Safety

To evaluate the usefulness of a 20% lipid emulsion as a delivery system for amphotericin B (1 mg/mL) administered over 1 hour to patients with neutropenia with hematologic malignancies compared with amphotericin B (0.1 mg/mL) administered in dextrose 5% solution over the same time.. A prospective, comparative, randomized, labeled study.. Hematology unit, pharmacy service, university general hospital.. Twenty patients with neutropenia with hematologic malignancies and proven or suspected fungal infections, 10 in the fat emulsion group (group 1) and 10 in the dextrose 5% group (group 2).. Clinical tolerance (i.e., fever, shaking chills, nausea, blood pressure, pulse rate) and biologic tolerance (i.e., urea, creatinine, sodium, potassium).. Clinical tolerance was comparable in both groups although amphotericin B in fat emulsion was better tolerated. Medication for symptoms related to the administration of amphotericin B was given in 6 cases in group 1 and in 8 cases in group 2. There was a statistically significant difference in the urea concentrations between the 2 groups (p = 0.023); there was an observed increase between the initial and the final serum urea (56.8 mg/d in group 1, 79.8 mg/dL in group 2). Statistically significant differences in creatinine serum concentrations (84.9 mumol/L in group 1, 123.8 mumol/L in group 2) (p = 0.047) were found. No differences were found in the antifungal efficacy of the treatment. However, as amphotericin B was started in the majority of cases (75%) as empiric treatment for fever unresponsive to antibiotic therapy, it is difficult to compare the efficacy of both preparations.. The clinical tolerance of lipid-emulsion infusions is similar to that of conventionally administered amphotericin B therapy. Renal toxicity appears to be decreased when the drug is administered in a fat emulsion. This type of preparation permits the reduction of the volume and the time of administration for amphotericin B therapy.

Topics: Adolescent; Adult; Amphotericin B; Antifungal Agents; Fat Emulsions, Intravenous; Female; Glucose; Hematologic Diseases; Humans; Infusions, Intravenous; Male; Middle Aged; Mycoses; Neutropenia; Prospective Studies; Solutions

A randomized, comparative study was conducted in 502 patients in 23 centres world-wide to assess the efficacy and safety of fluconazole versus nystatin and amphotericin B for prevention of fungal infection in a severely immunocompromised pediatric population. Patients scheduled within 48 hours to undergo chemotherapy or radiotherapy for hematological or oncological malignancies were randomly allocated to receive 3 mg/kg oral fluconazole once daily, 50,000 U/kg oral nystatin four times daily or 25 mg/kg oral amphotericin B four times daily. Prophylaxis began with the initiation of chemotherapy or radiotherapy and continued throughout a patient's hospital stay or period of neutropenia as necessary. The mean duration of fluconazole prophylaxis was 27.8 days and of the oral polyenes 29.2 days. The outcome of prophylaxis with fluconazole was significantly superior to that with the polyenes (p = 0.01). Mycologically verified infections occurred in 5 patients (2.1%) given fluconazole and in 21 (8.4%) given polyenes (p = 0.002). Clinical evaluation at the end of prophylaxis showed that the clinical outcome was definitely or possibly successful in 87% in the fluconazole group and 82% in the polyenes group with no significant differences between the treatment groups. Mycological evaluation demonstrated reduction or control of colonization in 84% in the fluconazole group and 85% in the polyenes group, again with no significant between-group differences. Possibly drug-related side effects, mainly mild to moderate gastrointestinal disturbances, were reported in 38 patients given fluconazole, with eight subsequent withdrawals, and in 21 patients given oral polyenes, with three subsequent withdrawals. Laboratory test abnormalities occurred in 28 patients given fluconazole and 24 given polyenes.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Adolescent; Amphotericin B; Candida; Child; Child, Preschool; Female; Fluconazole; Hematologic Diseases; Humans; Immunocompromised Host; Infant; Infant, Newborn; Male; Mycoses; Neoplasms; Nystatin

The aim of this study was to determine the efficacy of orally administered amphotericin B (Ampho B) on the elimination and suppression of yeasts in the orointestinal tract and on the clinical success regarding the Ampho B concentrations in faeces and serum. A total of 23 newborns at risk suffering from oral and/or cutaneous candidosis and massive colonization of yeasts in the orointestinal tract received Ampho-Moronal suspension (Squibb-Heyden, München) for 10 days: newborns < 1500 g 4 x 20 mg Ampho B/d and newborns > 1500 g 4 x 40 mg/d. Ampho B was detected in concentrations between 0.6 and 20 micrograms/g in the faeces of all patients 24 hours after beginning and 2-6 days after the end of the application. During this time Ampho B concentrations between 0.06 and 0.58 microgram/ml were also detected in the serum of the newborns. During the administration of Ampho-Moronal suspension for 10 days the initial available yeasts were eliminated in 18 patients (78%) out of the faeces. In 7 out of 17 patients (41%) the oral and cutaneous candidosis was cured. After finishing the administration of Ampho-Moronal Candida albicans was isolated again from the faeces during the following 5 days in half of the newborns who had reached negative mycological findings during the prophylaxis. For that reason Ampho-Moronal should be prophylactically administered for a longer time during the period of increased risk for systemic mycosis.

Topics: Administration, Oral; Amphotericin B; Candidiasis; Feces; Humans; Infant, Newborn; Intestinal Diseases; Mycoses; Risk Factors

To evaluate the efficacy of i.v. amphotericin B (AmB) as prophylaxis of deep mycosis (DM) in allogenic bone marrow transplantation (BMT).. From July 1991 to May 1993, 45 consecutive patients treated by allogenic BMT with no previous history of systemic mycosis and with normal renal function were administered prophylactic AmB at a dose of 0.5 mg/kg/48 h from day + 1 BMT until hemoperipheral recovery (group A). These were compared with an historic control group made up of 45 consecutive patients submitted to BMT from January 1990 to June 1991 who did not receive prophylactic AmB (group B). During the neutropenic phase all the patients remained in isolation units with laminar flow of filtered air and were administered oral non absorbable antibiotic therapy and diet of low bacterial content. The incidence of DM and the dose of AmB administered during the first 120 days post BMT were evaluated.. In the first 30 days following BMT 3 (7%) cases of DM were observed in group A and 3 (7%) in group B. Four (9%) additional cases were found from days 30 to 120 in group A and 3 (7%) in group B. In 3 (7%) patients of the group which received prophylaxis and in 4 (9%) of the control group Candida spp. was isolated. In 3 (7%) patients from group A and 1 (2%) patient from group B the infection was due to Aspergillus. Although the patients from group A received therapeutic AmB less frequently (78% vs 91%) and later (13 [SD +/- 5.9] vs 9.2 [SD +/- 4.6] days) than those of group B (p < 0.002) the mean dose of AmB per patient treated was similar in both groups (11.3 [SD +/- 8.8] vs 11.8 [SD +/- 7] mg/kg).. The prophylactic use of systemic amphotericin during the neutropenic phase of bone marrow transplantation does not reduce either the incidence of deep mycosis or the mean dose of amphotericin administered.

Topics: Adolescent; Adult; Amphotericin B; Bone Marrow Transplantation; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Mycoses; Postoperative Care; Time Factors

The efficacy of an antimicrobial regimen for prevention of infections was prospectively evaluated in 113 patients undergoing autologous bone marrow transplantation (BMT). Ciprofloxacin, 500 mg orally twice a day plus antifungal prophylaxis, fluconazole 50 mg once daily plus amphotericin B tablets or suspension and tablets, each 200 mg four times a day, was given. In addition all patients received streptococcal prophylaxis for 10 days after BMT. Documented infections occurred in 39% (44 of 113) of patients and unexplained fever in 27% (30 of 113). The efficacy of this regimen was reflected in a low mortality rate (3.5%) from infections and in the low need for intravenous amphotericin B (7%). No benefit of protective isolation was found in 59 patients compared with 54 patients treated without isolation measures.

Topics: Adolescent; Adult; Amphotericin B; Bacterial Infections; Bone Marrow Transplantation; Ciprofloxacin; Drug Therapy, Combination; Female; Fluconazole; Humans; Male; Middle Aged; Mycoses; Patient Isolation; Prospective Studies; Transplantation, Autologous

To evaluate the efficacy of prophylactic low-dose amphotericin B (0.1 mg/kg per day) (LDA) in preventing fungal infections in patients who have had a bone marrow transplant (BMT).. Double-blind, randomized, controlled trial in which patients undergoing bone marrow transplantation received intravenous LDA or similar-appearing placebo from the onset of neutropenia until the absolute neutrophil count remained > 0.5 x 10(9)/L, or until high-dose amphotericin B was initiated. Weekly surveillance cultures were obtained from all patients.. Five of 18 patients (28%) randomized to placebo developed documented systemic fungal infections within the first 30 days after transplantation, compared to none of 17 patients who received LDA (P = 0.045). LDA recipients received fewer days of high-dose amphotericin B (P = 0.04) and fewer days of antibiotics (P = 0.008). There were trends towards fewer days of hospitalization (P = 0.14) and improved survival (P = 0.08); these differences were statistically significant among recipients of allogeneic BMT. No adverse effects occurred with LDA therapy.. LDA appears to be safe and to reduce early systemic fungal infections in BMT recipients. Improved survival was observed among LDA recipients, but this was not directly attributable to the prevention of fungal infection.

Topics: Adolescent; Adult; Amphotericin B; Bone Marrow Transplantation; Child; Confounding Factors, Epidemiologic; Double-Blind Method; Female; Humans; Infusions, Intravenous; Length of Stay; Male; Middle Aged; Mycoses; Survival Analysis; Treatment Outcome

Fungal urinary tract infection has become a frequent clinical entity. Despite limited evaluation of its efficacy, bladder irrigation with amphotericin B has become the usual means of therapy for such infections. The outcome of treatment with amphotericin B bladder irrigation for an average of 5 days for 95 hospitalized patients with funguria (mean age, 75 years) during a 14-month period is presented. All patients who received treatment were identified from pharmacy records; those for whom urine culture results were obtained after treatment were studied. Fever and/or pyuria was identified in the majority of cases. Funguria was eradicated in 80% (confidence interval, 72%-88%). Concomitant diabetes mellitus or the previous use of indwelling bladder catheters did not alter response to treatment. The mortality rate following treatment of funguria was 39%, compared to 30.5% for a similar population during the same period. Amphotericin B bladder irrigation may not prove to be ideal therapy despite the fact that it initially eradicated funguria in the majority of subjects in this study.

Topics: Administration, Intravesical; Aged; Amphotericin B; Diabetes Complications; Female; Humans; Male; Middle Aged; Mycoses; Retrospective Studies; Risk Factors; Urinary Catheterization; Urinary Tract Infections

Topics: Amphotericin B; Bone Marrow Transplantation; Double-Blind Method; Drug Carriers; Humans; Liposomes; Liver Transplantation; Mycoses; Prognosis

Twenty-one episodes of fungal peritonitis occurred over 35 months among 290 patients on CAPD, accounting for 6.3% of all peritonitis episodes. Patients with more frequent bacterial peritonitis were at higher risk of developing fungal peritonitis, and 28.6% of cases followed antimicrobial therapy. Candida species accounted for 85.7% of cases. Oral fluconazole was used as initial therapy in all patients, which was followed by catheter removal if peritonitis failed to improve. The cure rate with fluconazole therapy alone without catheter removal was 9.5%. Fluconazole plus catheter removal, the latter necessitated in 85.7% of cases, resulted in a cure rate of 66.7%. The remaining 3 (14.3%) patients responded to intravenous amphotericin given as salvage therapy. Disease-related mortality was 14.3%. Reinsertion of dialysis catheter was attempted in 15 patients and CAPD was successfully resumed in 13 (86.7%). We conclude that oral fluconazole can be safely used as initial therapy in patients with fungal peritonitis complicating CAPD. Although catheter removal was necessary in the majority of patients, this sequential approach resulted in a relatively low prevalence of peritoneal adhesions and subsequent CAPD failure.

Topics: Administration, Oral; Amphotericin B; Female; Fluconazole; Humans; Injections, Intravenous; Male; Middle Aged; Mycoses; Peritoneal Dialysis, Continuous Ambulatory; Peritonitis

Topics: Adolescent; Amphotericin B; Aspergillosis; Bone Marrow Transplantation; Candidiasis; Child; Child, Preschool; Female; Humans; Immunocompromised Host; Infant; Liposomes; Liver Transplantation; Male; Mycetoma; Mycoses

Fungal infection is a frequent and often fatal complication in patients undergoing remission induction therapy for acute leukemia. Although candidiasis is the most common infection, mold infections are increasing in frequency. Fluconazole (FLU) is a new antifungal agent that has been used successfully to treat Candida infections and has modest activity against aspergillosis in animal models. Subtherapeutic doses of amphotericin B (AMB) have been considered effective as prophylaxis in these patients. This study was designed to compare the efficacy and toxicity of these agents as antifungal prophylaxis.. Adults with acute leukemia undergoing remission induction chemotherapy randomly were assigned to receive antifungal prophylaxis with AMB (0.5 mg/kg three times weekly) or FLU (400 mg daily). Trimethoprim-sulfamethoxazole was administered as an antibacterial prophylaxis. Prophylaxis was continued until the patient achieved complete remission or was treated for 8 weeks without antileukemic response. Prophylaxis was discontinued if the patient experienced a possible or proven fungal infection or a serious toxicity.. Overall, 58% of the 36 patients assigned to AMB successfully completed prophylaxis compared with 80% of the 41 patients assigned to FLU (< 0.05). Proven, probable, or possible fungal infections occurred in 31% and 17% of the patients, respectively. The risk of discontinuing prophylaxis due to fungal infection or toxicity increased with time in the study and was significantly greater for AMB (P = 0.02).. At the dose used in this study, AMB was no more effective and was more toxic than FLU for prophylaxis of fungal infections in patients undergoing remission induction chemotherapy for acute leukemia.

Topics: Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Blast Crisis; Female; Fluconazole; Humans; Kidney Diseases; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Mycoses; Premedication; Prospective Studies; Remission Induction

To compare the efficacy and tolerability of fluconazole and oral amphotericin B in preventing fungal infection in neutropenic patients with acute leukemia.. A randomized, controlled, multicenter trial.. 30 hematologic units in tertiary care or university hospitals.. 820 consecutive, afebrile, adult patients with acute leukemia and chemotherapy-induced neutropenia.. Patients were randomly assigned to receive fluconazole, 150 mg, as a once-daily capsule, or amphotericin B suspension, 500 mg every 6 hours.. An intention-to-treat analysis was done for 820 patients: 420 treated with fluconazole and 400 treated with oral amphotericin B.. Definite systemic fungal infection occurred in 2.6% of fluconazole recipients and 2.5% of amphotericin B recipients; suspected systemic fungal infection requiring the empiric use of intravenous amphotericin B occurred in 16% of fluconazole recipients and 21% of oral amphotericin B recipients, a difference of 5 percentage points (95% CI for difference, -0.02% to 10%; P = 0.07). Superficial fungal infection was documented in 1.7% of fluconazole recipients compared with 2.7% of amphotericin B recipients, a difference of one percentage point (CI of difference, -0.9% to 3%; P > 0.2). The distribution of fungal isolates in systemic and superficial fungal infection was similar in both groups. The overall mortality rate accounted for 10% in both groups. An excellent compliance was documented for 90% of patients treated with fluconazole compared with 72% of those treated with amphotericin B suspension, a difference of 18 percentage points (CI for difference, 13% to 23%). Side effects were documented less frequently in fluconazole than in amphotericin B recipients (1.4% compared with 7%, a difference of 5.6 percentage points; CI for difference, 2% to 8%; P < 0.01).. Fluconazole was at least as effective as oral amphotericin B in preventing systemic and superficial fungal infection and the empiric use of amphotericin B in neutropenic patients with acute leukemia but was better tolerated.

Topics: Acute Disease; Administration, Oral; Administration, Topical; Adolescent; Adult; Aged; Amphotericin B; Antineoplastic Combined Chemotherapy Protocols; Child; Female; Fluconazole; Humans; Leukemia; Male; Middle Aged; Mycoses; Neutropenia; Patient Compliance; Treatment Outcome

Invasive fungal infection is a problem in patients undergoing bone marrow transplantation (BMT). To determine if a liposomal formulation of amphotericin B (Ambisome) is safe and can prevent fungal infection we performed a placebo controlled double-blind randomized prophylactic trial. Study drug was administered from when neutrophil count had decreased to < 0.5 x 10(9)/l and was continued until neutrophils recovered to this level or an infection or toxicity end-point was reached. Thirty-six patients received 1 mg/kg/day of ambisome and 40 patients received placebo daily. There were no statistical differences in characteristics or clinical course between the two groups. Fungal colonization decreased in the ambisome group while it increased in the placebo group. By the end of prophylaxis 8 of 24 (33%) patients receiving ambisome were colonized compared with 18 of 29 (62%) placebo patients (p = 0.05). Five and 7 patients on ambisome or placebo, respectively, were withdrawn due to a presumed fungal infection (NS). There was no statistical reduction of autopsy-proven fungal infection. Proven fungal infection occurred in one patient receiving ambisome (C. guillermondi) compared with three patients receiving placebo (C. guillermondi, 2; C. albicans, 1). Ambisome was well tolerated at the dose of 1 mg/kg/day but in three patients allergic reactions were observed.

Topics: Adolescent; Adult; Amphotericin B; Aspergillosis; Bone Marrow Transplantation; Candidiasis; Child; Child, Preschool; Double-Blind Method; Drug Carriers; Drug Hypersensitivity; Drug Tolerance; Female; Humans; Immunocompromised Host; Infant; Liposomes; Male; Middle Aged; Mycoses; Safety

The effect of a combination regimen using norfloxacin (NFLX) and amphotericin B (AMPH-B) for prevention of infections in patients with acute leukemia being treated by remission-induction chemotherapy in a randomized, controlled trial was studied. One hundred and six consecutive, evaluable patients were randomly assigned to receive orally 200 mg of norfloxacin two or four times daily and 200 mg of amphotericin B four times daily, or amphotericin B only. A smaller percentage of patients with bacteriologically-documented infections was observed in the study group compared with the control group (34.6% vs 56.9%; P < 0.05). The mean number of days that the patients received empirical antibiotic therapy was shorter in the study group (23 days vs 30 days; P < 0.05). The percentage of patients with a gram-negative bacterial infection (9.6% vs 27.5%; P < 0.05) or a fungal infection (17.3% vs 37.3%; P < 0.05) was decreased in the study group. This new combination antimicrobial regimen is safe and effective for prevention of gram-negative bacterial as well as fungal infections in patients with acute leukemia being treated with cytotoxic remission-induction chemotherapy.

Topics: Administration, Oral; Adult; Amphotericin B; Antineoplastic Agents; Bacterial Infections; Drug Combinations; Female; Fever; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Humans; Leukemia; Male; Middle Aged; Mycoses; Norfloxacin

An open, randomized study was performed at 18 European centres to compare the efficacy, safety and tolerance of oral fluconazole with oral polyenes for the prophylaxis of fungal colonization and infection in adults at high risk of developing neutropenia. Five hundred and thirty-six hospitalized patients with malignant disease, about to receive chemotherapy, radiotherapy, or bone marrow transplantation, and who were already neutropenic or were expected to develop neutropenia were included in the study. Before therapy or transplantation, patients commenced either oral fluconazole therapy (50 mg/day as a single dose) or oral polyenes therapy (amphotericin B 2 g/day and/or nystatin 4 x 10(6) units/day in four or more divided doses), for a mean of 29.3 days and 31.3 days, respectively. After baseline clinical and mycological testing, patients were re-evaluated at least weekly during prophylaxis, at the end of prophylaxis and two to six weeks later to identify proven or suspected fungal infection and to determine rates of colonization with fungi. Fungal infection was diagnosed in 41 of 511 evaluable patients, 10 (3.9%) of 256 in the fluconazole group and 31 (12.2%) of 255 in the polyene group (P = 0.001). This total included four patients (1.6%) in the fluconazole group who developed oropharyngeal candidiasis compared with 22 (8.6%) in the polyene group (P < 0.001). Systemic infections comprised 6 (2.3%) in the fluconazole group and 9 (3.5%) in the polyene group (P = not significant), and included three Candida krusei infections in each group. Parenteral amphotericin B therapy was given empirically for persistent fevers in an additional 62 (24.2%) patients receiving fluconazole and 59 (23.1%) receiving polyenes (P = not significant). Colonization with fungi was generally similar in each treatment group, although an increased proportion of patients receiving fluconazole developed colonization of the faeces (P < 0.01). Adverse reactions, possibly related to treatment, were recorded in 15 (5.6%) of 269 patients in the fluconazole group and 14 (5.2%) of 267 in the polyene group; these necessitated discontinuation of therapy in seven patients in each group. Once-a-day fluconazole was therefore more effective than oral polyenes for the prevention of oropharyngeal fungal infection and as effective for the prevention of infections at other sites in patients with neutropenia.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Child; Female; Fluconazole; Humans; Male; Middle Aged; Mycoses; Neutropenia; Nystatin

Although it has been suggested that selective decontamination of the digestive tract (SDD) decreases postoperative aerobic Gram-negative and fungal infections in orthotopic liver transplantation (OLT), no controlled trials exist in pediatric patients. This prospective, randomized controlled study of 36 pediatric OLT patients examines the effect of short-term SDD on postoperative infection and digestive tract flora. Patients were randomized into two groups. The control group received perioperative parenteral antibiotics only. The SDD group received in addition polymyxin E, tobramycin, and amphotericin B enterally and by oropharyngeal swab postoperatively until oral intake was tolerated (6 +/- 4 days). Indications for operation, preoperative status, age, and intensive care unit and hospital length of stay were no different in SDD (n = 18) and control (n = 18) groups. A total of 14 Gram-negative infections (intraabdominal abscess 7, septicemia 5, pneumonia 1, urinary tract 1) developed in the 36 patients studied. Mortality was not significantly different in the two groups. However, there were significantly fewer patients with Gram-negative infections in the SDD group: 3/18 patients (11%) vs. 11/18 patients (50%) in the control group, P < 0.001. There was also significant reduction in aerobic Gram-negative flora in the stool and pharynx in patients receiving SDD. Gram-positive and anaerobic organisms were unaffected. We conclude that short-term postoperative SDD significantly reduces Gram-negative infections in pediatric OLT patients.

Topics: Adolescent; Amphotericin B; Child; Child, Preschool; Communicable Diseases; Digestive System; Female; Humans; Infant; Liver Transplantation; Male; Mycoses; Polymyxins; Prospective Studies; Tobramycin; Virus Diseases

Treatment of fungal infections in neutropenic patients continues to be a major problem for the clinician. Treatment of such infections with amphotericin B is difficult, because of its many side-effects. In a neutropenic mouse model, itraconazole appeared to be as effective as amphotericin B against Candida albicans, and was more effective than amphotericin B in treating an Aspergillus infection in a patient with chronic granulomatous disease. In a randomized, comparative trial of itraconazole and amphotericin B as treatment for Candida and Aspergillus infections, 32 neutropenic patients were evaluated. Patients received either oral itraconazole, 200 mg twice daily, intravenous amphotericin B, 0.6 mg/kg/day, or in some cases of Candida infection intravenous amphotericin B, 0.3 mg/kg/day, plus flucytosine, 150 mg/kg/day. The causative organism of fungal infection was Candida spp. in 16 patients and Aspergillus spp. in 13 patients; 27 patients had pneumonia. The median duration of treatment was 13 days with amphotericin B and 20 days with itraconazole. Nine of 16 patients responded to amphotericin B, and 10 of 16 patients responded to itraconazole. Of the patients with Aspergillus infection, 6/8 treated with itraconazole and 2/5 treated with amphotericin B responded. Three patients with Aspergillus infection died in the amphotericin B arm and none in the itraconazole arm; 2 patients treated with itraconazole died from candidal infections. Absorption of itraconazole was unreliable in these seriously ill patients with disturbed gastrointestinal function. These results suggest that itraconazole could be an effective drug against systemic fungal infections in neutropenic patients. One retrospective study also suggest that itraconazole is superior to ketoconazole in prophylaxis for Aspergillus infections. Further studies are needed.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis; Humans; Itraconazole; Ketoconazole; Mycoses; Neutropenia

The clinical use of amphotericin B is sometimes limited by nephrotoxicity. In a randomized prospective study, 32 patients treated for haematological malignancies received either amphotericin B in 5% dextrose (group A, 16 patients, 0.7-1 mg/kg/day), or amphotericin B mixed with Intralipid (group B, 16 patients, 0.7-1 mg/kg/day) during prolonged neutropenia. Renal dysfunction occurred in 9/16 patients in group A and 2/16 patients in group B (P < 0.05). Clinical tolerance was improved with a reduction of fever with chills in 12/16 patients in group A compared with 5/16 in group B (P < 0.05). Preparation of amphotericin B with Intralipid reduces nephrotoxicity, improves clinical tolerance, may allow an increase in the daily dose of amphotericin B, and be an alternative to liposomal-amphotericin B infusion.

Topics: Adult; Aged; Amphotericin B; Creatinine; Drug Therapy, Combination; Drug Tolerance; Fat Emulsions, Intravenous; Female; Humans; Kidney; Male; Middle Aged; Mycoses; Neutropenia

The use of high-dose chemotherapy and the subsequent prolonged neutropenia in patients with haematological diseases has resulted in an increased incidence of fungal infections. The only drug with proven efficacy in the treatment of deep seated fungal infections or invasive aspergillosis is amphotericin B. Unfortunately, this drug has adverse side effects, most importantly dose dependent nephrotoxicity. Furthermore, some patients fail to show a response to amphotericin B. We have treated 40 patients undergoing myeloablative chemotherapy and or bone marrow transplantation for haematological diseases with liposomal amphotericin for proven or suspected fungal infections. All patients had failed treatment with conventional Amphotericin B. Fourteen patients received liposomal amphotericin (AmBisome) due to progression of infection on conventional amphotericin B. Twenty six patients received liposomal amphotericin due to nephrotoxicity caused by conventional Amphotericin B. Nine patients had mycologically proven fungal infection and of these, 7 patients (78%) showed a complete response to liposomal amphotericin. Thirty one patients received liposomal amphotericin due to suspected fungal infection. Eleven of these 31 patients (35%) showed a complete clinical response to liposomal amphotericin. However in the patients with suspected fungal infections 14 patients had no response and 6 patients could not be evaluated for response to liposomal amphotericin. Overall, of the 18 patients showing a response to liposomal amphotericin, 15 patients had either recovered their neutrophil count (> 0.5 x 10(9)/l) or achieved remission from their underlying haematological disease. Recovery from fungal infection in this group of patients occurred when there was complete remission of underlying disease and recovery of neutrophil counts, when concurrently treated by liposomal amphotericin.

Topics: Adolescent; Adult; Aged; Amphotericin B; Child; Female; Humans; Leukocyte Count; Liposomes; Male; Middle Aged; Mycoses; Neutropenia

This study assessed the efficacy, toxicity, and pharmacology of low-dose amphotericin B given prophylactically to patients (serum concentrations of 0.2-0.4 microgram/ml) undergoing bone marrow transplantation. Yeast isolates from patients' oropharyngeal areas had MICs of 0.1-0.2 microgram/ml, and none were amphotericin B resistant. The effect of low-dose amphotericin B on reducing the numbers of yeast colonizing the oropharyngeal area was significant (P less than .01). The average delay in switching to high-dose prophylactic amphotericin B was only 1 day; the decision to do so because of a perceived fungal infection occurred more frequently for the placebo group (P = .06). Fewer patients from the low-dose amphotericin B group (8.8%) than from the placebo group (14.3%) had fungi isolated from normally sterile body sites (P = .35). Infusion-related side effects but not systemic toxicities were significantly greater (P less than .001) in the amphotericin B group. The 6-week survival was greater in those receiving amphotericin B (P less than .03), but the improved survival could not be attributed to the prevention of fungal infections.

Topics: Adult; Amphotericin B; Bone Marrow Transplantation; Candidiasis, Oral; Female; Humans; Infusions, Intravenous; Male; Mycoses; Neutropenia; Oropharynx

Results of a double-blind randomized non-crossover study of rapid (45 min) versus slow (4 h) infusion of amphotericin B administered to 20 patients with proven or suspected fungal infection are reported. Toxicity was higher in the rapid infusion group than it was in the slow infusion group (mean total 7-day chill score, 173 +/- 276 versus 20 +/- 30 [P less than 0.01]; mean total 7-day dosage of meperidine required to abate rigors, 180 +/- 133 versus 58 +/- 78 mg [P less than 0.05]; and mean maximum total 7-day pulse rise, 225 +/- 64 versus 135 +/- 56 beats per min [P less than 0.02], respectively). When analyzed on a daily basis, the mean chill score, meperidine dosage, and pulse rise were also higher; and in addition, nausea and vomiting (5 of 11 patients who received a rapid infusion versus 0 of 9 patients who received a slow infusion [P less than 0.01]) appeared to be more common in those who received amphotericin B rapidly. The daily analysis approach proved that tolerance to these side effects developed with each subsequent infusion day, and by day 7 the incidence and severity were the same. This development of tolerance was significant for the mean chill score in the rapid infusion group (P less than 0.05) and for the proportion of patients with chills (P less than 0.005 for the slow infusion group; P less than 0.05 for the rapid infusion group). A decrease in creatinine clearance to greater than 51% of the baseline value was seen in two patients in each group. There were five deaths (four in the rapid infusion group, 1 in the slow infusion group) within 1 month, but none was clearly related to the amphotericin B infusion. The mean time to defervescence was similar for each group (10.8 +/- 4.1 days in the slow infusion group versus 9.9 +/- 5 days in the rapid infusion group). A rapid infusion regimen for amphotericin B cannot be recommended, at least during the first 5 to 7 days of treatment.

Topics: Adolescent; Adult; Amphotericin B; Double-Blind Method; Female; Humans; Infusions, Intravenous; Male; Meperidine; Middle Aged; Mycoses; Time Factors

Systemic mycosis constitute a serious threat for the patient with granulocytopenia. The most important causative agents are Candida spp., Aspergillus spp. and, to a lesser extent, Cryptococcus neoformans, Mucoraceae and Pseudoallescheria boydii. Treatment of such infections with amphotericin B is difficult, because of the many side-effects of this medicine, such as hypotension, fever, shivering, thrombophlebitis, nephrotoxicity, renal tubular acidosis, hypokalaemia, anaemia and thrombocytopenia. In addition, the efficacy of amphotericin B in the treatment of proven mycotic infections in granulocytopenic patients is not very great. Itraconazole is a new, oral antifungal agent which is active in vitro and in animal experiments against both Candida and Aspergillus. In patients without granulocytopenia, itraconazole appeared to be effective in the treatment of deep Candida and Aspergillus infections. On the basis of the above data, a randomized comparative investigation was carried out unto the efficacy of amphotericin B and itraconazole in the treatment of systemic mycoses in neutropenic patients.

Topics: Adolescent; Agranulocytosis; Amphotericin B; Antifungal Agents; Aspergillosis, Allergic Bronchopulmonary; Candidiasis; Humans; Itraconazole; Ketoconazole; Male; Mycoses

One hundred and twenty-six patients were treated for 137 episodes of fungal infection with liposomal amphotericin B (AmBisome) at 43 investigational centres. Among the patients were 72 with malignancies, 17 organ transplant recipients, 20 patients with immunological disorders and 17 others. AmBisome treatment was instituted after toxicity from previous amphotericin B treatment in 49 cases, nephrotoxicity or renal insufficiency in 40 and failure of previous antifungal treatment in 41. One hundred and eight episodes were clinically evaluable; among these 52 were caused by Candida spp. and 34 by Aspergillus spp. Ninety-nine patients were treated for at least eight days with a maximum dose of 0.7-5 mg/kg/day. Among 64 cases with proven invasive fungal infection 58% were cured. Fungi were eradicated in 35 of 54 (65%) mycologically evaluable cases. The cumulative dose was 3.2 +/- 3.2 (mean +/- S.D.) in cases where fungi were eradicated in comparison with 3.3 +/- 2.3 g in cases where fungi persisted. The eradication rate was 83% for Candida spp. compared with 41% for Aspergillus spp. (P less than 0.01). Among 24 cases with presumptive invasive fungal infections 14 (58%) were cured. Candida spp. were eradicated in seven of ten of these cases. Among 11 cases with superficial fungal infections eight were cured and three improved. Candida spp. were eradicated in four of five patients. It is concluded that AmBisome is an effective antifungal agent in a majority of patients with invasive or superficial fungal infections.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Aspergillosis; Candidiasis; Child; Child, Preschool; Drug Carriers; Drug Evaluation; Female; Humans; Immunocompromised Host; Immunosuppressive Agents; Liposomes; Male; Middle Aged; Mycoses

AmBisome is a commercially available preparation of amphotericin B incorporated in small unilamellar liposomes. The analysis of safety data provided in a multicentre compassionate phase II/III study evaluating 133 episodes of therapy with AmBisome in patients with severe underlying disease is very encouraging. Rapid (30-60 min) administration of a high daily dose of AmBisome is feasible without the well known side effects observed with the conventional formulation of amphotericin B (Fungizone). Although eleven of 71 patients with initially normal serum creatinine concentrations showed increased values after AmBisome therapy, 17 patients among 50 with initially high creatinine concentrations recovered normal renal function during AmBisome treatment. Hypokalaemia was observed in 24 episodes of treatment (18%). Increases in serum glutamyl oxaloacetic transaminase and alkaline phosphatase were also quite common in this selected population with severe underlying disease and the contribution of AmBisome to these changes is difficult to establish. AmBisome appears a safe alternative to conventional amphotericin B, and its efficacy should be further investigated.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alkaline Phosphatase; Amphotericin B; Aspartate Aminotransferases; Child; Child, Preschool; Creatinine; Drug Carriers; Drug Evaluation; Female; Humans; Liposomes; Male; Middle Aged; Mycoses

Topics: Adult; Aged; Amphotericin B; Double-Blind Method; Drug Administration Schedule; Fever; Humans; Immune Tolerance; Infusions, Intravenous; Leukemia; Middle Aged; Mycoses; Nausea; Prospective Studies; Vomiting

A prospective, randomized, double-blind crossover study was performed to compare the incidence and severity of amphotericin-B-induced acute toxicity (chills, fever, nausea and vomiting) after two- and four-hour infusions in 33 leukemic patients with suspected or microbiologically proven systemic fungal infections. Each patient was treated in an alternating fashion of two- and four-hour infusions every other day. Toxicity was graded according to modified WHO-criteria. Evaluation of 264 infusions revealed no difference between the two schedules neither in incidence nor severity of acute toxic reactions. These data indicate that amphotericin B given over 2 hours is equally well--or poorly (!)--tolerated than the four-hour regimen.

Topics: Adult; Aged; Amphotericin B; Double-Blind Method; Fever; Humans; Infusions, Intravenous; Leukemia; Middle Aged; Mycoses; Nausea; Prospective Studies; Shivering; Time Factors; Vomiting

We compared high-dose ketoconazole (800 mg/kg per day, orally) with amphotericin B (0.5 mg/kg per day, intravenously) for empirical antifungal therapy in a prospective, randomized study of persistently or recurrently febrile granulocytopenic cancer patients. Among 97 patients eligible for empirical antifungal therapy, 20 (21%) of these patients were ineligible for randomization to ketoconazole treatment because of their inability to tolerate oral medications. Among 72 patients eligible for randomization, 64 were assessable (32 in each arm of the study). Five of six patients with proved fungal infections who were randomized to receive ketoconazole treatment required crossover to amphotericin B treatment because of progressive infection. The conditions of three of these five patients improved after receiving amphotericin B. The frequency of transaminase elevation was higher in those receiving ketoconazole, while the frequency of azotemia was higher in those receiving amphotericin B. Bioavailability of ketoconazole was unpredictable. Amphotericin B remains the drug of choice for empirical antifungal therapy in granulocytopenic patients; whereas, lack of a parenteral formulation, ineffectiveness against proved mycoses, and unreliable bioavailability preclude high-dose ketoconazole from being an appropriate compound for this purpose.

Topics: Adult; Agranulocytosis; Amphotericin B; Fever; Humans; Immune Tolerance; Ketoconazole; Mycoses; Neoplasms; Prospective Studies

In a prospective randomized study the efficacy of fluconazole (50 mg in one single daily dose) was compared with oral amphotericin B in suspension and tablets (each 200 mg four times daily) for prevention of colonization and subsequent infection by yeasts in 50 patients undergoing remission induction treatment for acute leukaemia. All patients received ciprofloxacin for prevention of bacterial infections. Fluconazole was as effective as amphotericin B in preventing severe local and disseminated fungal disease (one documented and one highly suspected infection in each group of patients). Fluconazole effectively prevented yeast colonization of the oropharynx but was less effective than amphotericin B in preventing colonization of the lower alimentary tract. Fifty-two percent of patients receiving fluconazole had persistent positive stool cultures as compared to 4% in the amphotericin B group (P less than 0.01). Fluconazole was better tolerated than amphotericin B. One patient developed an extended rash leading to the termination of fluconazole.

Topics: Acute Disease; Administration, Oral; Adolescent; Adult; Aged; Agranulocytosis; Amphotericin B; Female; Fluconazole; Humans; Leukemia; Male; Middle Aged; Mycoses; Prospective Studies; Remission Induction

Between August 1985 and October 1988 125 children who were candidates for a bone marrow transplantation entered a randomized double-blind placebo-controlled trial (63 children in ketoconazole (K) group and 62 children in placebo (P) group) to evaluate the efficacy of ketoconazole in decreasing the incidence of digestive yeast colonization. Among the 38 children who were initially colonized, the proportion of children who became decolonized was higher (p less than 0.05) in group K (47%) than in group P (16%). Among the 87 children without initial colonization, the proportion of children in whom digestive colonization occurred was lower (p less than 0.01) in group K (20%) than in group P (49%). Three children in group K (5%) and six children in group P (9%) developed a documented fungal infection (NS). Thirty-nine children in each group developed a fever of unknown origin which did not respond to a 7-day course of antibiotherapy. One hundred and three children received amphotericin B (Ampho B) (83% in group K and 82% in group P). The mean duration (+/- SD) of Ampho B was similar in group K (28 +/- 26 days) and in group P (28 +/- 25 days). The mean total dose of Ampho B was similar in group K (475.5 +/- 1060 mg) and in group P (540.4 +/- 979 mg). The actuarial survival from the day of randomization until bone marrow recovery was not different in the two groups. We conclude that ketoconazole is efficient in preventing gut yeast colonization but does not reduce the incidence of fungal documented infections and fevers of unknown origin unresponsive to antibiotherapy which necessitate empirical coverage and treatment with Ampho B.

Topics: Amphotericin B; Bone Marrow Transplantation; Child; Child, Preschool; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Ketoconazole; Male; Mycoses

We report a prospective, randomized, controlled study of antifungal chemoprophylaxis in forty immunocompromised children with hematologic malignancies, receiving respectively itraconazole, ketoconazole, amphotericin-B and no prophylaxis. Fungal isolates from patients' saliva or stools were obtained from 19/40 patients (Candida albicans from 15 patients). Disseminated infection was never observed. Fungal isolates were significantly less frequent in the ketoconazole group of patients vs any other group. Systemic antifungal chemoprophylaxis with ketoconazole appears more effective even than the recently introduced itraconazole.

Topics: Adolescent; Amphotericin B; Antifungal Agents; Child; Child, Preschool; Feces; Female; Humans; Infant; Itraconazole; Ketoconazole; Male; Mycoses; Neoplasms; Pharynx; Prospective Studies

Forty patients with acute leukemia (age 16-71 years, 13 females, 27 males) with induced neutropenia due to chemotherapy received either 50 mg fluconazole or 800 mg amphotericin B per day orally as prophylaxis against fungal infection. Nasal and genital swabs, mouth washings, urine, stool and blood serum were taken for mycological and serological examination before and weekly during one episode of neutropenia (less than 10(9) granulocytes/l) per patient. The quantitative determination of the yeast concentration in stool specimens demonstrated that amphotericin B led to intestinal yeast count reduction in only one third of the patients and could not prevent the increase of the intestinal yeast flora in another third of the patients. Beyond that the quantitative determination of yeast colonization in oropharynx, genital region, blood and stool did not prove to be a reliable tool for evaluating the host-fungus relationship during neutropenia. On the other hand mycoserology reflected episodes of candidosis well. 19 patients treated with fluconazole showed only minor titer increases. In 21 patients treated with amphotericin B, four fungemias were found: two by both hemagglutination (HAT) and immunofluorescence (IFT), one by IFT and one by antigen detection (Ramco Cand-Tec) alone. In only one of these cases yeast cells were released in urine. From these results is concluded that control of serology is essential in studies of that type and that fluconazole seems to provide better protection from candidosis than amphotericin B during induced neutropenia.

Topics: Administration, Oral; Adolescent; Adult; Aged; Amphotericin B; Antineoplastic Agents; Female; Fluconazole; Humans; Leukemia; Male; Middle Aged; Mycoses; Neutropenia

The prophylactic effect of the oral administration of high-dose amphotericin B syrup for the systemic fungal infection was studied in 36 patients with hematological neoplasms. Twenty nine patients received 2,400 mg/day of Amphotericin B syrup for during the remission induction therapy. One patient received 1,200 mg/day, 3 received 800 mg/day and 3 received 400 mg/day of Amphotericin B syrup. The prophylactic effect was recognized in 24 of 36 patients, 66.7%. As adverse effects gastrointestinal symptoms such as nausea and vomiting, hypochloremia and hypopotassemia associated with hypochloremia was observed in one patient, respectively, however, they were all controllable. The blood levels of Amphotericin B in patients received 2,400 mg/day was 0.092 +/- 0.055 micrograms/ml (n = 40) on 7th day and 0.110 +/- 0.046 micrograms/ml (n = 21) on 28th day, respectively. The administration of high-dose of Amphotericin B syrup is expected not only for the prophylaxis but also for the treatment of the systemic fungal infection.

Topics: Administration, Oral; Adolescent; Adult; Aged; Amphotericin B; Drug Administration Schedule; Female; Humans; Leukemia, Lymphoid; Leukemia, T-Cell; Male; Middle Aged; Multicenter Studies as Topic; Multiple Myeloma; Mycoses

The prophylactic and therapeutic effects of the oral administration of amphotericin B (AMPH) to patients with deep mycosis associated with hematologic diseases were evaluated in an investigation including determination of serum concentrations of the antibiotic. Prophylactic effects were examined in 111 subjects, and the efficacy rates averaged 83.8% at daily doses from 1,200 to 4,800 mg. The efficacy was significantly higher at a dose of 2,400 mg/day than at a dose of 1,200 mg/day (P less than 0.05). The efficacy rate tended to be higher when the length of administration period was 1 month or more. The percentage of the number of days of fever by neutrophil count was significantly less at a daily dose of 2,400 mg than at 1,200 mg in patients with neutrophil count of 1,000 cells/mm3 or less (P less than 0.001). The safety was evaluated in 131 subjects, and adverse effects were found in only 2 cases of nausea for an incidence rate of 1.5%. Therapeutic effects were studied in 12 cases, and efficacy rates averaged 58.3% at daily doses from 2,400 to 7,200 mg. Adverse effects consisted of 1 case of diarrhea among 15 subjects who were evaluated for the safety for an incidence rate of 6.7%. The serum concentrations of the antibiotic were examined in 60 of the prophylactic and therapeutic subjects. Average concentrations of AMPH at 4 hours after the first daily dose of 1,200, 2,400 and 4,800 mg were 0.040, 0.053 and 0.078 micrograms/ml, respectively. Concentrations gradually increased thereafter and reached averages of 0.089, 0.090 and 0.132 micrograms/ml, respectively, for the 3 dose levels on the 7th day. These results indicated that there were no serious adverse effects and serum concentrations were above the Candida MIC values at daily prophylactic and therapeutic doses of 1,200 to 7,200 mg of AMPH. Based on these findings, this drug can be expected to show prophylactic and therapeutic effects with safety in cases of deep mycosis.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Amphotericin B; Drug Evaluation; Female; Hematologic Diseases; Humans; Leukemia; Lymphoma; Male; Middle Aged; Multicenter Studies as Topic; Multiple Myeloma; Mycoses

Topics: Amphotericin B; Aspergillosis; Candidiasis; Cryptococcosis; Drug Synergism; Drug Therapy, Combination; Flucytosine; Humans; Mycoses; Prospective Studies; Rifampin

The optimal management of fever in granulocytopenic patients remains controversial. Invasive fungal infections are common and life-threatening but are difficult to diagnose early. In this randomized study, we investigated the potential value of empiric administration of amphotericin B (versus no empiric antifungal therapy) in 132 patients remaining febrile and granulocytopenic despite broad-spectrum antibiotic therapy for four days.. The patients were divided into two groups: 68 who were randomly assigned to receive empiric amphotericin B, and 64 who were randomly assigned to continue only the protocol antibiotics that they were already receiving. Amphotericin B was administered intravenously as follows: every other day at a dose of 1.2 mg/kg body weight or daily at a dose of 0.6 mg/kg body weight. Clinical response was evaluated as success or failure, depending upon the febrile course after randomization.. Based on the evolution of fever, the response rate was 69% in the group of patients receiving empiric amphotericin B and 53% for the other group (p = 0.09). There were six documented (four severe) fungal infections in 64 patients randomized not to receive the antifungal therapy as compared to only one fungemia among 68 patients treated empirically with amphotericin B (p = 0.1). No deaths due to fungal infection occurred among the patients receiving empiric amphotericin B compared to four in the other group (p = 0.05). However, this study did not demonstrate a difference in survival between the two groups of patients (with or without empiric amphotericin B). The benefit of empiric administration of amphotericin B was primarily observed in specific subgroups of patients, such as those who did not receive any antifungal prophylaxis (78% versus 45%, p = 0.04), those who were severely granulocytopenic (69% versus 46%, p = 0.06), febrile patients with a clinically documented infection (75% versus 41%, p = 0.03), and patients older than 15 years of age (67% versus 47%, p = 0.06).. These data suggest a benefit for early amphotericin B treatment in granulocytopenic patients with continued fever despite antibiotic therapy.

Topics: Agranulocytosis; Amphotericin B; Anti-Bacterial Agents; Clinical Trials as Topic; Fever; Humans; Infusions, Intravenous; Multicenter Studies as Topic; Mycoses; Neoplasms; Random Allocation; Regression Analysis; Time Factors

This report is a survey of epidemiological facts about oro-gastro-intestinal tract mycoses. It is documented that children and older people suffer more often from oro-gastro-intestinal tract mycoses than the rest of the average population. In addition older patients with oro-gastro-intestinal tract mycoses show predisposing factors more frequently than younger people.

Topics: Adolescent; Adult; Aged; Amphotericin B; Candidiasis, Oral; Child; Child, Preschool; Clinical Trials as Topic; Gastrointestinal Diseases; Humans; Infant; Middle Aged; Mycoses; Opportunistic Infections

Twenty neutropenic patients with various haematological disorders were randomised prospectively to receive either intravenous amphotericin B alone or amphotericin B and oral amiloride 5 mg twice a day for treatment of confirmed or suspected fungal infection. Patients receiving amiloride had a significantly higher plasma potassium (p less than 0.01), a significantly lower urinary potassium loss (p less than 0.01), and required significantly less potassium chloride supplementation to maintain their plasma potassium within the normal range (p less than 0.001). Amiloride was well tolerated, had no clinically important side effects, and provided effective control of plasma potassium in patients treated with amphotericin B.

Topics: Adolescent; Adult; Aged; Agranulocytosis; Amiloride; Amphotericin B; Clinical Trials as Topic; Humans; Hypokalemia; Middle Aged; Mycoses; Neutropenia; Potassium; Random Allocation

The ecologic effect of empiric systemic antibiotic therapy on the endogenous microflora was evaluated in 83 febrile granulocytopenic patients with cancer who were randomly allocated to receive moxalactam plus ticarcillin (45 patients) or tobramycin plus ticarcillin (38 patients) for suspected infection. Serial surveillance cultures of the nasal passages, oropharynx and feces performed twice a week showed that patients who received the former regimen had higher elimination rates and significantly lower acquisition rates (p = 0.027) for aerobic gram-negative bacilli than did patients who received the latter regimen. However, therapy with moxalactam plus ticarcillin also resulted in significantly higher acquisition rates for yeasts (p = 0.004). This was associated with a significantly higher fungal superinfection rate among these patients than among those who received tobramycin plus ticarcillin (40% v. 16%) (p less than 0.05). Moxalactam plus ticarcillin therapy created a greater microbial ecologic vacuum by the elimination of intestinal anaerobes, which, in turn, permitted fungal colonization and an increased risk of superinfection. Our results support the recommendation that an antipseudomonal penicillin plus an aminoglycoside be selected as empiric therapy for suspected infection in febrile granulocytopenic patients with cancer. Such a regimen would spare the anaerobic intestinal microflora, thereby reducing the risk of fungal colonization and infection.

Topics: Agranulocytosis; Amphotericin B; Anti-Bacterial Agents; Bacterial Infections; Clinical Trials as Topic; Drug Therapy, Combination; Fever; Fungi; Gram-Negative Bacteria; Humans; Moxalactam; Mycoses; Ticarcillin; Tobramycin

Patients treated with cytotoxic therapy expected to produce neutropenia lasting two or more weeks were randomly assigned in a double-blind study to receive intravenous miconazole or placebo concomitant with empiric antibiotics to test whether miconazole can prevent fungal sepsis. The study drug was initiated at the time of first fever along with antibiotics and was continued until neutropenia resolved, fungal sepsis occurred, or persistent or recurrent unexplained fever after six or more days prompted substitution of the study drug by amphotericin B. Two hundred eight treatment courses in 180 patients were evaluated. Fungal sepsis occurred in only one patient receiving miconazole compared with eight patients receiving placebo (p = 0.03). Fatal fungal sepsis occurred in four patients receiving placebo and in none of the patients receiving miconazole (p = 0.08). There was no evidence for the development of resistance to polyenes or imidazoles in fungal isolates recovered from patients in this randomized trial or an increase in Aspergillus infections in patients who received miconazole in this randomized trial or in 121 subsequently treated patients who received unblinded use of miconazole. Thus, intravenous miconazole was more effective than placebo in preventing fungal sepsis in patients with chemotherapy-induced prolonged neutropenia.

Topics: Adolescent; Adult; Aged; Agranulocytosis; Amphotericin B; Bacterial Infections; Bone Marrow Transplantation; Child; Clinical Trials as Topic; Double-Blind Method; Humans; Injections, Intravenous; Miconazole; Middle Aged; Mycoses; Neutropenia; Random Allocation

Fungal infections in neutropenic cancer patients have increased in frequency and constitute an important cause of morbidity and mortality. Empiric antifungal therapy is often administered to those patients who have failed to respond to antibacterial antibiotics. We conducted a prospective, randomized trial of amphotericin B and ketoconazole for 172 neutropenic cancer patients with presumed or proven fungal infections. Overall, amphotericin B and ketoconazole were equally effective. Amphotericin B may have been more effective than ketoconazole for the treatment of pneumonia. Also, five of eight Candida tropicalis infections treated with amphotericin B responded, whereas all eight infections treated with ketoconazole failed to respond (P = 0.03). Response rates for localized fungal infections were similar with both drugs. Ketoconazole should not be used as empiric antifungal therapy at institutions where there is a high frequency of infections caused by Aspergillus spp. or C. tropicalis because this agent lacks activity in vitro against these species.

Topics: Adolescent; Adult; Aged; Amphotericin B; Female; Humans; Ketoconazole; Male; Middle Aged; Mycoses; Neoplasms; Neutropenia; Prospective Studies; Random Allocation

As invasive fungal infection remains a common problem in the management of cancer patients, chemoprophylaxis of these opportunistic infections is desperately needed. The most frequently investigated antifungal agents have been nystatin, amphotericin B, and ketoconazole. In placebo-controlled studies, high doses of antifungal agents decreased the positive results from surveillance cultures, and there is some suggestion that such chemoprophylaxis may reduce the incidence of invasive candidiasis in neutropenic cancer patients. However, no oral chemoprophylaxis has effectively prevented aspergillosis or mucormycoses in these patients. There are still many areas of controversy, and the most adequate regimens, if any, remain to be defined.

Topics: Administration, Oral; Administration, Topical; Amphotericin B; Antifungal Agents; Candidiasis; Clinical Trials as Topic; Humans; Ketoconazole; Miconazole; Mycoses; Neoplasms; Nystatin

We administered miconazole to patients with deep-seated fungal infections, to investigate into the clinical and mycological responses to the drug and also into its clinical safety. We also looked into the responses of amphotericin B (AMPH), flucytosine (5-FC) and the combination of the 2 drugs to deep mycoses in the past 10 years, for retrospective comparison of the findings achieved in the treatment with miconazole. A clinical response rate of 85% (29/34 patients) was achieved in the treatment of deep-seated fungal infections with miconazole. Mycologically, a fungus eradication rate of 79% (22/28 patients) and a fungus decrease rate of 11% (3/28) were achieved with the miconazole treatment, comparison of the response to miconazole alone and that to AMPH alone revealed that the former was significantly preferable. Side effects of miconazole were observed in 23% of the treated patients (15/66). Statistical analysis of the incidence of side effects of miconazole and that of AMPH showed that the former was significantly lower.

Topics: Adolescent; Adult; Aged; Amphotericin B; Child; Child, Preschool; Clinical Trials as Topic; Female; Humans; Male; Miconazole; Middle Aged; Mycoses

To evaluate the possibility that in febrile granulocytopenic patients amphotericin B given along with granulocyte transfusions could increase the incidence of pulmonary complications, we studied 43 severely granulocytopenic patients during 46 episodes of fever. Granulocytes were administered as part of the clinical protocol to all 19 patients who had clinically or microbiologically documented infection; the other 24 patients were randomly allocated to treatment with granulocytes (13 patients) or without granulocytes (11 patients). In all, 32 patients received granulocyte transfusions during 35 episodes of fever. Pulmonary complications developed in six patients in each of the two randomized groups. The incidence of pulmonary complications was not influenced by the number of granulocyte transfusions or by the number of granulocytes per transfusion. Pulmonary complications were significantly more likely to occur in patients with fungal infections. Amphotericin B was given according to clinical indications; 21 patients in all received it. Survival was significantly poorer in patients with pulmonary complications, but the administration of amphotericin B was not related either to survival or to the incidence of pulmonary complications. We conclude that pulmonary complications and poor prognosis are related to underlying pulmonary fungal infection and not to any interaction between amphotericin B and granulocyte transfusions.

Topics: Adult; Aged; Amphotericin B; Bacterial Infections; Female; Granulocytes; Humans; Lung Diseases; Male; Middle Aged; Mycoses; Transfusion Reaction

72 patients severely immunocompromised by their underlying disease (marrow aplasia, acute leukaemia, or solid tumour) or by the treatment they were receiving, or both, were randomised to receive antifungal prophylaxis with either oral ketoconazole or conventional doses of oral amphotericin B and nystatin. All patients also had gut decontamination with non-absorbable antibiotics, skin antisepsis, sterile food, and oral cotrimoxazole. Protection against fungal infection was significantly superior with ketaconazole. When patients who had received allogeneic bone-marrow transplant were studied separately, there was no significant difference between the two treatments, probably because there was a fall-off in ketoconazole absorption from the end of the third week after the transplant. However, ketoconazole greatly reduced the likelihood of fungal infection in non-transplant patients.

Topics: Amphotericin B; Clinical Trials as Topic; Drug Therapy, Combination; Humans; Imidazoles; Immunosuppressive Agents; Ketoconazole; Leukemia; Mycoses; Neutropenia; Nystatin; Piperazines; Random Allocation

From August 1977 to October 1978, 23 patients with acute myelogenous leukemia (AML) received induction therapy at Vanderbilt University Hospital. Six patients died of documented fungal infection, predominantly aspergillus pneumonia; the complete remission rate was only 40%. Based on this experience we began using amphotericin B empirically in any AML patient remaining febrile or having recurrent fever after a week of broad spectrum antibiotics. Of 22 patients treated from October 1978 to August 1980, none died of fungal infection during induction therapy; the remission rate increased significantly to 77%. Chemotherapy and supportive care were otherwise unchanged during this period. While the first group was older, the improvement in remission rate was also seen in patients younger than 60 years of age. Since fungal infection may be difficult to document, this study suggests that empirical amphotericin B is reasonable therapy in leukemic patients remaining febrile or having a recurrent fever following a week of broad spectrum antibiotics, if the institution has a high incidence of fungal infections.

Topics: Adult; Aged; Amphotericin B; Anti-Bacterial Agents; Clinical Trials as Topic; Cytarabine; Daunorubicin; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Mycoses; Pneumonia

The past 40 years have brought great advances in the knowledge of morphology, immunology and epidemiology of fungal infections in man. Each general advance in the science of medicine has had its counterpart in man's improved facility to deal with these infections therapeutically. Although satisfactory control of fungal infections of man is still lacking, productive paths of investigation seem to have been found and the continued application of rigorous discipline to research efforts should provide even more efficient treatment in the future.

Topics: Amphotericin B; Antifungal Agents; Blastomycosis; Clinical Trials as Topic; Flucytosine; History, 18th Century; History, 19th Century; History, 20th Century; Humans; Mycoses; Nystatin; Stilbamidines; United States

Topics: Adult; Amphotericin B; Animals; Cats; Clinical Trials as Topic; Coccidioidomycosis; Dermatomycoses; Dogs; Drug Evaluation; Drug Evaluation, Preclinical; Drug Resistance, Microbial; Humans; Imidazoles; Lung Diseases, Fungal; Male; Miconazole; Middle Aged; Mycoses

In 100 patients with denture stomatitis cultures and direct smears were used to evaluate 5 treatments, including sucking of chlorhexidine, amphotericin B or placebo tablets combined with denture soaking in 0.2% chlorhexidine or water. After 14 days of treatment the amphotericin B lozenges had brought about a significant reduction in the quantity of fungus on the oral mucosa, whereas they barely affected the large amount present on the fitting surface of the upper denture. Denture immersion in chlorhexidine significantly reduced the number of organisms both on the mucous membrane and on the denture. It therefore seems at least as important to treat the denture as the patient in denture stomatitis. Fourteen days after withdrawal of the drugs the mycotic flora was largely re-established.

Topics: Amphotericin B; Biguanides; Chlorhexidine; Clinical Trials as Topic; Denture, Complete, Upper; Drug Therapy, Combination; Female; Humans; Male; Mycoses; Stomatitis; Stomatitis, Denture

The clinical effects of an antibacterial substance with antifungal activity (chlorhexidine) and specific antimycotic (amphotericin B) in denture stomatitis were studied in 100 patients. Five 14-day regimens of chlorhexidine, amphotericin B or placebo lozenges combined with denture immersion in 0.2% chlorhexidine or water were tested. The efficiency of amphotericin B and chlorhexidine was comparable. This indicates that chlorhexidine has a considerable antifungal effect in the oral cavity and, further, that fungi are the responsible micro-organism in denture stomatitis rather than bacteria. Chlorhexidine frequently discloured the dentures. A high incidence of local and general predisposing factors to denture stomatitis, as well as of relapse 14 days after treatment, was observed.

Topics: Amphotericin B; Biguanides; Chlorhexidine; Clinical Trials as Topic; Drug Therapy, Combination; Erythema; Humans; Maxillary Diseases; Mycoses; Stomatitis; Stomatitis, Denture

The incidence and prevalence of invasive fungal infections have increased significantly over the last few years, leading to a global health problem due to the lack of effective treatments. Amphotericin B (AmB) and itraconazole (ITR) are two antifungal drugs with different mechanisms of action. In this work, AmB and ITR have been formulated within granules to elicit an enhanced pharmacological effect, while enhancing the oral bioavailability of AmB. A Quality by Design (QbD) approach was utilised to prepare fixed-dose combination (FDC) granules consisting of a core containing AmB with functional excipients, such as inulin, microcrystalline cellulose (MCC), chitosan, sodium deoxycholate (NaDC) and Soluplus® and polyvinyl pyrrolidone (PVP), coated with a polymeric layer containing ITR with Soluplus® or a combination of Poloxamer 188 and hydroxypropyl methyl cellulose-acetyl succinate (HPMCAS). A Taguchi design of experiments (DoE) with 7 factors and 2 levels was carried out to understand the key factors impacting on the physicochemical properties of the formulation followed by a Box-Behnken design with 3 factors in 3 levels chosen to optimise the formulation parameters. The core of the FDC granules was obtained by wet granulation and later coated using a fluidized bed. In vitro antifungal efficacy was demonstrated by measuring the inhibition halo against different species of Candida spp., including C. albicans (24.19-30.48 mm), C. parapsilosis (26.38-27.84 mm) and C. krusei (11.48-17.92 mm). AmB release was prolonged from 3 to 24 h when the AmB granules were coated. In vivo in CD-1 male mice studies showed that these granules were more selective towards liver, spleen and lung compared to kidney (up to 5-fold more selective in liver, with an accumulation of 8.07 µg AmB/g liver after twice-daily 5 days administration of granules coated with soluplus-ITR), resulting in an excellent oral administration option in the treatment of invasive mycosis. Nevertheless, some biochemical alterations were found, including a decrease in blood urea nitrogen (∼17 g/dl) and alanine aminotransferase (<30 U/l) and an increase in the levels of bilirubin (∼0.2 mg/dl) and alkaline phosphatase (<80 U/l), which could be indicative of a liver failure. Once-daily regimen for 10 days can be a promising therapy.

Topics: Amphotericin B; Animals; Antifungal Agents; Candida albicans; Itraconazole; Male; Mice; Mycoses

Amphotericin B is a gold-standard drug, particularly for the treatment of systemic fungal infections. However, its low solubility and permeability limit its application. To improve its bioavailability, AmB may be conjugated with various water-soluble auxiliary groups.. Custom R group Enumeration was used at the designated sites of Amphotericin B. The designated sites taken into consideration are the carboxyl moiety of the aglycone part and the amine moiety of the glycone part of Amphotericin B for Enumeration purposes. The enumerated molecules were subjected to QikProp properties.. We identified fourteen hits with improved predicted aqueous solubility and cell permeability.. Enumeration might be applicable in improving bioavailability, which could lead to the oral formulation of the Amphotericin B drug.

Topics: Amphotericin B; Antifungal Agents; Humans; Mycoses; Solubility

Systemic fungal infections are an increasingly prevalent health problem. Amphotericin B (AmB), a hydrophobic polyene antibiotic, remains the drug of choice for life-threatening invasive fungal infections. However, it has dose-limiting side effects, including nephrotoxicity. The efficacy and toxicity of AmB are directly related to its aggregation state. Here, we report the preparation of a series of telodendrimer (TD) nanocarriers with the freely engineered core structures for AmB encapsulation to fine-tune AmB aggregation status. The reduced aggregation status correlates well with the optimized antifungal activity, attenuated hemolytic properties, and reduced cytotoxicity to mammalian cells. The optimized TD nanocarrier for monomeric AmB encapsulation significantly increases the therapeutic index, reduces the

Topics: Amphotericin B; Animals; Antifungal Agents; Candida albicans; Drug Compounding; Mammals; Mice; Mycoses

Chromoblastomycosis (CBM) is a form of chronic mycosis that affects the skin and mucous membranes and is caused by species of dematiaceous fungi including Exophiala spp., Phialophora spp., and Fonsecaea spp. The persistence of this disease and limitations associated with single-drug treatment have complicated efforts to adequately manage this condition.. In this study, a microdilution assay was used to explore the synergistic antifungal activity of everolimus (EVL) in combination with itraconazole (ITC), voriconazole (VRC), posaconazole (POS), and amphotericin B (AMB) against a range of clinical dematiaceous fungal isolates.. These analyses revealed that the EVL+POS and EVL+ITC exhibited superior in vitro synergistic efficacy, respectively inhibiting the growth of 64% (14/22) and 59% (13/22) of tested strains. In contrast, the growth of just 9% (2/22) of tested strains was inhibited by a combination of EVL+AMB, and no synergistic efficacy was observed for the combination of EVL+VRC.. Overall, these findings indicate that EVL holds promise as a novel drug that can be synergistically combined with extant antifungal drugs to improve their efficacy, thereby aiding in the treatment of CBM.

Topics: Amphotericin B; Antifungal Agents; Everolimus; Fungi; Humans; Microbial Sensitivity Tests; Mycoses; Voriconazole

Acute invasive fungal rhinosinusitis (AIFRS) is a fatal infection associated with high morbidity and mortality. Although it is a rare disease, upsurge of AIFRS was noticed during the second wave of COVID-19 disease. Early diagnosis and management is the cornerstone for good outcomes. However, management of AIFRS is challengeable especially in developing countries due to limited resources and high prices of antifungal agents. No previous studies have been conducted to evaluate the outcomes of management of AIFRS in Syria. The purpose of this study is to report the results of management of AIFRS with low doses of liposomal amphotericin B in our tertiary hospital in Syria.. The outcomes of management of AIFRS cases were followed through a prospective observational study between January 2021 and July 2022. The required medical data were collected for each individual. Three-month mortality rate was studied. SPSS v.26 was used to perform the statistical analysis. Pearson Chi-square test was used to study the associations between different variables and mortality. Survival curves were plotted by the Kaplan-Meier to compare the survival probability. Log Rank (Mantel-Cox) test and Cox regression were conducted to evaluate the factors affecting survival within the follow up period.. Of 70 cases, 36 (51.4%) were males and 34 (48.6%) were females. The mean age of patients was 52.5 years old. The most common underlying risk factor was diabetes mellitus (84.3%). The used dose of liposomal amphotericin B ranged between 2-3 mg/kg per day. The overall 3-month mortality rate was 35.7%. Significant association was found between survival and the following variables: Age, orbital involvement, stage, and comorbidity.. The overall mortality rate was close to other studies. However, survival rate was worse than comparable studies in selected cases of AIFRS (older ages, involved orbits, advanced stages, and chronic immunodeficiency). Therefore, low doses of liposomal amphotericin B could be less effective in such cases and high doses are recommended.

Topics: Acute Disease; Antifungal Agents; COVID-19; Female; Hospitals, University; Humans; Male; Middle Aged; Mycoses; Rhinitis; Sinusitis; Syria

Decades of previous efforts to develop renal-sparing polyene antifungals were misguided by the classic membrane permeabilization model

Topics: Amphotericin B; Animals; Antifungal Agents; Cells, Cultured; Cholesterol; Drug Resistance, Fungal; Ergosterol; Humans; Kidney; Kinetics; Mice; Microbial Sensitivity Tests; Mycoses; Polyenes; Serial Passage; Sterols; Time Factors

Fibrin-based systems offer promises in drug and gene delivery as well as tissue engineering. We established earlier a fibrin-based plasma beads (PB) system as an efficient carrier of drugs and antigens. In the present work, attempts were made to further improve its therapeutic efficacy exploiting innovative ideas, including the use of plasma alginate composite matrices, proteolytic inhibitors, cross linkers, and dual entrapment in various liposomal formulations. In vitro efficacy of the different formulations was examined. Pharmacokinetics of the formulations encapsulating Amphotericin B (AmpB), an antifungal compound, were investigated in Swiss albino mice. While administration of the free AmpB led to its rapid elimination (<72 h), PB/liposome-PB systems were significantly effective in sustaining AmpB release in the circulation (>144 h) and its gradual accumulation in the vital organs, also compared to the liposomal formulations alone. Interestingly, the slow release of AmpB from PB was unusual compared to other small molecules in our earlier findings, suggesting strong interaction with plasma proteins. Molecular interaction studies of bovine serum albumin constituting approximately 60% of plasma with AmpB using isothermal titration calorimetry and in silico docking verify these interactions, explaining the slow release of AmpB entrapped in PB alone. The above findings suggest that PB/liposome-PB could be used as safe and effective delivery systems to combat fungal infections in humans.

Topics: Alginates; Amphotericin B; Animals; Antifungal Agents; Drug Delivery Systems; Female; Fungi; Liposomes; Mice; Mycoses; Plasma; Rabbits

Amphotericin B (AmB) has been the gold standard to treat systemic fungal infections. The use of AmB is restricted to hospitals because it poses several risks, mainly risks related to its high nephrotoxicity. Given the importance of this drug in medicine, new therapeutics and AmB formulations with nanotechnological improvements are required and could bring many benefits to patients. A new drug formulation with gastro-resistant coated granules has been proposed. The lipid-based system containing AmB was produced and used as raw material in the granulation/coated process. The new developed formulation (AmB-NP-GR) was characterized by optical microscopy, granulometry, and atomic force microscopy (AFM) after disintegration test. AmB-NP-GR showed granular shape, with most granules measured between 250 and 500 µm (37 ± 7% w/w). The AFM images indicated that the granule formulation should disintegrate in the intestine, to release the lipid-based carriers, making them available for absorption and allowing them to reach the blood circulation. The developed formulation was administered to rats in a single dose of 4.0 or 8.0 mg kg

Topics: Amphotericin B; Animals; Antifungal Agents; Humans; Leishmaniasis; Lipids; Mycoses; Rats

Combinations of antifungal drugs can have synergistic antifungal activity, achieving high therapeutic efficacy while minimizing the side effects. Amphotericin B (AMB) has been used as a standard antifungal drug for fungal infections; however, because of its high toxicity, new strategies to minimize the required dose are desirable. Chitinases have recently received attention as alternative safe antifungal agents. Herein, we report the combination of palmitoylated chitinase domains with AMB to enhance the antifungal activity. The chitin-binding domain (LysM) from

Topics: Amphotericin B; Antifungal Agents; Chitin; Chitinases; Humans; Lipoylation; Mycoses; Palmitic Acid

Inhaled formulations of amphotericin B are the most widely used antifungal prophylactic agents in lung transplant recipients, yet there are limited data on their safety. We performed a single-center retrospective cohort study of 603 consecutive patients who underwent lung transplantation between 2012 and 2017 and received antifungal prophylaxis with inhaled amphotericin B lipid complex (iABLC) from the day of transplantation until hospital discharge. Of 603 patients, 600 (99.5%) received ≥1 dose of iABLC, and 544 (90.2%) completed the recommended prophylactic course. In total, 4,128 iABLC doses (median, 5; range, 1 to 48 per patient) were administered; 24 patients received >3 months of therapy. Only one (0.2%) patient discontinued therapy due to a drug-attributable adverse event. During the first posttransplant year, 80 (13.3%) patients died (median time to death, 171 days; interquartile range [IQR], 80 to 272 days), and 3,352 (median, 6 per patient) lung biopsies were performed; 414 (68.7%) patients developed biopsy-proven acute cellular rejection. One-year adverse events in our cohort of lung transplant recipients treated with iABLC during transplant hospitalization matched national outcomes for rejection, graft loss, and death. iABLC is a safe and well-tolerated antifungal prophylactic agent in lung transplant recipients.

Topics: Amphotericin B; Antifungal Agents; Humans; Lung; Lung Transplantation; Mycoses; Retrospective Studies; Transplant Recipients

Amphotericin B deoxycholate (AMB-D) remains an antifungal agent with great therapeutic value in pediatric patients. The currrent consensus is that its use in neonates is safer than in older children. However, childhood presents different periods of development that deserve to be evaluated more precisely. Our goal was to assess the usage profile of AMB-D in stratified pediatric age groups, adapted according to the National Institute of Child Health and Human Development classification.. This retrospective cross-sectional observational study was conducted at a Brazilian tertiary children's hospital between January 2014 and December 2019.  Data of patients who received at least two doses of intravenous AMB-D while hospitalized were extracted from electronic health files. Information on patient demographics, underlying diseases and comorbidities, laboratory examinations, fungal infection diagnosis, and AMB-D use were gathered following specific criteria. Nonparametric tests were applied, such as the chi-square test to compare proportions and Fisher's exact test to assess the association between categorical variables or contingency tables.. One hundred and twenty-seven (127) medical records were stratified as preterm neonatal (birth <37 weeks postmenstrual age), term neonatal (birth-27 days), infants (28 days-12 months), toddlers (13 months-2 years), early childhood (3-5 years), middle childhood (6-11 years), and early adolescence (12-18 years). The criteria for the indication of AMB-D followed empirical use as the main indication (n = 74; 58.26%), proven and probable fungal infection (n = 39; 30.71%), and medical suspicion (n = 14; 11.02%). Candida spp. was the main etiologic agent isolated in cultures, with the highest frequency of C. albicans (n = 18; 40%), followed by Candida parapsilosis (n = 14; 31.11%), and Candida tropicalis (n = 6; 13.33%). Very few acute infusion-related adverse effects were observed during the administration of AMB-D in pediatric patients. We found an unfavorable impact of AMB-D use in patients from 13 months of age onwards suggesting this group as a turning point for a greater chance of adverse events, and not soon after the neonatal period.. Clinical or observational studies based on age stratification are essential to accurately elucidate whether potentially toxic drugs can be used safely in the pediatric population. Our search for a turning point was shown to contribute to the accuracy of the study, as it provided data on the impact of D-AMB in specific pediatric age groups.

Topics: Adolescent; Amphotericin B; Antifungal Agents; Child; Child, Preschool; Cross-Sectional Studies; Humans; Infant; Infant, Newborn; Mycoses; Retrospective Studies

To determine the impact of amphotericin B supplementation to donor cornea preservation solutions on the rates of positive donor rim fungal cultures and postkeratoplasty fungal infections.. This was a retrospective analysis of cases undergoing corneal transplantations at a single tertiary referral center from 2016 to 2021. Patients undergoing corneal transplantations with and without amphotericin B supplementation to the storage media were reviewed for donor rim culture results and postoperative infection. The primary outcome measures were positive donor rim fungal culture results and postkeratoplasty fungal infection.. A total of 1238 corneal transplants were analyzed. Of these, 849 were stored in preservation solution without amphotericin B, while 389 had amphotericin B included. There was a lower incidence of positive donor rim fungal cultures in cases with amphotericin B supplementation (1.8%) compared to the cases without amphotericin B (2.9%), although this difference was not statistically significant (P = 0.24). Of the 389 cases with amphotericin B supplementation, one (0.25%) went on to develop clinically significant infection, while three of 849 (0.35%) cases without amphotericin B developed infection. The sample size was too small to determine the effect of amphotericin B on the incidence of postkeratoplasty fungal infection.. The addition of amphotericin B to donor cornea preservation solution resulted in a downward trend of positive donor rim fungal cultures and postkeratoplasty fungal infections, although these differences did not reach statistical significance. Further studies with larger sample sizes are necessary to appropriately determine the impact of amphotericin B supplementation in the storage solution on positive donor rims and postkeratoplasty fungal infections.

Topics: Amphotericin B; Cornea; Corneal Transplantation; Humans; Mycoses; Retrospective Studies; Tissue Donors

Platelets are currently thought to harbor antimicrobial functions and might therefore play a crucial role in infections, e.g., those caused by Aspergillus or mucormycetes. The incidence of invasive fungal infections is increasing, particularly during the coronavirus disease 2019 (COVID-19) pandemic, and such infections continue to be life-threatening in immunocompromised patients. For this reason, the interaction of antimycotics with platelets is a key issue to evaluate modern therapeutic regimens. Amphotericin B (AmB) is widely used for the therapy of invasive fungal infections either as deoxycholate (AmB-D) or as a liposomal formulation (L-AmB). We showed that AmB strongly activates platelets within a few minutes. AmB concentrations commonly measured in the blood of patients were sufficient to stimulate platelets, indicating that this effect is highly relevant

Topics: Amphotericin B; Antifungal Agents; Aspergillus; COVID-19; Deoxycholic Acid; Fibrinolytic Agents; Humans; Invasive Fungal Infections; Liposomes; Mycoses

The resistance and the birth of new intrinsic and multidrug-resistant pathogenic species like C. auris is creating great concern in the antifungal world. Given the limited drug arsenal and the lack of effectiveness of the available compounds, there is an urgent need for innovative approaches. The murine mAb 2G8 was humanized and engineered in silico to develop a single-chain fragment variable (hscFv) antibody against β-1,3-glucans which was then expressed in E. coli. Among the recombinant proteins developed, a soluble candidate with high stability and affinity was obtained. This selected protein is VL-linker-VH oriented, and it is characterized by the presence of two ubiquitin monomers at the N-terminus and a His tag at the C-terminus. This construct, Ub2-hscFv-His, guaranteed stability, solubility, efficient purification and satisfactory recovery of the recombinant product. HscFv can bind β-1,3-glucans both as coated antigens and on C. auris and C. albicans cells similarly to its murine parental and showed long stability and retention of binding ability when stored at 4°, -20° and -80° C. Furthermore, it was efficient in enhancing the antifungal activity of drugs caspofungin and amphotericin B against C. auris. The use of biological drugs as antifungals is limited; here we present a promising hscFv which has the potential to be useful in combination with currently available antifungal drugs.

Topics: Amphotericin B; Animals; Antifungal Agents; Escherichia coli; Glucans; Mice; Microbial Sensitivity Tests; Mycoses

The discovery of amphotericin B, a polyene antifungal compound, in the 1950s, and the formulation of this compound in a liposomal drug delivery system, has resulted in decades of use in systemic fungal infections. The use of liposomal amphotericin B formulation is referenced in many international guidelines for the treatment of fungal infections such as Aspergillus and cryptococcal disease and Candida infections, as well as other less common infections such as visceral leishmaniasis. With the development of liposomal amphotericin B, an improved therapeutic index could be achieved that allowed the attainment of higher drug concentrations in both the plasma and tissue while simultaneously lowering the toxicity compared with amphotericin B deoxycholate. In over 30 years of experience with this drug, a vast amount of information has been collected on preclinical and clinical efficacy against a wide variety of pathogens, as well as evidence on its toxicity. This article explores the history and nature of the liposomal formulation, the key clinical studies that developed the pharmacokinetic, safety and efficacy profile of the liposomal formulation, and the available microbiological data.

Topics: Amphotericin B; Antifungal Agents; Candidiasis; Humans; Liposomes; Mycoses

Advances in medicine have led to a growing number of people with compromised or suppressed immune systems who are susceptible to invasive fungal infections. In particular, severe fungal infections are becoming increasingly common in ICUs, affecting people within and outside of traditional risk groups alike. This is exemplified by the emergence of severe viral pneumonia as a significant risk factor for invasive pulmonary aspergillosis, and the recognition of influenza-associated pulmonary aspergillosis and, more recently, COVID-19-associated pulmonary aspergillosis. The treatment landscape for haematological malignancies has changed considerably in recent years, and some recently introduced targeted agents, such as ibrutinib, are increasing the risk of invasive fungal infections. Consideration must also be given to the risk of drug-drug interactions between mould-active azoles and small-molecule kinase inhibitors. At the same time, infections caused by rare moulds and yeasts are increasing, and diagnosis continues to be challenging. There is growing concern about azole resistance among both moulds and yeasts, mandating continuous surveillance and personalized treatment strategies. It is anticipated that the epidemiology of fungal infections will continue to change and that new populations will be at risk. Early diagnosis and appropriate treatment remain the most important predictors of survival, and broad-spectrum antifungal agents will become increasingly important. Liposomal amphotericin B will remain an essential therapeutic agent in the armamentarium needed to manage future challenges, given its broad antifungal spectrum, low level of acquired resistance and limited potential for drug-drug interactions.

Topics: Antifungal Agents; Azoles; COVID-19 Drug Treatment; Fungi; Humans; Invasive Fungal Infections; Mycoses; Pulmonary Aspergillosis

Due to the increased morbidity and mortality by fungal infections and the emergence of severe antifungal resistance, there is an urgent need for new antifungal agents. Here, we screened for antifungal activity in our in-house library through the minimum inhibitory concentration test and derived two hit compounds with moderate antifungal activities. The hit compounds' antifungal activities and drug-like properties were optimized by substituting various aryl ring, alkyl chain, and methyl groups. Among the optimized compounds,

Topics: Animals; Antifungal Agents; Cell Wall; Drug Evaluation, Preclinical; Drug Synergism; Female; Fungi; Humans; Male; Mice; Microbial Sensitivity Tests; Mycoses; Rats, Sprague-Dawley

Topics: Amphotericin B; Antifungal Agents; Benzoates; Biofilms; Cinnamates; Drug Combinations; Fungi; Humans; Microbial Sensitivity Tests; Mycoses; Terpenes; Voriconazole

To minimize the intrinsic toxicity of the antibacterial agent hydrazinyloxadiazole 1, the hydrazine moiety was replaced with ethylenediamine (compound 7). This replacement generated a potent antifungal agent with no antibacterial activity. Notably, use of a 1,2-diaminocyclohexane moiety, as a conformationally-restricted isostere for ethylenediamine, potentiated the antifungal activity in both the cis and trans forms of N-(5-(2-([1,1'-biphenyl]-4-yl)-4-methylthiazol-5-yl)-1,3,4-oxadiazol-2-yl)cyclohexane-1,2-diamine (compounds 16 and 17). Both compounds 16 and 17 were void of any antibacterial activity; nonetheless, they showed equipotent antifungal activity in vitro to that of the most potent approved antifungal agent, amphotericin B. The promising antifungal effects of compounds 16 and 17 were maintained when assessed against an additional panel of 26 yeast and mold clinical isolates, including the Candida auris and C. krusei. Furthermore, compound 17 showed superior activity to amphotericin B in vitro against Candida glabrata and Cryptococcus gattii. Additionally, neither compound inhibited the normal human microbiota, and both possessed excellent safety profiles and were 16 times more tolerable than amphotericin B.

Topics: Amphotericin B; Antifungal Agents; Candidiasis; Drug Resistance, Multiple; Fluconazole; Humans; Microbial Sensitivity Tests; Mycoses; Thiazoles

Infectious keratitis is the main cause of preventable blindness worldwide, with about 1.5-2.0 million new cases occurring per year. This inflammatory response may be due to infections caused by bacteria, fungi, viruses or parasites. Fungal keratitis is a poorly studied health problem.. This study aimed to identify a new fungal species by molecular methods and to explore the possible efficacy of the three most common antifungals used in human keratitis in Mexico by performing in vitro analysis. The capacity of this pathogen to cause corneal infection in a murine model was also evaluated.. The fungal strain was isolated from a patient with a corneal ulcer. To identify the fungus, taxonomic and phylogenetic analyses (nrDNA ITS and LSU data set) were performed. An antifungal susceptibility assay for amphotericin B, itraconazole and voriconazole was carried out. The fungal isolate was used to develop a keratitis model in BALB/c mice; entire eyes and ocular tissues were preserved and processed for histopathologic examination.. This fungal genus has hitherto not been reported with human keratitis in Mexico. We described a new species Purpurecillium roseum isolated from corneal infection. P roseum showed resistance to amphotericin B and itraconazole and was sensitive to voriconazole. In vivo study demonstrated that P roseum had capacity to developed corneal infection and to penetrate deeper corneal tissue. The global change in fungal infections has emphasised the need to develop better diagnostic mycology laboratories and to recognise the group of potential fungal pathogens.

Topics: Aged; Amphotericin B; Animals; Antifungal Agents; Cornea; DNA, Fungal; Drug Resistance, Fungal; Female; Humans; Hypocreales; Itraconazole; Keratitis; Mexico; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Mycological Typing Techniques; Mycoses; Phylogeny; Voriconazole

Liposomal amphotericin B (L-AMB), a broad-spectrum antifungicidal drug, is often used to treat fungal infections. However, clinical evidence of its use in patients with renal dysfunction, especially those receiving renal replacement therapy (RRT), is limited. Therefore, we evaluated the usage and occurrence of adverse reactions during L-AMB therapy in patients undergoing RRT.. Using claims data and laboratory data, we retrospectively evaluated patients who were administered L-AMB. The presence of comorbidities, mortality rate, treatment with L-AMB and other anti-infective agents, and the incidence of adverse reactions were compared between patients receiving RRT, including continuous renal replacement therapy (CRRT) and maintenance hemodialysis (HD), and those that did not receive RRT.. In total, 900 cases met the eligibility criteria: 24, 19, and 842 cases in the maintenance HD, CRRT, and non-RRT groups, respectively. Of the patients administered L-AMB, mortality at discharge was higher for those undergoing either CRRT (15/19; 79%) or maintenance HD (16/24; 67%) than for those not receiving RRT (353/842; 42%). After propensity score matching, the average daily and cumulative dose, treatment duration, and dosing interval for L-AMB were not significantly different between patients receiving and not receiving RRT. L-AMB was used as the first-line antifungal agent for patients undergoing CRRT in most cases (12/19; 63%). Although the number of subjects was limited, the incidence of adverse events did not markedly differ among the groups.. L-AMB may be used for patients undergoing maintenance HD or CRRT without any dosing, duration, or interval adjustments.

Topics: Amphotericin B; Antifungal Agents; Databases, Factual; Humans; Japan; Kidney Diseases; Mycoses; Renal Replacement Therapy; Retrospective Studies; Time Factors; Treatment Outcome

Disseminated talaromycosis caused by Talaromyces marneffei is a life-threatening opportunistic infection. Although amphotericin B deoxycholate (dAmB) remains the first-line induction treatment, voriconazole can also be used. However, no clinical trials have compared dAmB and voriconazole in the administration of talaromycosis. We retrospectively evaluated the efficacy and safety of voriconazole or dAmB as induction therapy for talaromycosis in HIV-infected patients. We enrolled HIV-infected patients with a confirmed Talaromyces marneffei infection who received intravenous dAmB (0.6 to 0.7 mg/kg daily for 2 weeks) or voriconazole (6 mg/kg every 12 h on day 1 and 4 mg/kg every 12 h afterward) as induction therapy, followed by oral itraconazole as consolidation and maintenance therapy. Drug efficacy was evaluated based on response rate. Drug safety was evaluated based on the occurrence of adverse events. In total, 58 patients who received voriconazole and 82 who received dAmB were enrolled from two hospitals. The voriconazole and dAmB treatment groups had similar response rates at the primary and follow-up efficacy evaluations. However, the durations of induction antifungal therapy and hospital stay were shorter for patients in the voriconazole group than in the dAmB group. Few adverse reactions occurred in either the voriconazole or dAmB group. Our retrospective study indicated that voriconazole is an effective and safe induction antifungal drug for HIV-associated disseminated talaromycosis. The duration of induction treatment with voriconazole was shorter, indicating its potential as a better choice in clinical practice. The duration of voriconazole induction therapy is 11 to 13 days.

Topics: Acquired Immunodeficiency Syndrome; Amphotericin B; Antifungal Agents; Humans; Induction Chemotherapy; Mycoses; Retrospective Studies; Talaromyces; Voriconazole

Talaromycosis is a leading cause of AIDS-associated opportunistic infections and death in Southeast Asia. We have recently shown in the Itraconazole versus Amphotericin for Talaromycosis (IVAP) trial that induction therapy with amphotericin B reduced mortality over 24 weeks, but not during the first 2 weeks. Antifungal treatment effects in real-world settings have not been rigorously evaluated. Using data obtained from patient records at the Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam from 2004 to 2009, we first developed a prognostic model using Bayesian logistic regression to identify predictors of death. Second, we developed a causal model using propensity score matching to assess the treatment effects of amphotericin B and itraconazole. Our prognostic model identified intravenous drug use (odds ratio [OR] = 2.01), higher respiratory rate (OR = 1.12), higher absolute lymphocyte count (OR = 1.62), a concurrent respiratory infection (OR = 1.67) or central nervous system infection (OR = 2.66) as independent predictors of death. Fever (OR = 0.56) was a protective factor. Our prognostic model exhibits good in-sample performance and out-of-sample validation, with a discrimination power of 0.85 and 0.91, respectively. Our causal model showed no significant difference in treatment outcomes between amphotericin B and itraconazole over the first 2 weeks (95% credible interval: 0.62, 2.50). Our prognostic model provides a simple tool based on routinely collected clinical data to predict individual patient outcome. Our causal model shows similar results to the IVAP trial at 2 weeks, demonstrating an agreement between real-world data and clinical trial data.

Topics: Adult; AIDS-Related Opportunistic Infections; Amphotericin B; Antifungal Agents; Bayes Theorem; Cohort Studies; Female; Humans; Itraconazole; Male; Mycoses; Prognosis; Risk Factors; Talaromyces; Treatment Outcome; Vietnam; Young Adult

Amphotericin B-deoxycholate (Fungizone [FZ]) is a widely used potent antimycotic drug in spite of its nephrotoxic effect via different mechanisms. The effect of FZ on renal cell bioenergetics is not clear. The current study evaluated the effect of FZ on the bioenergetics of albino rats' isolated renal proximal tubule cells (PTCs). The cytotoxic effect of FZ on the isolated renal cells was assessed by MTT and lactate dehydrogenase (LDH) assays. The effect of FZ on the PTCs uptake (OAT1 and OCT2) and efflux (P-gp and MRP2) transporters was evaluated. Then, the effect of FZ on mitochondria was assessed by studying complexes I-IV activities, lactate assay, oxygen consumption rates (OCR), and western blotting for all mitochondrial complexes. Moreover, the effect of FZ on mitochondrial membrane fluidity (MMF) and fatty acids composition was evaluated. Additionally, the protective effect of coenzyme q10 was studied. Outcomes showed that FZ was cytotoxic to the PTCs in a concentration and time-dependent patterns. FZ significantly inhibited the studied uptake and efflux tubular transporters with inhibition of the mitochondrial complexes activities and parallel increase in lactate production and decrease in OCRs. Finally, FZ significantly reduced the expression of all mitochondrial complexes in addition to significant increase in MMF and MMFA concentration. Coenzyme Q10 was found to significantly decrease FZ-induced cytotoxicity and transporters impairment in the PTC. FZ significantly inhibits bioenergetics of PTC, which may stimulate the cascade of cell death and clinical nephrotoxicity.

Topics: Amphotericin B; Animals; Antifungal Agents; Cells, Cultured; Deoxycholic Acid; Disease Models, Animal; Drug Combinations; Humans; Kidney Tubules, Proximal; Mitochondria; Mycoses; Rats; Rats, Wistar

Amphotericin B (AMB), with widespread antifungal and anti-parasitic activities and low cross-resistance with other drugs, has long been identified as a potent antimicrobial drug. However, its clinical toxicities, especially nephrotoxicity, have limited its use in clinical practice. Lately, nano-based systems have been the subject of serious research and becoming an effective strategy to improve toxicity and antimicrobial potency. Commercial AMB lipid formulations have been developed in order to improve the therapeutic index and nephrotoxicity, while limited use is mainly due to their high cost. The review aimed to highlight the updated information on nanotechnology-based approaches to the development of AMB delivery and targeting systems for treatment of fungal diseases and leishmaniasis, regarding therapeutic challenges and achievements of various delivery systems.

Topics: Amphotericin B; Antifungal Agents; Humans; Leishmaniasis; Mycoses; Nanotechnology

To determine the association between antifungal susceptibility test (AFST) results and in vivo therapeutic response in Indian patients with fungal rhinosinusitis.. The clinicoradiological, fungal culture, AFST, histopathology results and outcomes of 48 patients with fungal rhinosinusitis seen between 20132015 were analysed. Minimum inhibitory concentration (MIC) determination was performed for amphotericin B, itraconazole, voriconazole and posaconazole.. Forty patients had invasive and 8 had non-invasive fungal sinusitis. Rhizopus and Aspergillus species which comprised 46.9% each of isolates were mostly associated with acute invasive fungal rhinosinusitis and chronic granulomatous fungal rhinosinusitis respectively. All patients with non-invasive fungal rhinosinusitis had Aspergillus isolates. The Geometric Mean (GM) MIC for R. arrhizus of amphotericin B and posaconazole was 0.51 mcg/mL and 3.08 mcg/mL respectively and for A. flavus species for amphotericin B and voriconazole values were 1.41mcg/mL and 0.35 mcg/mL respectively. In patients with Aspergillus infections, while there was no association of MICs for azoles and outcome (p = 1), a strong association was noted between azole therapy and a good outcome (p = 0.003). In patients with Rhizopus infections, no association was found between MICs for amphotericin B and outcome (p = 1) and because of therapeutic complications, no association was found between amphotericin B therapy and outcome (p = 1).. No significant association exists between in vitro (AFST) and in vivo responses despite low GM MICs for the drugs used in Aspergillus and Rhizopus infections. Therapeutic complications following conventional amphotericin B therapy confounds analysis. Clinical responses suggest that azoles are the drug of choice for Aspergillus infections.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus; Azoles; Humans; Itraconazole; Microbial Sensitivity Tests; Mucormycosis; Mycoses; Sinusitis; Triazoles; Voriconazole

We report on a 22-years-old Thai male patient with congenital HIV infection. Due to his non-adherence to antiretroviral treatment he developed disseminated

Topics: Amphotericin B; Anterior Chamber; Antifungal Agents; Fungemia; Granuloma; HIV Infections; Humans; Male; Mycoses; Talaromyces; Uveitis, Anterior; Young Adult

The emergence of non-Aspergillus mold pathogens has increased notoriously in the last decades with serious health consequences. The options of treatment for these microorganisms often resistant to a wide variety of antifungals is limited. Sertraline is an antidepressant with in vitro and in vivo antifungal properties which has been recently studied as an adjuvant in the treatment of invasive infections. In this study, we evaluated the in vitro interaction of sertraline with voriconazole and amphotericin B against Lomentospora prolificans, Scedosporium spp., Fusarium spp., Paecilomyces spp., Alternaria spp. and Curvularia spp. The minimum inhibitory concentration and minimum fungicidal concentration for sertraline were in the range of 8-32 μg/mL. Sertraline showed antifungal capacity against all fungi tested and synergism in combination with amphotericin B against some strains of Lomentospora prolificans, Scedosporium apiospermum and Alternaria alternata, antagonism with voriconazole against Purpureocillium lilacinum and indifference in both combinations for most of the other strains tested. These results suggest a potential role of sertraline as an adjuvant in the treatment of some of these serious mycoses.

Topics: Amphotericin B; Antifungal Agents; Ascomycota; Drug Repositioning; Drug Synergism; Humans; Microbial Sensitivity Tests; Mitosporic Fungi; Mycoses; Sertraline; Voriconazole

Infections caused by Rhodotorula spp. are increasing worldwide. This study identified, through the light of the new taxonomic advances on the subphylum Pucciniomycotina, 16 isolates from blood cultures and compared their antifungal susceptibility on microdilution and gradient diffusion methods. Internal transcriber spacer sequencing identified Rhodotorula mucilaginosa (n = 12), Rhodotorula toruloides (n = 2), Rhodotorula dairenensis (n = 1), and Cystobasidium minutum (n = 1). Amphotericin B was the most effective drug. A good essential agreement was observed on MIC values of amphotericin B and voriconazole determined by the two methods. Therefore, the gradient method is useful for susceptibility tests of R. mucilaginosa against these drugs.

Topics: Amphotericin B; Antifungal Agents; Blood Culture; Brazil; Diffusion; DNA, Intergenic; Humans; Microbial Sensitivity Tests; Mycoses; Rhodotorula; Voriconazole

Topics: Academic Medical Centers; Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Child; Child, Preschool; Comorbidity; Early Diagnosis; Endoscopy; Female; Fungi; Humans; Male; Middle Aged; Mycoses; Retrospective Studies; Rhinitis; Sinusitis; United States; Young Adult

Current knowledge on infections caused by Scedosporium spp. and Lomentospora prolificans in children is scarce. We therefore aim to provide an overview of risk groups, clinical manifestation and treatment strategies of these infections.. Pediatric patients (age ≤18 years) with proven/probable Scedosporium spp. or L. prolificans infection were identified in PubMed and the FungiScope® registry. Data on diagnosis, treatment and outcome were collected.. Fifty-five children (median age 9 years [IQR: 5-14]) with invasive Scedosporium spp. (n = 33) or L. prolificans (n = 22) infection were identified between 1990 and 2019. Malignancy, trauma and near drowning were the most common risk factors. Infections were frequently disseminated. Most patients received systemic antifungal therapy, mainly voriconazole and amphotericin B, plus surgical treatment. Overall, day 42 mortality was 31%, higher for L. prolificans (50%) compared to Scedosporium spp. (18%). L. prolificans infection was associated with a shorter median survival time compared to Scedosporium spp. (6 days [IQR: 3-28] versus 61 days [IQR: 16-148]). Treatment for malignancy and severe disseminated infection were associated with particularly poor outcome (HR 8.33 [95% CI 1.35-51.40] and HR 6.12 [95% CI 1.52-24.66], respectively). Voriconazole use at any time and surgery for antifungal treatment were associated with improved clinical outcome (HR 0.33 [95% CI 0.11-0.99] and HR 0.09 [95% CI 0.02-0.40], respectively).. Scedosporium spp. and L. prolificans infections in children are associated with high mortality despite comprehensive antifungal therapy. Voriconazole usage and surgical intervention are associated with successful outcome.

Topics: Adolescent; Amphotericin B; Antifungal Agents; Child; Child, Preschool; Female; Humans; Infant; Male; Mycoses; Risk Factors; Scedosporium; Voriconazole

We report a retroviral positive patient who presented to us with recurrent skin lesions along with intermittent, colicky periumbilical abdominal pain associated with non-projectile, postprandial vomiting. Contrast-enhanced CT (CECT) of abdomen and pelvis was suggestive of proximal jejunal obstruction. Double balloon enteroscopy done which showed extensive deep ulceration with surrounding nodular surface and friable mucosa at 60 cm from pylorus with luminal narrowing. The biopsy from this region as well as the skin lesion on the forehead grew

Topics: Adult; AIDS-Related Opportunistic Infections; Amphotericin B; Anti-Retroviral Agents; Antifungal Agents; Enteral Nutrition; Female; HIV Infections; HIV Seropositivity; Humans; Intestinal Obstruction; Itraconazole; Jejunostomy; Mycoses; Nutritional Status

To assess the efficacy of a commercially available in-water amphotericin B treatment for Macrorhabdus ornithogaster.. Clinical treatment trial.. Faecal shedding of 16 naturally infected budgerigars (Melopsittacus undulatus) was monitored while they were being treated using in-water amphotericin B, as per the manufacturer's instructions, for 10 days. Any birds that remained positive after 10 days received a further 10 day course of treatment. All birds were rechecked 16 days after the end of the second treatment period.. At the conclusion of treatment, 11 birds had stopped shedding M. ornithogaster, and 5 birds were still shedding. Sixteen days after the conclusion of the second treatment period, four birds that were negative after 10 days of treatment were shedding again, and two of the birds that were treated for 20 days were shedding. In addition, one bird from each treatment group died after treatment and before follow-up testing.. These findings represent a 36% treatment failure, suggesting that treatment with the commercially available, water-soluble amphotericin B has inconsistent efficacy against M. ornithogaster in some budgerigars in Australia and is not effective for eliminating it from budgerigar aviaries.

Topics: Amphotericin B; Animals; Australia; Bird Diseases; Melopsittacus; Mycoses; Water

In the Fall of 1999, we presented at medical "Grand Rounds" to a number of Infectious Diseases physicians at Vancouver General Hospital about the co-administration of several antifungal compounds in the treatment of blood-borne fungal infections to patients who were immunocompromised (i.e. cancer patients, patients waiting organ transplantation, HIV/AIDs patients, etc.). During the presentation, a physician from the back of the room called out "can you develop an oral formulation of amphotericin B which could be effective and not have the side-effects associated with the parenteral formulations of the drug". The physician stated that an oral formulation would be a big step forward, improving patient compliance, helping in pre-treatment without admitting patients to the hospital prior to organ transplantation and it would be cost-effective. Initially, I responded to the physician, that it would not be possible to develop an oral amphotericin B formulation that could be absorbed from the gastrointestinal (GI) tract in a high enough concentration to be effective in treating blood-borne fungal infections and yet remains non-toxic due to the physical chemical properties of the drug. However, as I travelled back to my lab from the meeting, it struck me that our understanding of how lipids had been processed and orally absorbed from the GI had advanced to the point the maybe incorporating amphotericin B into such lipids might work. Within several years, our laboratory was able to develop a novel oral amphotericin B formulation that was indeed effective in treating systemic fungal infections without the side-effects associated with the drug in a variety of fungal animal models.

Topics: Administration, Oral; Amphotericin B; Animals; Antifungal Agents; Fungi; Humans; Mycoses

is a thermally dimorphic fungus that causes penicilliosis, and become the third-most-common opportunistic fungal infection in immunocompromised patients in Southeast Asia. Azoles and amphotericin B have been introduced for the treatment, however, it is important to investigate possible mechanisms of azole resistance for future treatment failure. We identified 177 putative MFS transporters and classified into 17 subfamilies. Among those, members of the Drug:H

Topics: Amino Acid Sequence; Amphotericin B; Antifungal Agents; Asia, Southeastern; ATP Binding Cassette Transporter, Subfamily B; Candida albicans; Drug Resistance, Fungal; Humans; Immunocompromised Host; Microbial Sensitivity Tests; Mycoses; Phylogeny; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Talaromyces; Transcriptome; Triazoles

Liposomal amphotericin B (L-AMB) is a broad-spectrum antifungal drug that is used to treat fungal infections. However, clinical evidence of its use in patients with renal failure is limited. Here, we aimed to identify factors associated with acute kidney injury (AKI) in patients administered L-AMB. We retrospectively utilized a combination of Diagnosis Procedure Combination data and laboratory data obtained from hospitals throughout Japan between April 2008 and January 2018. In total, 507 patients administered L-AMB were identified. After L-AMB treatment initiation, AKI, which was defined as a ≥ 1.5-fold increase within 7 days or ≥ 0.3 mg/dL increase within 2 days in serum creatinine according to the KDIGO criteria, was recognized in 37% of the total patients (189/507). The stages of AKI were stage 1 in 20%, stage 2 in 11%, and stage 3 in 7%. Five factors were associated with AKI of all stages: prior treatment with angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers or carbapenem; concomitant administration of catecholamines or immunosuppressants; and ≥ 3.52 mg/kg/day of L-AMB dosing. Serum potassium < 3.5 mEq/L before L-AMB therapy was associated with severe AKI of stage 2 and 3. Altogether, these factors should be carefully considered to reduce the occurrence of AKI in patients administered L-AMB.

Topics: Acute Kidney Injury; Aged; Amphotericin B; Angiotensin-Converting Enzyme Inhibitors; Antifungal Agents; Carbapenems; Catecholamines; Creatinine; Factor Analysis, Statistical; Female; Humans; Immunocompromised Host; Immunosuppressive Agents; Liposomes; Male; Middle Aged; Mycoses

Peritoneal dialysis-associated peritonitis can uncommonly be caused by fungal infections. When they do present, they are associated with significant mortality and morbidity. We describe a case where a sample of peritoneal dialysate fluid grew Rhodotorula muciliginosa, a yeast organism present in the normal environment which has previously been reported as rarely causing peritonitis. We believe this is the first case where the Rhodotorula spp. and its origin has been identified.. A 20 year old male grew Rhodotorula muciliginosa from his peritoneal dialysis fluid on three separate occasions when a fluid sample was sent following a disconnection and subsequent set change. He was not systemically unwell and his peritoneal dialysate was clear. As Rhodotorula spp. is exceedingly difficult to treat our patient had his Tenchkoff catheter removed. Subsequent samples of soil and sand from his bearded dragon and Chilean tarantula cases, kept in his bedroom where dialysis occurred, were tested. The tarantula sand was identified as the source of the Rhodotorula spp. Of note, Candida was isolated from sand from the bearded dragon case. Once his Tenchkoff was removed he was treated with an intravenous course of antifungal therapy. He has since had a new Tenchkoff catheter inserted and recommenced PD following education around pets and hygiene.. In this era where people are keeping increasingly rare and unusual wildlife in their homes, this case highlights the need for clinician and nursing staff awareness of a patient's home environment and hobbies when they are undergoing peritoneal dialysis. Sand from our patient's tarantula case grew the colonising organism but interestingly soil from his bearded dragon case also isolated candida. This can also cause difficult to treat peritonitis.

Topics: Amphotericin B; Animals; Antifungal Agents; Ascitic Fluid; Candida; Humans; Kidney Failure, Chronic; Lizards; Male; Mycoses; Peritoneal Dialysis, Continuous Ambulatory; Peritonitis; Rhodotorula; Spiders; Young Adult

Talaromycosis (penicillinosis) is multiresistent opportunistic mycosis. The infection can be inapparent and it can simmulate malignant tumor dissemination in some patients.. We present a case of 33-years-old patient with mucinous adenocarcinoma of left ovary, initially FIGO IIC. The patient had had hysterectomy, bilateral adnexectomy, omentectomy and port-site metastasis extirpation. Six cycles of 1st chemother-apy paclitaxel and carboplatin had been administered to patient follow-ing the surgery. Positron emission tomography / computed tomography (PET/CT) scan after the treatment, had shown metabolic activity infiltrat-ing both lung apexes, supposedly with no dis-ease correlation, and hypermetabolic foci in spleen, suspicious of be-ing metastases. Pa-cient showed no clinical symp-toms, nor markers of inflammation elevation. Initially elevated serum tumor markers CA125 and CA72-4 had decreased after the treatment. Bronchoalveolar lavage cytology described presence of inflammatory infiltration with fungiform-ing hyphae - most probably an aspergillosis. Mannan and galactomannan serology was negative. In regard to splenectomy plans, treatment with voriconazol was initiated empirically. Result of fungi cultivation out of bronchoalveolar lavage was finalized later, show-ing sporadic presence o Penicillium sp. with resistance to antimycotic treatment except for amphotericin B. Liposomal amphotericin B treatment was administered in two cures, 28 days in total. Immunomodulatory treatment of secondary cellular immunodeficiency and vaccination against encapsulated bacteria was given to the patient. Splenectomy was performed 6 months after the end of chemother-apy treatment. Histopathology showed chronic granulomatous inflammation without mycotic hyphae, with no evidence of tumor cells. After the splenectomy, patient was treated by surgical incision and drainage and by klindamycin for intraabdominal abscess in left hypogastric area.. Patient is under follow up by oncologist, immunologist and gynecologist 12 months after the splenectomy, she is surveilled by PET/CT and serum tumor markers. Talaromycosis can be clinically inapparent in spite of its dissemination. It can be present in diffuse, granulomatous and mixed form. Therapeutic agent is sometimes limited to amphotericin B due to its resistence. Liposomal form of amphotericin B is recommended regard-ing its pharmacokinetic properties. In case of dissemination, administration period of more than 14 days is recommended, even in inapparent form. Immunomodulatory treatment is recommended due to opportunistic infection.

Topics: Adenocarcinoma, Mucinous; Adult; Amphotericin B; Antifungal Agents; Drug Resistance, Multiple, Fungal; Female; Humans; Mycoses; Opportunistic Infections; Ovarian Neoplasms; Penicillium; Splenectomy; Splenic Neoplasms

Talaromyces marneffei is a thermally dimorphic fungus endemic in south-east Asia. It predominantly occurs in both immunocompromised and immunosuppressed patients and can be fatal if diagnosis and treatment are delayed. The clinical manifestations of T. marneffei infection are nonspecific and rapid diagnosis of T. marneffei infection remains challenging.. A 24-year-old man came to our outpatient department with the sign of common skin lesions. The lesions were cuticolor follicular papules with or without central umbilication, nodules and acne-like lesions, which are common in syringoma, steatocystoma multiplex and trichoepithelioma. A dermatoscopy examination was performed to differentiate these skin lesions. The dermatoscopic images revealed circular or quasi-circular whitish amorphous structure with a central brownish keratin plug, providing the diagnostic clues of T. marneffei infection. Therefore, a skin scrapings culture, skin biopsy and serological detection for human immunodeficiency virus (HIV) were performed. The final diagnosis of this patient was T. marneffei and HIV co-infection.. Rapid diagnosis of T. marneffei infection is clinically challenging since presenting clinical manifestations are nonspecific with significant overlap with other common conditions. This case highlights that dermatoscopy is a promising tool for the rapid diagnosis of T. marneffei infection in patients with nonspecific skin lesions, assisting clinicians to avoid delayed diagnosis or misdiagnosis.

Topics: Amphotericin B; Anti-HIV Agents; Antifungal Agents; China; Dermoscopy; HIV Infections; Humans; Itraconazole; Male; Mycology; Mycoses; Talaromyces; Young Adult

Amphotericin B (AmB) is a very potent antifungal drug with very rare resistance among clinical isolates. Treatment with the AmB formulations available currently is associated with severe side effects. A promising strategy to minimize the toxicity of AmB is reducing its dose by combination therapy with other antifungals, showing synergistic interactions. Therefore, substances that display synergistic interactions with AmB are still being searched for. Screening tests carried out on several dozen of synthetic 1,3,4-thiadiazole derivatives allowed selection of a compound called 4-(5-methyl-1,3,4-thiadiazole-2-yl) benzene-1,3-diol (abbreviated as C1), which shows strong synergistic interaction with AmB and low toxicity towards human cells. The aim of the present study was to investigate the type of in vitro antifungal interactions of the C1 compound with AmB against fungal clinical isolates differing in susceptibility. The results presented in the present paper indicate that the C1 derivative shows strong synergistic interaction with AmB, which allows the use of a dozen to several dozen times lower AmB concentration necessary for 100% inhibition of the growth of pathogenic fungi in vitro. Synergistic interactions were noted for all tested strains, including strains with reduced sensitivity to AmB and azole-resistant isolates. These observations give hope for the possibility of application of the AmB - C1 combinatory therapy in the treatment of fungal infections.

Topics: Amphotericin B; Antifungal Agents; Drug Synergism; Fungi; Humans; Mycoses; Thiadiazoles

To report our experience in the diagnosis and management of invasive fungal infections with orbital involvement in children from a subtropical population.. The medical records of children (<18 years of age) with orbital mycosis and treated by the senior author (TJS) from 1995 to 2017 in multiple pediatric tertiary centers were reviewed retrospectively.. Six patients (aged 12 weeks to 15 years) were included in this series. Four patients had confirmed infection with isolated pathogens, including mucormycosis (3) and Exserohilum (2). One patient rapidly deteriorated and died before biopsy could be performed; however, the patient was presumed to have invasive fungal disease. Four patients had underlying hematological malignancy, and 1 presented in diabetic ketoacidosis. Orbital apex syndrome was observed in one patient. All patients received liposomal amphotericin B and five underwent at least one debridement surgery. One patient proceeded to orbital exenteration and survived. The overall survival rate was 67%.. Orbital mycoses can affect children of all ages. Immunocompromised patients are particularly at risk, and mortality rates are high. In a subtropical population, these infections may be caused by a different spectrum of fungi compared to other climate zones. We believe extensive surgical debridement, including exenteration may still be necessary in the management of this disease in a young population, particularly if there is extensive orbital involvement.

Topics: Adolescent; Amphotericin B; Antifungal Agents; Australia; Child; Child, Preschool; Eye Infections, Fungal; Female; Humans; Infant; Male; Mycoses; Orbital Diseases; Retrospective Studies; Tomography, X-Ray Computed

Topics: Amphotericin B; Antifungal Agents; Drug Resistance, Fungal; Fluconazole; Fungi; Humans; Itraconazole; Microbial Sensitivity Tests; Mycoses; Triazoles; Voriconazole

The incidence of Taralomyces marneffei infection in HIV-infected individuals has been decreasing, whereas its rate is rising among non-HIV immunodeficient persons, particularly patients with anti-interferon-gamma autoantibodies. T. marneffei usually causes invasive and disseminated infections, including fungemia. T. marneffei oro-pharyngo-laryngitis is an unusual manifestation of talaromycosis.. A 52-year-old Thai woman had been diagnosed anti-IFNɣ autoantibodies for 4 years. She had a sore throat, odynophagia, and hoarseness for 3 weeks. She also had febrile symptoms and lost 5 kg in weight. Physical examination revealed marked swelling and hyperemia of both sides of the tonsils, the uvula and palatal arches including a swelling of the epiglottis, and arytenoid. The right tonsillar biopsy exhibited a few intracellular oval and elongated yeast-like organisms with some central transverse septum seen, which subsequently grew a few colonies of T. marneffei on fungal cultures. The patient received amphotericin B deoxycholate 45 mg/dayfor 1 weeks, followed by oral itraconazole 400 mg/day for several months. Her symptoms completely resolved without complication.. In patients with anti-IFN-ɣ autoantibodies, T. marneffei can rarely cause a local infection involving oropharynx and larynx. Fungal culture and pathological examination are warranted for diagnosis T. marneffei oro-pharyngo-laryngitis. This condition requires a long term antifungal therapy.

Topics: Amphotericin B; Antifungal Agents; Autoantibodies; Deoxycholic Acid; Drug Combinations; Female; Humans; Interferon-gamma; Itraconazole; Laryngitis; Middle Aged; Mycobacterium abscessus; Mycobacterium Infections, Nontuberculous; Mycoses; Pharyngitis; Talaromyces; Thailand

Cladophialophora bantiana (C. bantiana) is a life-threatening melanized mycelial fungus causing brain abscess. C. bantiana is usually observed in tropical countries, including India. We report a Japanese case of C. bantiana presenting with myelitis mimicking neuromyelitis optica (NMO) and brain abscess. A 73-year-old man was administered prednisolone (30 mg/day) for antineutrophil cytoplasmic antibody (ANCA)-related vasculitis 100 days before admission. He had right side-dominant paraplegia and sensory loss in the right leg. T2-weighted spinal cord MRI revealed longitudinal high-intensity signals at the T7 to T12 levels. A ring-enhancing lesion at the T10 level was detected on gadolinium (Gd)-enhanced MRI. He was tentatively diagnosed with NMO, and steroid pulse therapy was performed. One month later, an abscess at the right cerebropontine angle was noted on Gd-enhanced brain MRI. Two months later, several subcutaneous intramuscular tumors were detected. Based on the morphological study of the cultured organelle obtained by tumor enucleation and the internal transcribed spacer sequence of ribosomal RNA, the pathogen was identified as C. bantiana. Although he received liposomal amphotericin B treatment, the patient died of respiratory insufficiency. C. bantiana infection should be considered in patients with myelitis presenting with longitudinal lesions and CNS abscess in an immunocompromised state.

Topics: Aged; Amphotericin B; Antifungal Agents; Ascomycota; Brain Abscess; Diagnosis, Differential; Fatal Outcome; Humans; Male; Mycoses; Neuromyelitis Optica

Invasive fungal disease (IFD) has a poor prognosis in children with hematological disorders after hematopoietic stem cell transplantation (HSCT). We assessed if drug combinations with different targets may improve the outcome.. Retrospective study to assess the outcome of combination antifungal therapy (CAT) for proven-probable IFD (PP-IFD) in children with hematological disorders after HSCT from January 2008 to June 2018.. Over the 10-year period, 95 PP-IFD were diagnosed in pediatric recipients, median age of 5.6 years. Twenty-seven patients received combinations of caspofungin and voriconazole, 28 patients received combinations of caspofungin and amphotericin B, and 40 patients received combinations of voriconazole and amphotericin B. The overall response rate of PP-IFD was 77.9%, while the 100-day overall survival rates were 66.8%. Univariate analysis showed that factors that significantly affected the response to combination treatments were type of combination (P = 0.02), the stem cell source (P = 0.04), the donor type (P = 0.03), HLA-match (P = 0.03), aGVHD (P = 0.02), period of treatment (P = 0.044), use of corticosteroids (0.036), CD4:CD8 ratio (P = 0.014), and CMV viremia (P = 0.033). In addition, multivariate analysis demonstrated that only the type of combination remained a significant factor (odds ratio = 0.335, 95% confidence interval: 0.071-0.812, P = 0.042). Forty-three children suffered from mild and reversible adverse reactions, no serious side effects during treatment.. A variety of factors can affect the outcome of CAT. Combination of caspofungin with voriconazole is a safe and helpful treatment option for HSCT recipients with IFD.

Topics: Adolescent; Amphotericin B; Antifungal Agents; Caspofungin; Child; Child, Preschool; Drug Therapy, Combination; Female; Hematologic Diseases; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Infant; Invasive Fungal Infections; Male; Mycoses; Retrospective Studies; Survival Analysis; Transplantation, Homologous; Treatment Outcome; Voriconazole

A 54-year-old Caucasian woman presented with corneal ulcer of the right eye of 4 weeks duration after scratching her cornea while removing her contact lens and artificial eye lashes. Her visual acuity was 20/32 (left eye) and finger counting (right eye). She had a 3x3 mm epithelial defect with underlying corneal oedema and hypopyon. Right eye cultures grew

Topics: Amphotericin B; Antifungal Agents; Corneal Edema; Corneal Ulcer; Eye Infections, Fungal; Female; Humans; Injections, Intraocular; Keratitis; Middle Aged; Mycoses; Paecilomyces; Recurrence; Surgical Flaps; Treatment Outcome; Visual Acuity

We report the first case of liver abscess due to Sterigmatomyces halophilus. Because this pathogen grows poorly in culture medium without added salts, it was identified by sequencing analysis targeting the rRNA gene internal transcribed spacer (ITS) region. This method could be useful for pathogens that cannot be cultured using standard methods.

Topics: Amphotericin B; Antifungal Agents; Antineoplastic Agents; Basidiomycota; Biopsy; Bone Marrow Transplantation; Cefozopran; Cephalosporins; Chemotherapy-Induced Febrile Neutropenia; Child; Hematopoietic Stem Cell Transplantation; Humans; Liver; Liver Abscess; Male; Micafungin; Mycoses; Neoplasm Recurrence, Local; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Treatment Outcome

Topics: Amphotericin B; Antifungal Agents; Antitubercular Agents; Conidiobolus; Face; Female; Humans; Itraconazole; Middle Aged; Mycoses

Invasive fungal infections are a major cause of mortality among solid organ transplant recipients. Scopulariopsis species and their teleomorph Microascus are molds found in soil and decaying organic matter. We report here the case of a woman who underwent bilateral lung transplantation for severe emphysema. On day 25 after transplantation, endobronchial green-black lesions were detected during routine endoscopy. Endobronchial swabs, biopsies, and bronchoalveolar lavage samples were positive for Microascus cirrosus. This fungal infection developed despite voriconazole given for previous persistent invasive aspergillosis. Treatment consisted of a combination of antifungal medication (voriconazole, terbinafine, amphotericin B, and caspofungin) and endoscopic resection of necrosed bronchial mucosa. A favorable clinical outcome was achieved after 7 weeks of treatment. Seven cases of Scopulariopsis/Microascus infection have been previously described in solid organ transplant recipients. Only two survived after treatment with an antifungal combination therapy including echinocandins, posaconazole, and terbinafine. In immunocompromised patients, infection by Microascus species is a rare but life-threatening event because of innate resistance to most common antifungal drugs. Our patient was successfully cured by combined therapy including intravenous voriconazole and caspofungin, oral terbinafine, and inhaled voriconazole and amphotericin B administered for 7 weeks in association with iterative endoscopic debridement to reduce fungal inoculum.

Topics: Amphotericin B; Antifungal Agents; Ascomycota; Bronchi; Bronchitis; Endoscopy; Female; Humans; Immunocompromised Host; Lung Transplantation; Middle Aged; Mycoses; Necrosis; Transplant Recipients; Treatment Outcome; Triazoles

Central nervous system (CNS) infections due to filamentous basidiomycetes are extremely rare. We encountered a case of epidural abscess due to Schizophyllum commune that extended from sinusitis. A 53-year-old Japanese man presented at our hospital with a headache. Computed tomography (CT) of the cranium and sinuses showed ethmoid and sphenoid sinusitis with no intracranial abnormalities. The patient was diagnosed with acute sinusitis and underwent antibiotic treatment. However, the symptoms deteriorated, and the patient came to our hospital again with consciousness disturbance. CT scan of the cranium and sinuses showed no improvement of sinusitis after antibiotic therapy and an epidural abscess emerged in the middle cranial fossa. Therefore, emergency craniotomy and endoscopic sinus fenestration were performed. Filamentous fungal elements were observed in both rhinorrhoea and epidural abscess. The symptoms improved after the operation and administration of liposomal amphotericin B. The clinical isolate was identified as S. commune by a molecular-based method. To our knowledge, this is the first report of epidural abscess due to this fungus. Although rare, clinicians should be aware that S. commune could be a causative agent of CNS infections.

Topics: Amphotericin B; Anti-Bacterial Agents; Epidural Abscess; Humans; Male; Middle Aged; Mycoses; Paranasal Sinuses; Schizophyllum; Sinusitis; Skull; Tomography Scanners, X-Ray Computed; Treatment Outcome

Liposomal amphotericin B (L-AMB) has the potential to cause two major adverse events, renal dysfunction and serum potassium abnormality; however, appropriate clinical management of these events remains unclear. We retrospectively analyzed data regarding 128 hematology patients who received L-AMB in our institute and examined the association between clinical characteristics and renal dysfunction or serum potassium abnormality. We found that the median weight-normalized dose of L-AMB was 2.69mg/kg and the median administration period was 16days. The overall occurrence rates of renal dysfunction and hypokalemia were 55.7% and 76.6%, respectively. Multivariate analysis revealed that pre-existing renal dysfunction (P=0.017) and concomitant use of nephrotoxic (P<0.0001) or antifungal drugs (P=0.012) were independent risk factors for renal dysfunction. A higher infusion volume did not mitigate the risk of renal dysfunction. Hypokalemia occurred significantly less often in men (P=0.028) and in patients who concomitantly used nephrotoxic drugs (P=0.013). Approximately 40% of the adverse events were improved at 30days after L-AMB termination and there was no significant association between these adverse events improvement and L-AMB dosage or infusion volume. Of note, hyperkalemia was observed in more patients who received allogeneic hematopoietic stem cell transplantation (P=0.0303) and concomitant treatment with nephrotoxic drugs (P=0.0281). These results suggest that imprudent reduction of L-AMB dose or redundant intravenous infusion may have minimal benefit for critical patients with suspected invasive fungal infection.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Female; Hematologic Diseases; Humans; Hyperkalemia; Hypokalemia; Kidney Diseases; Kidney Function Tests; Male; Middle Aged; Mycoses; Retrospective Studies; Risk Factors; Young Adult

Invasive fungal infection (IFI) is a severe complication of liver transplantation burdened by high mortality. Guidelines recommend targeted rather than universal antifungal prophylaxis based on tiers of risk.. We aimed to evaluate IFI incidence, risk factors, and outcome after implementation of a simplified two-tiered targeted prophylaxis regimen based on a single broad-spectrum antifungal drug (amphotericin B). Patients presenting 1 or more risk factors according to literature were administered prophylaxis. Prospectively collected data on all adult patients transplanted in Turin from January 2011 to December 2015 were reviewed.. Patients re-transplanted before postoperative day 7 were considered once, yielding a study cohort of 581 cases. Prophylaxis was administered to 299 (51.4%) patients; adherence to protocol was 94.1%. Sixteen patients developed 18 IFIs for an overall rate of 2.8%. All IFI cases were in targeted prophylaxis group; none of the non-prophylaxis group developed IFI. Most cases (81.3%) presented within 30 days after transplantation during prophylaxis; predominant pathogens were molds (94.4%). Only 1 case of candidemia was observed. One-year mortality in IFI patients was 33.3% vs 6.4% in patients without IFI (P = .001); IFI attributable mortality was 6.3%. At multivariate analysis, significant risk factors for IFI were renal replacement therapy (OR = 8.1) and re-operation (OR = 5.2).. The implementation of a simplified targeted prophylaxis regimen appeared to be safe and applicable and was associated with low IFI incidence and mortality. Association of IFI with re-operation and renal replacement therapy calls for further studies to identify optimal prophylaxis in this subset of patients.

Topics: Amphotericin B; Antifungal Agents; Female; Humans; Invasive Fungal Infections; Liver Transplantation; Male; Middle Aged; Mycoses; Risk Factors; Scedosporium

Continuous administration of amphotericin B deoxycholate over 24 hours (24 h-D-AmB) is better tolerated than rapid infusions. However, toxicity and outcome have not been assessed in a homogenous patient population with acute myeloid leukaemia (AML). We retrospectively analysed renal function and outcome in all adult patients with AML undergoing intensive chemotherapy between 2007 and 2012 at our institution. We compared a patient group with exposure to 24 h-D-AmB to a patient group without exposure to 24 h-D-AmB. One hundred and eighty-one consecutive patients were analysed, 133 (73.5%) received at least 1 dose of 24 h-D-AmB, and 48 (26.5%) did not. Reasons for 24 h-D-AmB initiation were invasive fungal disease (IFD) in 63.5% and empirical treatment for febrile neutropenia in 36.5% of the cases. Most patients with IFD received an oral triazole drug at hospital discharge. Baseline characteristics were well matched. Amphotericin B deoxycholate over 24 hours was given for a median 7 days (interquartile range 3-13). Peak creatinine concentration was higher in the 24 h-D-AmB-group (104.5 vs. 76 μmol/L, P < .001) but normalized within 1 month after therapy (65.5 vs. 65 μmol/L, P = .979). In neither of the 2 groups, end-stage renal disease occurred. There was no difference in 60-day survival (90% vs. 90%) and 2-year survival (58% vs. 58%). Invasive fungal disease partial response or better was observed in 68% of the patients. We conclude that antifungal therapy with continuously infused amphotericin B deoxycholate is safe in patients with AML. An antiinfective strategy based on 24 h-D-AmB in first line followed by an oral triazole compound represents an economically attractive treatment option.

Topics: Acute Disease; Adult; Aged; Amphotericin B; Antifungal Agents; Antineoplastic Agents; Deoxycholic Acid; Drug Combinations; Female; Humans; Infusion Pumps; Leukemia, Myeloid; Male; Middle Aged; Mycoses; Neutropenia; Retrospective Studies; Survival Analysis; Treatment Outcome

Antifungal polyene macrolide antibiotics Amphotericin B (AmB) and Nystatin (NYS) were conjugated through the ω-amino acid linkers with diwalled "molecular umbrellas" composed of spermidine-linked deoxycholic or cholic acids. The presence of "umbrella" substituents modulated biological properties of the antibiotics, especially their selective toxicity. Some of the AmB-umbrella conjugates demonstrated antifungal in vitro activity comparable to that of the mother antibiotic but diminished mammalian toxicity, especially the hemolytic activity. In contrast, antifungal in vitro activity of NYS-umbrella conjugates was strongly reduced and all these conjugates demonstrated poorer than NYS selective toxicity. No correlation between the aggregation state and hemolytic activity of the novel conjugates was found.

Topics: Amphotericin B; Antifungal Agents; Fungi; HEK293 Cells; Hemolysis; Hep G2 Cells; Humans; Mycoses; Nystatin; Polyenes

We reviewed the antifungal susceptibility testing results of local yeast isolates (2001-2015) to record the impact of recently updated interpretive criteria and epidemiological cut-off values (ECVs) for yeast species.. Susceptibility testing was performed using Sensititre. A total of 2345 isolates were tested; 62.0% were from sterile body sites or tissue. Application of new CLSI interpretative criteria for fluconazole increased the proportion of non-susceptible isolates of Candida parapsilosis, Candida tropicalis and Candida glabrata (P≤0.03 for all species). For voriconazole, the greatest increase was for C. tropicalis (P<0.0001). Application of new CLSI interpretive criteria for caspofungin increased the proportion of non-susceptible isolates for C. glabrata and Pichia kudriavzevii (P<0.0001 for both). The new amphotericin ECV (≤2mg/L) did not reveal any non-wild-type (non-WT) isolates in the five species covered. YeastOne itraconazole ECVs detected 2%, 5% and 6% non-WT isolates for P. kudriavzevii, C. tropicalis and C. glabrata, respectively. No itraconazole non-WT isolates of Clavispora lusitaniae were detected.. Whilst most results are similar to other large surveys of fungal susceptibility, the new CLSI interpretive criteria significantly altered the proportion of non-susceptible isolates to fluconazole, voriconazole and caspofungin for several Candida spp. Application of CLSI and YeastOne-derived ECVs revealed the presence of a low proportion of non-WT isolates for many species. The results serve as a baseline to monitor the susceptibility of Candida and other yeast species in New Zealand over time.

Topics: Amphotericin B; Antifungal Agents; Candida; Caspofungin; Drug Resistance, Fungal; Fluconazole; Humans; Microbial Sensitivity Tests; Mycoses; New Zealand; Pichia

Talaromyces marneffei (T. marneffei) can cause talaromycosis, a fatal systemic mycosis, in patients with AIDS. With the increasing number of talaromycosis cases in Guangdong, China, we aimed to investigate the susceptibility of 189 T. marneffei clinical strains to eight antifungal agents, including three echinocandins (anidulafungin, micafungin, and caspofungin), four azoles (posaconazole, itraconazole, voriconazole, and fluconazole), and amphotericin B, with determining minimal inhibition concentrations (MIC) by Sensititre YeastOne™ YO10 assay in the yeast phase. The MICs of anidulafungin, micafungin, caspofungin, posaconazole, itraconazole, voriconazole, fluconazole, and amphotericin B were 2 to > 8 μg/ml, >8 μg/ml, 2 to > 8 μg/ml, ≤ 0.008 to 0.06 μg/ml, ≤ 0.015 to 0.03 μg/ml, ≤ 0.008 to 0.06 μg/ml, 1 to 32 μg/ml, and ≤ 0.12 to 1 μg/ml, respectively. The MICs of all echinocandins were very high, while the MICs of posaconazole, itraconazole, and voriconazole, as well as amphotericin B were comparatively low. Notably, fluconazole was found to have a higher MIC than other azoles, and exhibited particularly weak activity against some isolates with MICs over 8 μg/ml. Our data in vitro support the use of amphotericin B, itraconazole, voriconazole, and posaconazole in management of talaromycosis and suggest potential resistance to fluconazole.

Topics: Amphotericin B; Anidulafungin; Antifungal Agents; Azoles; Echinocandins; HIV Infections; Humans; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Mycoses; Reagent Kits, Diagnostic; Talaromyces; Voriconazole

Liposomal amphotericin B (L-AmB) was developed to reduce nephrotoxicity and maximize the therapeutic utility of amphotericin B in the treatment of invasive fungal infections. However, there is little investigation into the safety of L-AmB in patients with several renal functions. Therefore, we retrospectively evaluated the clinical safety of L-AmB among patients with several renal functions.. We divided patients treated with L-AmB from April 2014 to September 2016 into 4 groups (estimated glomerular filtration rate (eGFR)≥60, 60 > eGFR≥30, eGFR<30 and hemodialysis). The main endpoint was the incidence of nephrotoxicity and the difference in the serum creatinine values at the end of L-AmB treatment as compared with baseline.. The incidence of nephrotoxicity was not significantly different among four groups (eGFR≥60; 27.0%, 60 > eGFR≥30; 30.8%, eGFR<30; 50.0%, hemodialysis; 40.0%, p = 0.56).Only one group of patients with eGFR≥60 admitted the significant increase of serum creatinine value after L-AmB treatment started (p < 0.01). Patients admitted 0.5 mg/dL or more of increase in serum creatinine values until 9 days from the L-AmB therapy started (eGFR≥60; 5.0 days [3.0-8.0 days], 60 > eGFR≥30; 5.0 days [4.0-9.0 days], eGFR<30; 4.5 days [3.0-5.0 days], hemodialysis; 5.5 days [4.0-7.0 days], p = 0.46).. Take previous clinical study results together, our data suggested that L-AmB is safer agent than amphotericin B for the treatment of fungal infections in patients with eGFR<60 and hemodialysis patients at the start of treatment. Also, especially, we should use L-AmB more carefully until 9 days from the treatment started.

Topics: Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Creatinine; Female; Glomerular Filtration Rate; Humans; Invasive Fungal Infections; Male; Middle Aged; Mycoses; Renal Dialysis; Renal Insufficiency; Retrospective Studies

The number of new cases of emerging fungal infections has increased considerably in recent years, mainly due to the large number of immunocompromised individuals. The objective of this study was to evaluate the susceptibility of emerging fungi to fluconazole, itraconazole and amphotericin B by disk diffusion method. In 2015, 82 emerging fungi were evaluated in IPB-LACEN/RS and 13 (15.8%) were resistant: 10/52 were from superficial mycoses and 3/30 from systemic mycoses. The data from the study point to the need for permanent vigilance regarding the careful evaluation in the prescription and clinical and laboratory follow-up of patients affected by fungal infections.

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; Drug Resistance, Fungal; Female; Fluconazole; Fungi; HIV Infections; Humans; Itraconazole; Male; Microbial Sensitivity Tests; Mycoses

Infected walled-off pancreatic necrosis (WON) is associated with increased morbidity and mortality. Systemic antibiotics are the main treatment, but are associated with adverse reactions and risk of superinfections. This study evaluates the efficacy of local instillation of antibiotics into WON.. We performed a retrospective cohort study of all consecutive patients with infected WON, who were treated with endoscopic transmural drainage and necrosectomy (ETDN) at a tertiary referral hospital between 2012 and 2016. A total of 91 patients were included. Patients often received concomitant intravenous and local antibiotics. Local antibiotics were added to the irrigation fluid depending on microbiological findings. A beneficial response was defined as the eradication of a microbe on subsequent culturing. Univariable and multivariable logistic regression analyses were used to evaluate antimicrobial efficacy.. At the first drainage 81 (86%) patients had infected and 10 sterile WON. Among patients with bacterial infections, neither local nor systemic antibiotics were associated with the eradication of microbes between first and second culture. Between the second and third culture, the use of local antibiotics was associated with the eradication of microbes (OR, 2.54; 95% CI, 1.25-5.18; p = 0.01), but not systemic antibiotics (OR, 0.75; 95% CI, 0.38-1.38; p = 0.33). Twelve patients had fungal infections treated with local amphotericin B between first and second culture. The fungus was eradicated in all 12 patients.. Local instillation of antibiotics may be a promising supplement to systemic administration.

Topics: Administration, Intravenous; Adult; Aged; Aged, 80 and over; Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Bacterial Infections; Cohort Studies; Drainage; Female; Humans; Male; Middle Aged; Mycoses; Pancreatitis, Acute Necrotizing; Retrospective Studies

Liposomal amphotericin B (L-AMB) is widely used for empirical or preemptive therapy and treatment of invasive fungal infections after cord blood transplantation (CBT). We retrospectively examined the efficacy and safety of low-dose L-AMB in 48 adult patients who underwent CBT between 2006 and 2017 in our institute. Within the entire cohort, 42 patients (88%) received L-AMB as empirical or preemptive therapy. The median daily dose of L-AMB and the median cumulative dose of L-AMB were 1.20 mg/kg/day (range, 0.62 to 2.60 mg/kg/day) and 30.6 mg/kg (range, 0.7 to 241.5 mg/kg), respectively. The median duration of L-AMB administration was 21.5 days (range, 1 to 313 days). A documented breakthrough fungal infection occurred in 1 patient during L-AMB treatment, and 43 patients (90%) survived for at least 7 days after the end of L-AMB treatment. Grade 3 or higher hypokalemia and hepatotoxicity were frequently observed during L-AMB treatment. However, no patient developed an increase in serum creatinine levels of grade 3 or higher. In univariate analyses using a logistic regression model, a duration of L-AMB treatment of more than 21 days and a cumulative dose of L-AMB of more than 30 mg/kg were significantly associated with nephrotoxicity and grade 3 hypokalemia. These data suggest that low-dose L-AMB may be safe and effective in adult patients undergoing CBT.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Cord Blood Stem Cell Transplantation; Female; Humans; Hypokalemia; Liposomes; Male; Middle Aged; Mycoses; Retrospective Studies; Young Adult

Pseudogymnoascus destructans is the fungal pathogen responsible for White-nose Syndrome (WNS), a disease that has killed millions of bats in North America over the last decade. A major obstacle to research on P. destructans has been the lack of a tractable infection model for monitoring virulence. Here, we establish a high-throughput model of infection using larvae of Galleria mellonella, an invertebrate used to study host-pathogen interactions for a wide range of microbial species. We demonstrate that P. destructans can kill G. mellonella larvae in an inoculum-dependent manner when infected larvae are housed at 13°C or 18°C. Larval killing is an active process, as heat-killed P. destructans spores caused significantly decreased levels of larval death compared to live spores. We also show that fungal spores that were germinated prior to inoculation were able to kill larvae 3-4 times faster than non-germinated spores. Lastly, we identified chemical inhibitors of P. destructans and used G. mellonella to evaluate these inhibitors for their ability to reduce virulence. We demonstrate that amphotericin B can effectively block larval killing by P. destructans and thereby establish that this infection model can be used to screen biocontrol agents against this fungal pathogen.

Topics: Amphotericin B; Animals; Antifungal Agents; Ascomycota; Chiroptera; Host-Pathogen Interactions; Hot Temperature; Insecta; Larva; Moths; Mycoses; North America; Spores, Fungal; Syndrome; Virulence

Invasive fungal wound infections (IFIs) were an unexpected complication associated with blast-related wounds during Operation Enduring Freedom. Between 2010 and 2012, IFI incidence rates were as high as 10-12% for patients injured during Operation Enduring Freedom and admitted to the intensive care unit at the Landstuhl Regional Medical Center. Independent risk factors for the development of IFIs include dismounted blast injuries, above knee amputations and massive (>20 units) packed red blood cell transfusions within 24 hours after injury. The Joint Trauma System developed a Clinical Practice Guideline on IFI prevention, identification and management. Aggressive and frequent surgical debridement remains the primary therapy accompanied by topical antifungal therapy (e.g., Dakins solution). Empiric systemic antifungal therapy with both liposomal amphotericin B and an intravenous broad-spectrum triazole (e.g., voriconazole or posaconazole) should be administered when there is strong suspicion of IFI based on the occurrence of recurrent wound necrosis following serial surgical debridements, since many cases involve multiple fungal species. Other recommendations include: (1) early tissue sampling for wound histopathology and fungal cultures, (2) early consultation with infectious disease specialists, and (3) coordination with surgical pathology and clinical microbiology.

Topics: Administration, Topical; Afghan Campaign 2001-; Amphotericin B; Antifungal Agents; beta-Cyclodextrins; Debridement; Excipients; Humans; Mycoses; Recurrence; Risk Factors; Tobramycin; Treatment Outcome; Triazoles; Vancomycin; Voriconazole; Wounds and Injuries

To compare the clinical and epidemiological features, treatments, and outcomes of patients with isolated right-sided and left-sided fungal endocarditis and to determine the risk factors for in-hospital mortality in patients with Candida sp endocarditis.. A retrospective review of all consecutive cases of fungal endocarditis from five hospitals was performed. Clinical features were compared between patients with isolated right-sided and left-sided endocarditis. In the subgroup of fungal endocarditis due to Candida species, binary logistic regression analysis was performed to determine variables related to in-hospital mortality.. Seventy-eight patients with fungal endocarditis were studied. Their median age was 50 years; 55% were male and 19 patients (24%) had isolated right-sided endocarditis. Overall, cardiac surgery was performed in 46 patients (59%), and in-hospital mortality was 54%. Compared to patients with left-side fungal endocarditis, patients with isolated right-sided endocarditis had lower mortality (32% vs. 61%; p=0.025) and were less often submitted to cardiac surgery (37% vs. 66%; p=0.024). The most frequent etiology was Candida spp (85%). In this subgroup, acute heart failure (odds ratio 5.0; p=0.027) and exclusive medical treatment (odds ratio 11.1; p=0.004) were independent predictors of in-hospital death, whereas isolated right-sided endocarditis was related to a lower risk of mortality (odds ratio 0.13; p=0.023).. Patients with isolated right-sided fungal endocarditis have particular clinical and epidemiological features. They were submitted to cardiac surgery less often and had better survival than patients with left-sided fungal endocarditis. Isolated right-sided endocarditis was also a marker of a less harmful illness in the subgroup of Candida sp endocarditis.

Topics: Adult; Amphotericin B; Antifungal Agents; Candida; Echinocandins; Endocarditis; Female; Fluconazole; Follow-Up Studies; Heart Failure; Hospital Mortality; Humans; Male; Middle Aged; Mycoses; Retrospective Studies; Risk Factors; Treatment Outcome

In recent years, there has been a significant increase in the incidence of fungal infections attributed to Candida species worldwide, with a major shift toward non-albicans Candida (NAC). In this study, we have described the distribution of Candida species among different hospital departments and calculated the antifungal consumption in our facility. We also correlated the consumption of certain antifungals and the prevalence of specific Candida species.. This was a retrospective review of all the Candida isolates recovered from the computerised microbiology laboratory database of Makassed General Hospital, a tertiary care centre in Beirut, Lebanon, between January 2010 and December 2015. Data on antifungal consumption between January 2008 and December 2015 were extracted from the hospital pharmacy electronic database. We used Spearman's coefficient to find a correlation between Candida species distribution and antifungal consumption.. Between 2008 and 2015, we observed that the highest antifungal consumption was in the haematology/oncology department (days of therapy/1000 patient days = 348.12 ± 85.41), and the lowest was in the obstetrics/gynaecology department (1.36 ± 0.47). In general, the difference in antifungal consumption among various departments was statistically significant (P < 0.0001). Overall, azoles were the most common first-line antifungals in our hospital. Echinocandins and amphotericin B were mostly prescribed in the haematology/oncology department. As for Candida species distribution, a total of 1377 non-duplicate isolates were identified between 2010 and 2015. A non-homologous distribution of albicans vs. non-albicans was noted among the different departments (P = 0.02). The most commonly isolated NAC was Candida glabrata, representing 14% of total Candida species and 59% of NAC. Candida famata (9% of NAC), Candida parapsilosis (3.6% of NAC) and Candida krusei (3% of NAC) were recovered unequally from the different departments. The total antifungal consumption correlated positively with the emergence of NAC. The use of azoles correlated positively with Candida glabrata, while amphotericin B formulations correlated negatively with it. None of these correlations reached statistical significance.. Different Candida species were unequally distributed among different hospital departments, and this correlated with consumption of antifungals in respective departments, highlighting the need for antifungal stewardship.

Topics: Academic Medical Centers; Adult; Amphotericin B; Antifungal Agents; Candida; Candida albicans; Candida glabrata; Candidiasis; Child; Drug Resistance, Fungal; Echinocandins; Female; Hospital Departments; Humans; Incidence; Lebanon; Male; Microbial Sensitivity Tests; Mycoses; Retrospective Studies

Conidiobolomycosis is a rare fungal infection that affects adults in tropical regions. We report a 42-year-old male patient who was referred to the Sulaiman Al Habib Hospital, Dubai, United Arab Emirates (UAE), in 2013 with excessive nasal bleeding and a suspected nasal tumour. He reported having briefly visited central India nine months previously. Computed tomography and magnetic resonance imaging showed a highly vascularised mass in the nasal cavity. However, after surgical excision, initial treatment with amphotericin B deoxycholate was unsuccessful and the disease progressed, leading to external and internal nasal deformation and necessitating further excision and facial reconstruction. Histopathological analysis of the second biopsy revealed Splendore-Hoeppli changes consistent with a fungal infection. Microbiological findings subsequently confirmed

Topics: Adult; Amphotericin B; Antifungal Agents; Conidiobolus; Humans; Male; Mycoses; Nasal Cavity; Neoplasms; Tomography, X-Ray Computed; United Arab Emirates; Zygomycosis

The emergence of multidrug-resistant bacterial and fungal strains poses a threat to human health that requires the design and synthesis of new classes of antimicrobial agents. We evaluated bis(N-amidinohydrazones) and N-(amidino)-N'-aryl-bishydrazones for their antibacterial and antifungal activities against panels of Gram-positive/Gram-negative bacteria as well as fungi. We investigated their potential to develop resistance against both bacteria and fungi by a multi-step resistance-selection method, explored their potential to induce the production of reactive oxygen species, and assessed their toxicity. In summary, we found that these compounds exhibited broad-spectrum antibacterial and antifungal activities against most of the tested strains with minimum inhibitory concentration (MIC) values ranging from <0.5 to >500μM against bacteria and 1.0 to >31.3μg/mL against fungi; and in most cases, they exhibited either superior or similar antimicrobial activity compared to those of the standard drugs used in the clinic. We also observed minimal emergence of drug resistance to these newly synthesized compounds by bacteria and fungi even after 15 passages, and we found weak to moderate inhibition of the human Ether-à-go-go-related gene (hERG) channel with acceptable IC

Topics: Anti-Bacterial Agents; Antifungal Agents; Bacteria; Bacterial Infections; Candida albicans; Candidiasis; Cell Line; Drug Discovery; Drug Resistance, Multiple; Fungi; Humans; Hydrazones; Microbial Sensitivity Tests; Mycoses

Fluconazole (FLC) is the drug of choice when it comes to treat fungal infections such as invasive candidiasis in humans. However, the widespread use of FLC has resulted in the development of resistance to this drug in various fungal strains and, simultaneously has occasioned the need for new antifungal agents. Herein, we report the synthesis of 27 new FLC derivatives along with their antifungal activity against a panel of 13 clinically relevant fungal strains. We also explore their toxicity against mammalian cells, their hemolytic activity, as well as their mechanism of action. Overall, many of our FLC derivatives exhibited broad-spectrum antifungal activity and all compounds displayed an MIC value of <0.03 μg/mL against at least one of the fungal strains tested. We also found them to be less hemolytic and less cytotoxic to mammalian cells than the FDA approved antifungal agent amphotericin B. Finally, we demonstrated with our best derivative that the mechanism of action of our compounds is the inhibition of the sterol 14α-demethylase enzyme involved in ergosterol biosynthesis.

Topics: Alkylation; Animals; Antifungal Agents; Azoles; Candida albicans; Candidiasis; Cell Line; Ergosterol; Fungi; Hemolysis; Humans; Mice; Microbial Sensitivity Tests; Mycoses

To assess compliance with international guidelines for costly antifungal prescriptions and to compare these results with a first study performed in 2007.. Retrospective study including all costly antifungal prescriptions made in surgical and medical intensive care units and in a hepatobiliary, pancreatic, and digestive surgery unit. Prescriptions were assessed in terms of indication, dosage, and antifungal de-escalation.. Seventy-four treatments were analyzed. Treatments were prescribed for prophylactic (1%), empirical (22%), pre-emptive (16%), or targeted therapy (61%). Caspofungin accounted for 68% of prescriptions, followed by voriconazole (20%) and liposomal amphotericin B (12%). Indication was appropriate in 91%, debatable in 1%, and inappropriate in 8%. Dosage was appropriate in 69%, debatable in 8%, and inappropriate in 23%. Prescriptions were inappropriate for the following reasons: lack of dosage adjustment in light of the hepatic function (10 cases), underdosage or excessive dosage by>25% of the recommended dose in seven cases. De-escalation to fluconazole was implemented in 40% of patients presenting with a fluconazole-susceptible candidiasis.. The overall incidence of appropriate use was higher in 2012 compared with 2007 (62% and 37% respectively, P=0.004). Nevertheless, costly antifungal prescriptions need to be optimized in particular for empirical therapy, dosage adjustment, and potential de-escalation to fluconazole.

Topics: Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Caspofungin; Echinocandins; Female; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Lipopeptides; Male; Middle Aged; Multiple Organ Failure; Mycoses; Organ Transplantation; Retrospective Studies; Survival Rate; Treatment Outcome; Voriconazole; Young Adult

Intravenous radiographic contrast medium and amphotericin B are commonly required in the care of patients with fungal infections. Both interventions have proposed nephrotoxicity through similar mechanisms. We systematically examined patients who received coadministration of liposomal amphotericin B (AmBisome; GE Healthcare) and intravenous contrast medium within a 24-h period and compared the results for those patients with the results for patients who underwent non-contrast medium studies. We found 114 cases and 85 controls during our study period. Overall, no increased risk of renal injury was seen with coadministration of these 2 agents. Adjustment for age, baseline kidney function, and other clinical factors through propensity score adjustment did not change this result. Our observations suggest that, when clinically indicated, coadministration of contrast medium and liposomal amphotericin B does not present excess risk compared with that from the administration of liposomal amphotericin B alone.

Topics: Acute Kidney Injury; Adult; Amphotericin B; Antifungal Agents; Contrast Media; Drug Therapy, Combination; Female; Humans; Kidney; Male; Metabolic Clearance Rate; Middle Aged; Mycoses; Tomography, X-Ray Computed

In this study, we present the in vitro antifungal activity of silver nanoparticles (AgNPs) synthesized from acidophilic actinobacterium Pilimelia columellifera subsp. pallida SL19 strain, alone and in combination with antibiotics viz., amphotericin B, fluconazole, and ketoconazole against pathogenic fungi, namely Candida albicans, Malassezia furfur, and Trichophyton erinacei. The minimum inhibitory concentration (MIC) and minimum biocidal concentration (MBC) of AgNPs against test fungi were evaluated. The fractional inhibitory concentration (FIC) index was determined to estimate antifungal activity of AgNPs combined with antibiotics. Antifungal activity of AgNPs varied among the tested fungal strains. M. furfur was found to be most sensitive to biogenic silver nanoparticles, followed by C. albicans and T. erinacei. The lowest MIC of AgNPs was noticed against M. furfur (16 μg ml

Topics: 3T3 Cells; Actinobacteria; Amphotericin B; Animals; Anti-Bacterial Agents; Antifungal Agents; Candida albicans; Fungi; HeLa Cells; Humans; Ketoconazole; Metal Nanoparticles; Mice; Microbial Sensitivity Tests; Mycoses; Silver

Topics: Amphotericin B; Anniversaries and Special Events; Antifungal Agents; Density Functional Theory; Humans; Leishmaniasis, Visceral; Mycoses

To study the clinical efficacy of amphotericin B and voriconazole in the treatment of invasive fungal infection in children with acute lymphoblastic leukemia(ALL) during chemotherapy.. The clinical data of 214 patients with acute lymphoblastic leukemia admitted in our hospital from March 2014 to February 2017 was retrospectively analyzed. Among them 65 patients had invasive fungal infection (IFI) during the chemotherapy period, out of them 35 patients treated with voriconazole were enrolled in group A; anather 30 patients treated with amphotericin B were enrolled in group B. The clinical factors that affected the incidence of IFI was statistically analyzed. And the efficacy and adverse reactions in children with ALL were compared after treatment for 8 weeks.. The incidence of IFI in children with ALL in this study was 30.37%, and was related with the duration of hospitalization and the level of neutrophil deficiency (P<0.05). The total effective rates of group A and group B were 72.28% and 43.33%, respectively, their difference was statistically significant between 2 group (P<0.05). The incidence of renal function impairment, digestive dysfunction and neurotoxicity were 8.57%, 5.71% and 5.71% in children with ALL treated with voriconazole respectively, which were lower than those in children treated with amphotericin B (P<0.05). The score index of Physical health, energy state, emotion control and overall health in group A were significantly higher than those in B group, and the difference was statistically significant (P<0.05).. The occurrence of IFI in children with ALL relats with the time of hospitalization and the level of neutrophils. The clinical effect of voriconazole is better, and the incidence of adverse reactions can be reduced, suggesting important clinical significance.

Topics: Amphotericin B; Antifungal Agents; Antineoplastic Agents; Child; Humans; Invasive Fungal Infections; Mycoses; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Voriconazole

Several polyene macrolides are potent antifungal agents that have severe side effects. Increased glycosylation of these compounds can improve water solubility and reduce toxicity. Three extending glycosyltransferases are known to add hexoses to the mycosaminyl sugar residues of polyenes. The Actinoplanes caeruleus PegA enzyme catalyses attachment of a D-mannosyl residue in a β-1,4 linkage to the mycosamine of the aromatic heptaene 67-121A to form 67-121C. NppY from Pseudonocardia autotrophica adds an N-acetyl-D-glucosamine to the mycosamine of 10-deoxynystatin. NypY from Pseudonocardia sp. P1 adds an extra hexose to a nystatin, but the identity of the sugar is unknown. Here, we express the nypY gene in Streptomyces nodosus amphL and show that NypY modifies 8-deoxyamphotericins more efficiently than C-8 hydroxylated forms. The modified heptaene was purified and shown to be mannosyl-8-deoxyamphotericin B. This had the same antifungal activity as amphotericin B but was slightly less haemolytic. Chemical modification of this new disaccharide polyene could give better antifungal antibiotics.

Topics: Acetylglucosamine; Actinobacteria; Amphotericin B; Antifungal Agents; Candida albicans; Glycosyltransferases; Hexosamines; Leishmania; Leishmaniasis; Macrolides; Mycoses; Nystatin; Streptomyces

We describe two serious Trametes polyzona pulmonary infections, which occurred in Réunion Island, in critically ill patients. The identification was performed using sequencing of the internal transcribed spacer region of ribosomal DNA and D1/D2 region of 28S rDNA. In one case, the significance of T. polyzona in the pathological process was certain, proven by histopathological evidence of fungal lung infection. T. polyzona, an emerging filamentous basidiomycete, prevalent in tropical areas, has not been described so far in human infections.

Topics: Amphotericin B; Antifungal Agents; Child, Preschool; DNA, Fungal; Female; Humans; Lung Diseases, Fungal; Male; Microbial Sensitivity Tests; Middle Aged; Mycoses; Reunion; RNA, Ribosomal, 28S; Sequence Analysis, DNA; Trametes

To evaluate the efficacy and safety of low-dose amphotericin B (AmB) in different antifungal strategies for treatment of invasive fungal disease(IFD) in patients with hematologic malignancies. Metheds: The clinical dada of the patients were collected and analyzed retrospectively and the levels of creatinine (Cr), urea nitrogen (BUN) and potassium (K. Among 97 cases, 2 cases were diagnosed as invasive fungal disease (IFD), 11 cases were diagnosed as clinical probable IFD, 15 cases were diagnosed as possible IFD, 69 cases were undefined IFD. The response rate of all patients treated with low-dose AmB was 69.4%, the response rate for targed therapy was 72.7%, the response rate for diagnosis-driven therapy was 63.6%, the response rate of empirical therapy was 75%, the efficacy of the combination with other antibiotics was 50%, 66.7% and 75%. According to all the patients received AmB, only 7 cases was detected with higher level of Cr (7.2) than normal and this level come back to normal with in 7 days after drug withdrew. Although the Cr level in serum after 1 day of drug withdrew was higher than that before administration of drug(64.86±3.00 vs 58.76±1.67 µmol/L) and was with statistical difference(P<0.05), but did not show significant difference in comparison with the level after drug withdrew 7 days (58.43±1.68 µmol/L,P>0.05).. AmB injection is an effective and safe method in empirical therapy and diagnosis-driven antifungal therapy for neutropenic, febrile patients with hematological malignancies.

Topics: Amphotericin B; Antifungal Agents; Creatinine; Hematologic Neoplasms; Humans; Mycoses; Retrospective Studies

Despite the development of various guidelines, the approach to antifungal treatment in stem cell transplantation centers differs according to country or even between centers. This led to the development of another survey that aims to understand the antifungal treatment policies of Turkish stem cell transplantation centers. Although there has been an increasing trend towards the use of diagnostic-based treatments in Turkey in the last few years, empirical treatment is still the main approach. The practices of the stem cell transplantation centers reflect the general trends and controversies in this area, while there is a considerable use of antifungal combination therapy.. Çeşitli kılavuzlara rağmen, antifungal hastalıkların tedavisine yaklaşım kök hücre nakil merkezlerinde ülkeden ülkeye, hatta aynı ülke içerisinde farklı merkezlerde farklılık göstermektedir. Bu farklılıkları belirlemek amacı ile ilk defa 2010 yılında Türkiye’deki kök hücre nakli merkezlerinde profilaksi yaklaşımlarını anlamak üzere bir anket düzenlemiştik. Bu anket, Türkiye’deki merkezlerde tedavi yaklaşımlarını anlamamıza yol açacak yeni bir çalışma yapmamızı sağladı. Genel olarak tanı-güdümlü yaklaşım giderek artma eğilimi gösterse de, ampirik yaklaşım hala ilk seçenektir. Kök hücre nakli merkezlerindeki yaklaşımlar genel eğilimlere ve tartışmalar uygun gözükse de, kombine antifungal kullanımının yaygın olduğu görülmektedir.

Topics: Adult; Allografts; Amphotericin B; Antifungal Agents; Child; Cross Infection; Diagnostic Tests, Routine; Drug Substitution; Drug Therapy, Combination; Drug Utilization; Febrile Neutropenia; Health Care Surveys; Health Facilities; Humans; Infection Control; Mycoses; Stem Cell Transplantation; Transplantation, Autologous; Turkey; Voriconazole

Dematiaceous fungi have melanin-like pigment in the cell wall and usually cause a variety of dermal infections in humans. Infections of the central nervous system(cerebral phaeohyphomycosis)are rare but serious, since they commonly occur in immunocompromized patients. A 76-year-old man was admitted with mild motor aphasia and underwent total excision of a mass in the left frontal lobe. With the postoperative diagnosis of brain abscess due to infection with dematiaceous fungi (C. bantiana) associated with hypogammaglobulinemia following gastrectomy, intravenous antifungal drugs including amphotericin B and fluconazole were administered. Regrowth of the abscess with intraventricular rupture was noted at about the 88th day after the initial surgery, and the patient underwent neuroendoscopic aspiration of the pus and placement of a ventricular drain. Following intraventricular administration of miconazole through ventricular drainage or an Ommaya reservoir, neuroradiological findings improved, but general and neurological conditions worsened. Further treatment was discontinued and the patient died 9 months after onset. The poor outcome in this patient is attributed to 1)intractability of dematiaceous fungi, 2)development of ventriculitis and the need for intraventricular administration of antifungal drugs, and 3)untreatable hypogammaglobulinemia following gastrectomy.

Topics: Agammaglobulinemia; Aged; Amphotericin B; Antifungal Agents; Ascomycota; Brain Abscess; Drug Combinations; Fluconazole; Gastrectomy; Humans; Male; Mycoses

High antifungal activity is reported, in comparison with commercially available products, of a novel hybrid system based on silver nanoparticles synthesized using a popular antifungal macrocyclic polyene amphotericin B (AmB) acting both as a reducing and stabilizing/capping agent. The synthesis reaction proceeds in an alkaline environment which prevents aggregation of AmB itself and promotes nanoparticle formation. The innovative approach produces monodisperse (PDI=0.05), AmB-coated silver nanoparticles (AmB-AgNPs) with the diameter ~7nm. The products were characterized using imaging (electron microscopy) and spectroscopic (UV-vis and infrared absorption, dynamic light scattering and Raman scattering) methods. The nanoparticles were tested against Candida albicans, Aspergillus niger and Fusarium culmorum species. For cytotoxicity studies CCD-841CoTr and THP-1 cell lines were used. Particularly high antifungal activity of AmB-AgNPs is interpreted as the result of synergy between the antifungal activity of amphotericin B and silver antimicrobial properties (Ag(+) ions release).. Amphotericin B (AmB) is a common agent used for the treatment against severe fungal infections. In this article, the authors described a new approach in using a combination of AmB and silver nanoparticles, in which the silver nanoparticles were synthesized and stabilized by AmB. Experimental data confirmed synergistic antifungal effects between amphotericin B and silver. This novel synthesis process could potentially be important in future drug development and fabrication.

Topics: Amphotericin B; Antifungal Agents; Aspergillus niger; Candida albicans; Drug Delivery Systems; Fusarium; Humans; Mycoses; Nanoparticles; Silver

Scopulariopsisis an emerging opportunistic fungus characterized by its high resistance to antifungal therapies. We have developed a murine model of disseminated infection in immunosuppressed animals by intravenous inoculation ofScopulariopsis brevicaulisandScopulariopsis brumptii, the most clinically relevant species, in order to evaluate their virulence and their responses to conventional antifungal treatments. Survival and tissue burden studies showed thatS. brumptiiwas more virulent thanS. brevicaulis The three drugs tested, liposomal amphotericin B, posaconazole, and voriconazole, prolonged the survival of mice infected withS. brumptii, but none showed efficacy againstS. brevicaulis The different therapies were only able to modestly reduce the fungal burden of infected tissue; however, in general, despite the high serum levels reached, they showed poor efficacy in the treatment of the infection. Unfortunately, the most effective therapy forScopulariopsisinfections remains unresolved.

Topics: Amphotericin B; Animals; Antifungal Agents; Cyclophosphamide; Disease Models, Animal; Drug Resistance, Fungal; Humans; Immunocompromised Host; Male; Mice; Mycoses; Neutropenia; Scopulariopsis; Species Specificity; Survival Analysis; Triazoles; Virulence; Voriconazole

Among filamentous fungal pathogens, Aspergillus spp. and zygomycetes account for highest rates of morbidity and mortality among immunocompromised patients. Recently developed antifungal drugs offer the potential to improve management and therapeutic outcomes of fungal infections. The aim of this study was to analyse the in vitro activities of voriconazole, itraconazole, amphotericin B and caspofungin against clinical isolates of Aspergillus spp. and Rhizopus oryzae.. The in vitro antifungal susceptibility of 54 isolates belonging to different clinical isolates of Aspergillus spp. and R. oryzae was tested for four antifungal agents using a microdilution reference method (CLSI, M38-A2). All isolates were identified by typical colony and microscopic characteristics, and also characterized by molecular methods.. Caspofungin (MEC range: 0.008-0.25 and MEC50: 0.0023μg/mL) was the most active drug in vitro against Aspergillus spp., followed by voriconazole (MIC range: 0.031-8 and MIC50: 0.5μg/mL), itraconazole (MIC range: 0.031-16 and MIC50: 0.25μg/mL), and amphotericin B (MIC range: 0.125-4 and MIC50: 0.5μg/mL), in order of decreasing activity. The caspofungin, voriconazole, and itraconazole demonstrated poor in vitro activity against R. oryzae isolates evaluated, followed by amphotericin B.. This study demonstrates that caspofungin had good antifungal activity and azole agents had better activity than amphotericin B against Aspergillus species. Although, azole drugs are considered ineffective against R. oryzae. This result is just from a small scale in vitro susceptibility study and we did not take other factors into consideration.

Topics: Amphotericin B; Antifungal Agents; Aspergillus; Base Sequence; Caspofungin; DNA, Fungal; Echinocandins; Itraconazole; Lipopeptides; Microbial Sensitivity Tests; Mycoses; Rhizopus; Tubulin; Voriconazole

Topics: Amphotericin B; Antifungal Agents; Evidence-Based Medicine; Fluconazole; Humans; Immunocompromised Host; Immunosuppressive Agents; Mycoses; Risk Factors

Investigations of both virulence factors and antifungal susceptibility profiles are crucial for understanding the pathogenesis and prognosis of ophthalmic mycoses. In this study, we investigated the in vitro antifungal susceptibility of amphotericin B (AMB), voriconazole (VRC), and natamycin (NAT) against a set of 50 fungal isolates obtained from patients with ocular mycoses using the Clinical and Laboratory Standards Institute broth microdilution method. In addition, putative virulence factor, such as secretory phospholipases and proteinases, and biofilm formation activity were analyzed. The geometric means (GMs) of the minimum inhibitory concentrations (MICs) of the antifungals across all isolates were the following (in increasing order): VRC (0.70 μg/mL), AMB (0.81 μg/mL), and NAT (1.05 μg/mL). The highest activity against 14 Aspergillus strains was exhibited by VRC (GM MIC: 0.10 μg/mL), followed by AMB and NAT (GM MICs: 0.21 and 0.27 μg/mL), respectively. However, for 12 Fusarium spp., the GM MIC of VRC (2.66) was higher than those of NAT and AMB (GM MICs 1.3 and 0.8 μg/mL, respectively). Proteinase and phospholipase activity were observed in 30 % and 42 % of the isolates, respectively, whereas only 8 % of the isolates were able to produce biofilms. Phospholipase activity was observed in all Fusarium isolates, but not in any of the Aspergillus isolates. In contrast, biofilm-forming capability was detected in 25 % of the Fusarium isolates, but none of the Aspergillus isolates. The differences in the MICs of AMB, VRC, and NAT, biofilm-forming ability and proteinase and phospholipase activities among the isolates were not significant (p > 0.05). Overall, our study suggests no significant correlation between the antifungal susceptibility profiles and virulence attributes of ocular fungal isolates.

Topics: Amphotericin B; Antifungal Agents; Biofilms; Drug Resistance, Fungal; Eye Diseases; Fungi; Humans; Microbial Sensitivity Tests; Mycoses; Natamycin; Opportunistic Infections; Peptide Hydrolases; Phospholipases; Virulence; Virulence Factors; Voriconazole

Different inocula of Trichoderma longibrachiatum were tested in a murine model, and only the highest one (1 × 10(7) CFU/animal) killed all of the mice at day 15 postinfection, with spleen and liver the most affected organs. The efficacies of amphotericin B deoxycholate, liposomal amphotericin B, voriconazole, and micafungin were evaluated in the same model, with very poor results. Our study demonstrated the low virulence but high resistance to antifungal compounds of this fungus.

Topics: Amphotericin B; Animals; Antifungal Agents; Deoxycholic Acid; Drug Combinations; Echinocandins; Lipopeptides; Liver; Male; Micafungin; Mice; Mycoses; Spleen; Trichoderma; Virulence

Cystic fibrosis (CF) is the most common monogenetic autosomal recessive disease in the human population. This systemic disease is characterized by changes in multiple organs, mainly in the lung tissue and digestive tract. More than 59% of CF patients become sensitized to fungal spores, mostly Aspergillus fumigatus. 5-15% of CF patients develop allergic bronchopulmonary aspergillosis. The aim of the study was to analyse the occurrence of yeast and filamentous fungi of the respiratory infections in CF patients and evaluation of drug resistance.. Between 2006 and 2014, mycological evaluation of 42 patients hospitalized at the National Institute of Tuberculosis and Lung Diseases was carried out.. 217 specimens from pulmonary tract were collected from 42 patients with cystic fibrosis. 205 (68%) strains of yeast and 96 (32%) filamentous fungi strains were cultured. The most common mould strain was A. fumigatus - 22,2% (67 species). All isolates of filamentous fungi were in vitro 100% susceptible to itraconazole, voriconazole, posaconazole and amphotericin B.. A. fumigatus and C. albicans were the most common etiological agents of fungal respiratory pathogens associated with CF patients. A. fumigatus strains were in vitro 100% susceptible to azole and amphotericin B. Two strains of C. albicans and one strain of C. tropicalis were non-susceptible to azole (fluconazole, itraconazole and voriconazole). Scedosporium apiospermum was resistant to amphotericin B (MIC > 32 mg/l) and susceptible to voriconazole (MIC 0.094 mg/l).

Topics: Amphotericin B; Antifungal Agents; Aspergillosis, Allergic Bronchopulmonary; Aspergillus fumigatus; Candida albicans; Candida tropicalis; Cystic Fibrosis; Drug Resistance, Multiple, Fungal; Fungi; Humans; Itraconazole; Microbial Sensitivity Tests; Mycoses; Scedosporium; Triazoles; Voriconazole; Yeasts

Topics: Amphotericin B; Antifungal Agents; Granulomatous Disease, Chronic; Humans; Lung Diseases; Mycoses

New strategies are required to improve the efficacy of drugs and to treat the emerging microbial resistance. An effective strategy is to combine drugs with metal nanoparticles for the control of microbial infections and resistance. Keeping in view this fact, we developed a facile and eco-friendly protocol for the synthesis of amphotericin B-conjugated silver nanoparticles and their assessment as an antifungal agent. Phytochemicals from the aqueous extract of Maytenus royleanus and amphotericin B were used as capping agents to prepare two types of silver nanoparticles i.e. (i) biogenic silver nanoparticles (b-AgNPs) and (ii) amphotericin B-conjugated biogenic silver nanoparticles (Amp-bAgNPs). UV-Vis spectroscopy was used to detect the characteristic surface Plasmon resonance peaks (SPR) for the prepared nanoparticles (424-433 nm). High-resolution transmission electron microscopy (HRTEM) study revealed the formation of well dispersed and spherical silver nanoparticles and Amp-bAgNPs with an average particles size of 10 and 15 nm. EDX and FTIR studies confirmed the elemental composition and surface adhered biomolecules in the prepared nanoparticles respectively. Biogenic silver nanoparticles revealed low to moderate antifungal activity (4-8 mm ± 0.2), however, the amphotericin B conjugated silver nanoparticles exhibited significant activity against Candida albicans (16 mm ± 1.4) and Candida tropicalis (18 mm ± 1.5). In conclusion, the enhanced antifungal activity of the Amp-AgNPs conjugate system is due to the synergy between the antifungal activity of amphotericin B and the antimicrobial property of silver. The findings of this study suggest that the conjugated nanoparticles could be used as efficient antifungal agents and drug delivery vehicles. Furthermore, this is the first report describing the synthesis of silver nanoparticles using the aqueous extract of Maytenus royleanus and the conjugation of amphotericin B, an antifungal drug, to the phytosynthesized silver nanoparticles.

Topics: Amphotericin B; Antifungal Agents; Candida albicans; Candida tropicalis; Drug Synergism; Maytenus; Microbial Sensitivity Tests; Microscopy, Electron, Transmission; Mycoses; Nanoparticles; Plant Extracts; Silver; Spectrometry, X-Ray Emission; Spectrophotometry; Spectroscopy, Fourier Transform Infrared; Surface Plasmon Resonance

Saprochaete capitata (formerly known as Geotrichum capitatum and Blastoschizomyces capitatus) is a rare invasive fungal agent that may lead to mortal clinical course in patients with hematological malignancies. This agent can be colonized in skin, lungs and intestines, and it can cause major opportunistic infections. Invasive systemic infections due to S.capitata have been reported in immunosuppressed patients. In this report, two patients with invasive S.capitata infections detected during the course of persistent neutropenic fever in acute leukemia, were presented. In both cases empirical caspofungin was added to the treatment, as no response was obtained by board-spectrum antibacterial therapy in neutropenic fever. In the first patient, there were no significant findings except the chronic inflammation observed in the biopsies which was performed for the symptoms of lymphadenitis, myositis, and hepatosplenic candidiasis. While persistent fever was on going, S.capitata was isolated from the blood and catheter cultures. There was no response after catheter removing and the introduction of amphotericin B and voriconazole therapy, therefore allogeneic stem cell transplantation plan for the second time for bone marrow aplasia was taken an earlier time. However, the patient died due to progressive pericardial and pleural effusion and multiorgan failure, although an afebrile process after stem cell transplantation could be obtained. Similarly the second patient had persistent fever despite empirical caspofungin treatment. The additional symptoms of diarrhea, abdominal pain and subileus have indicated an intraabdominal infection. During the follow up, S.capitata was isolated from the blood and catheter cultures. Catheter was removed and amphotericin B was initiated. No response was obtained, and voriconazole was added to treatment. Despite of an afebrile and culture-negative period, the patient died as a result of Acinetobacter sepsis and multiorgan failure. Minimal inhibitory concentration values for both of the Saprochete strains were found as 0.25 µg/ml for amfoterisin B, 1 µg/ml for flukonazol, 0.125 µg/ml for vorikonazol and 0.25 µg/ml for itrakonazol. Virulence model was created by injecting the isolates to the Galleria mellonella larvae, and the life cycle of the larvae were determined. The observation revealed that the infected larvae began to die on the second day and there was no live larvae remained on the eleventh day. In conclusion, S.capitata sho

Topics: Adult; Amphotericin B; Animals; Antifungal Agents; Caspofungin; Catheter-Related Infections; Echinocandins; Fatal Outcome; Female; Fungemia; Humans; Leukemia; Lipopeptides; Moths; Mycoses; Opportunistic Infections; Saccharomycetales; Voriconazole; Young Adult

Cationic amphiphiles derived from aminoglycosides (AGs) have been shown to exhibit enhanced antimicrobial activity. Through the attachment of hydrophobic residues such as linear alkyl chains on the AG backbone, interesting antibacterial and antifungal agents with a novel mechanism of action have been developed. Herein, we report the design and synthesis of seven kanamycin B (KANB) derivatives. Their antibacterial and antifungal activities, along with resistance/enzymatic, hemolytic, and cytotoxicity assays were also studied. Two of these compounds, with a C12 and C14 aliphatic chain attached at the 6″-position of KANB through a thioether linkage, exhibited good antibacterial and antifungal activity, were poorer substrates than KANB for several AG-modifying enzymes, and could delay the development of resistance in bacteria and fungi. Also, they were both relatively less hemolytic than the known membrane targeting antibiotic gramicidin and the known antifungal agent amphotericin B and were not toxic at their antifungal MIC values. Their oxidation to sulfones was also demonstrated to have no effect on their activities. Moreover, they both acted synergistically with posaconazole, an azole currently used in the treatment of human fungal infections.

Topics: Animals; Anti-Bacterial Agents; Antifungal Agents; Bacteria; Bacterial Infections; Cell Line; Cell Survival; Drug Design; Drug Resistance, Microbial; Fungi; Hemolysis; Humans; Kanamycin; Mice; Mycoses; Surface-Active Agents

Amphotericin B (AMB) was often used in intra-articular injection administration for fungal arthritis, because it could often bring a satisfactory therapeutic efficacy and a minimum systemic toxic side effect. However, because of the multiple operations and the frequent injections, the compliance of the patients was bad. Therefore, to develop a long-term sustained-released preparation of AMB for mycotic arthritis intra-articular administration is of great significance. The purpose of present study was to develop a long-term sustained-released in situ gel of a water-insoluble drug AMB for mycotic arthritis intra-articular administration. Based on the evaluations of the in vitro properties of the formulations, the formulation containing 10% (w/w) ethanol, 15% (w/w) PG, 0.75% (w/w) HA, 5% (w/w) purified soybean oil, 0.03% (w/w) α-tocopherol, 15% (w/w) water and 55% (w/w) glyceryl monooleate was selected as a suitable intra-articular injectable in situ gel drug delivery system for water-insoluble drug AMB. Furthermore, the results of the in vivo study on rabbits showed that the selected formulation was a safe and effective long-term sustained-released intra-articular injectable AMB preparation. Therefore, the presented in situ AMB gel could reduce the frequency of the administration in the AMB treatment of fungal arthritis, and then would get a good patient compliance.

Topics: Amphotericin B; Animals; Antifungal Agents; Arthritis, Infectious; Biological Availability; Delayed-Action Preparations; Drug Compounding; Drug Delivery Systems; Drug Liberation; Elastic Modulus; Excipients; Gels; Glycerides; Hyaluronic Acid; Injections, Intra-Articular; Mycoses; Rabbits; Random Allocation; Synovial Fluid; Viscosity

Topics: Amphotericin B; Cellulitis; Humans; Infant, Extremely Low Birth Weight; Infant, Extremely Premature; Infant, Newborn; Itraconazole; Mycoses; Neosartorya

To describe the isolates and susceptibilities to antifungal agents for patients with culture-proven exogenous fungal endophthalmitis.. Noncomparative case series.. The clinical records of all patients treated for culture-proven exogenous fungal endophthalmitis at a university referral center from 1990 to 2010 were reviewed. Specimens initially used for diagnosis were recovered from the microbiology department and then underwent antifungal sensitivity analysis.. The antifungal susceptibilities of 47 fungal isolates from culture-positive fungal endophthalmitis are reported. Included are 14 isolates from yeast and 33 from mold. The mean (±standard deviation) minimum inhibitory concetrations (MICs) for amphotericin B (2.6 ± 3.5 μg/mL), fluconazole (36.9 ± 30.7 μg/mL), and voriconazole (1.9 ± 2.9 μg/mL) are reported. Presumed susceptibility to oral fluconazole, intravenous amphotericin B, intravitreal amphotericin B, oral voriconazole, and intravitreal voriconazole occurred in 34.8%-43.5%, 0-8.3%, 68.8%, 69.8%, and 100% of isolates, respectively.. Based on this laboratory study of isolates from exogenous fungal endophthalmitis, intravitreal voriconazole appears to provide the broadest spectrum of antifungal coverage and, as such, may be considered for empiric therapy of endophthalmitis caused by yeast or mold.

Topics: Amphotericin B; Antifungal Agents; Endophthalmitis; Eye Infections, Fungal; Fluconazole; Fungi; Humans; Microbial Sensitivity Tests; Mycoses; Voriconazole

The interaction of amphotericin B (AmB) with fungal ergosterol (Erg) is stronger than its interaction with mammalian cholesterol (Cho), and this property of AmB as an antifungal drug is thought to be responsible for its selective toxicity toward fungi. However, the mechanism by which AmB recognizes the structural differences between sterols, particularly minor difference in the sterol alicyclic portion, is largely unknown. Thus, to investigate the mode of interaction between AmB and the sterol core, we assessed the affinity of AmB to various sterols with different alicyclic structures. Ion flux assays and UV spectral measurements clearly revealed the importance of the Δ7-double bond of the sterol B-ring for interaction with the drug. AmB showed lower affinity for triene sterols, which have double bonds at the Δ5, Δ7, and Δ9 positions. Intermolecular distance measurements by (13)C{(19)F} rotational echo double resonance (REDOR) revealed that the AmB macrolide ring is in closer contact with the steroid core of Erg than it is with the Cho core in the membrane. Conformational analysis suggested that an axial hydrogen atom at C7 of Δ5-sterol (2, 6) and the protruded A-ring of Δ5,7,9-sterol (4, 8) sterically hampered face-to-face contact between the van der Waals surface of the sterol core and the macrolide of AmB. These results further suggest that the α-face of sterol alicycle interacts with the flat macrolide structure of AmB.

Topics: Amphotericin B; Antifungal Agents; Cell Membrane; Fungi; Humans; Liposomes; Models, Molecular; Molecular Conformation; Mycoses; Sterols

Invasive fungal infections (IFIs) constitute a leading cause of morbidity and infection-related mortality among hematopoietic stem cell transplant (HSCT) recipients. With the use of secondary prophylaxis, a history of IFI is not an absolute contraindication to allo-HSCT. However, still, IFI recurrence remains a risk factor for transplant-related mortality. In this study, of the 105 children undergoing HSCT between April 2010 and February 2013, 10 patients who had IFI history before transplantation and had undergone allo-HSCT were evaluated retrospectively to investigate results of secondary prophylaxis. In conclusion, our study shows that amphotericin B and caspofungin was successful as secondary antifungal prophylaxis agents with no relapse of IFI. In addition, after engraftment, secondary prophylaxis was continued with voriconazole orally in 4 patients that yielded good results.

Topics: Adolescent; Amphotericin B; Antifungal Agents; Caspofungin; Child; Echinocandins; Female; Hematopoietic Stem Cell Transplantation; Humans; Lipopeptides; Male; Mycoses; Retrospective Studies

Topics: Amphotericin B; Antifungal Agents; Drug Therapy, Combination; Humans; Microbial Sensitivity Tests; Mycoses; Phosphorylcholine; Scedosporium; Voriconazole

Invasive fungal infections cause major problems during hematopoietic stem cell transplantation (HSCT). Fungal colonization of the upper airway passages occurs frequently, and may serve as a portal of entry for potentially life-threatening fungal infections, especially in immunocompromised patients.. A clinical practice was instituted at Northwestern Memorial Hospital in Chicago in 2005, to administer amphotericin B deoxycholate nasal spray (ABNS) 0.5% to all HSCT recipients with fungal colonization of their nasal passages, in addition to standard oral antifungal prophylaxis.. Among 1945 HSCT patients treated during the study period, 109 patients were identified with positive fungal surveillance cultures.. Breakthrough fungal infections occurred in only 2 patients (2%), thus in this select group of HSCT recipients, ABNS administration is associated with a very low rate of breakthrough infection.

Topics: Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Deoxycholic Acid; Drug Combinations; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Male; Middle Aged; Mycoses; Nasal Sprays; Young Adult

Antifungal stewardship aims to promote the optimal use of antifungals through the careful selection of agents based on patient profile, target organism, toxicity, costs and the likelihood of emergence and spread of resistance.. We report on an observational prospective 12 month study conducted by an antifungal stewardship team targeting the use of echinocandins (caspofungin and micafungin), voriconazole and liposomal amphotericin B in a tertiary referral hospital in the UK.. One-hundred-and-seventy-three patients were reviewed on 294 occasions. Clinical advice was given and implemented during review of 45 (88.2%) of micafungin prescriptions, 70 (78.7%) of those receiving voriconazole, 78 (62.4%) of those receiving liposomal amphotericin B and 3 (27.3%) of those receiving caspofungin. Except for voriconazole, nearly half of all treatments reviewed were stopped or changed. This study found that a crude cost saving of ∼£180 000 in antifungal drugs was generated compared with the previous year.. Using a multidisciplinary team, antifungal stewardship can achieve significant improvements in patient management and it may reduce costs.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Drug Prescriptions; Drug Utilization; Echinocandins; England; Female; Humans; Male; Middle Aged; Mycoses; Prospective Studies; Tertiary Care Centers; Voriconazole; Young Adult

Clinical deterioration during the treatment of tuberculosis remains a diagnostic challenge. We describe the case of a 46-year-old man with a history of oral cancer status after a radical operation who had pulmonary tuberculosis with pleura and neck lymph node involvement. The clinical condition improved after antituberculosis therapy. However, the patient suffered from low-grade fever, progressive dyspnea, and cough after 7 weeks of the therapy. The findings of chest plain films were relapse and progression of left lung haziness. The deterioration was caused by disseminated Penicillium marneffei infection. Disseminated P. marneffei in a non-HIV patient with tuberculosis is rarely seen, and the manifestations are similar to a paradoxical response and relapse of pulmonary tuberculosis, thereby making it difficult to establish a diagnosis.

Topics: Amphotericin B; Humans; Male; Middle Aged; Mycoses; Penicillium; Recurrence; Tuberculosis, Pulmonary

Survivors of combat trauma can have long and challenging recoveries, which may be complicated by infection. Invasive fungal infections are a rare but serious complication with limited treatment options. Currently, aggressive surgical debridement is the standard of care, with antifungal agents used adjunctively with uncertain efficacy. Anecdotal evidence suggests that antifungal agents may be ineffective in the absence of surgical debridement, and studies have yet to correlate antifungal concentrations in plasma and wounds.. Here we report the systemic pharmacokinetics and wound effluent antifungal concentrations of five wounds from two male patients, aged 28 and 30 years old who sustained combat-related blast injuries in southern Afghanistan, with proven or possible invasive fungal infection. Our data demonstrate that while voriconazole sufficiently penetrated the wound resulting in detectable effluent levels, free amphotericin B (unbound to plasma) was not present in wound effluent despite sufficient concentrations in circulating plasma. In addition, considerable between-patient and within-patient variability was observed in antifungal pharmacokinetic parameters.. These data highlight the need for further studies evaluating wound penetration of commonly used antifungals and the role for therapeutic drug monitoring in providing optimal care for critically ill and injured war fighters.

Topics: Adult; Amphotericin B; Amputation, Surgical; Antifungal Agents; Aspergillosis; Blast Injuries; Burns; Critical Illness; Debridement; Drug Monitoring; Fusariosis; Humans; Male; Mucormycosis; Mycoses; Voriconazole; War-Related Injuries; Wounds, Penetrating

The limited armamentarium of active and oral antifungal drugs against emerging non-Aspergillus molds is of particular concern. Current antifungal agents and the new orally available beta-1,3-d-glucan synthase inhibitor SCY-078 were tested in vitro against 135 clinical non-Aspergillus mold isolates. Akin to echinocandins, SCY-078 showed no or poor activity against Mucoromycotina and Fusarium spp. However, SCY-078 was highly active against Paecilomyces variotii and was the only compound displaying some activity against notoriously panresistant Scedosporium prolificans.

Topics: Amphotericin B; Antifungal Agents; Drug Resistance, Fungal; Echinocandins; Fungi; Glucosyltransferases; Glycosides; Humans; Microbial Sensitivity Tests; Mycoses; Retrospective Studies; Triterpenes

The treatment of chronic granulomatous fungal sinusitis (CGFS), a rare form of invasive fungal sinusitis, is controversial.. To assess the response to postoperative antifungal therapy in patients with CGFS and suggest an effective treatment protocol.. Clinical records of patients with CGFS who had undergone excisive surgery followed by antifungal therapy were reviewed to assess current disease status.. Fourteen male and 4 female patients were diagnosed with CGFS, based on typical histopathological and fungal smear/ culture results. Aspergillus flavus was isolated from 88.9% cases. Stage 1 patients had resectable sinonasal disease, stage 2 had additional spread to orbit/palate and stage 3 had extensive disease. Follow-up ranged from 6 months to 8 years. Residual disease was seen in all but one patient who received amphotericin B as first line therapy and in none of those who received itraconazole or voriconazole. Even those who received azoles as second line therapy were disease free at last follow-up.. Surgery followed by itraconazole or voriconazole for Stage 1 and 2 disease and voriconazole for stage 3 disease is recommended for a good outcome. Amphotericin B is not recommended as first line therapy for CGFS.

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; Chronic Disease; Combined Modality Therapy; Female; Granuloma; Humans; Itraconazole; Male; Middle Aged; Mycoses; Sinusitis; Treatment Outcome; Voriconazole

We report the isolation of the emerging fungal pathogen Rasamsonia aegroticola, which belongs Rasamsonia argillacea species complex, from a respiratory sample of a patient with cystic fibrosis. This filamentous fungus, resembling members of a Penicillium and Paecilomyces spp., was identified by morphology and confirmed by DNA sequence analysis. Susceptibility pattern showed high minimal inhibitory concentration of voriconazole and amphotericin B but low minimal inhibitory concentration of caspofungin, micafungin and itraconazole.

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Cystic Fibrosis; Echinocandins; Eurotiales; Humans; Lipopeptides; Male; Microbial Sensitivity Tests; Molecular Sequence Data; Mycoses; Pharynx; Sequence Analysis, DNA; Slovenia; Voriconazole; Young Adult

Fungal periprosthetic joint infections are rare, devastating complications of arthroplasty. There is conflicting evidence as to the efficacy of amphotericin B elution from cement spacers. The purpose of this study was to determine whether concentrations of amphotericin B released from bone cement over time would be efficacious in treating a periprosthetic infection. A continuous flow chamber was used to evaluate the in vitro release of amphotericin from cement beads containing 7.5% amphotericin. Following polymerization, 3.3% of the initially loaded amphotericin B was detected. The peak mean concentration eluted from the bone cement was 0.33 μg/mL at 8 hours. The AUC0-24 was 2.79 μg/mL/h; 0.20% of the amphotericin B was released. In conclusion, amphotericin B is released from bone cement at a clinically useful concentration.

Topics: Amphotericin B; Antifungal Agents; Bone Cements; Deoxycholic Acid; Drug Combinations; Microspheres; Mycoses; Polymethyl Methacrylate; Prosthesis-Related Infections

Studies that analyze the epidemiology and risk factors for invasive fungal disease (IFD) after engraftment in alloSCT are few in number. This single-center retrospective study included 404 alloSCT adult recipients surviving >40 days who engrafted and were discharged without prior IFD. All patients who received ⩾20 mg/day of prednisone were assigned to primary oral prophylaxis (itraconazole or low-dose voriconazole). The primary end point was the cumulative incidence (CI) of probable/proven IFD using the European Organization for Research and Treatment of Cancer and Mycoses Study Group (EORTC/MSG) criteria. The independent prognostic factors after multivariate analyses were used to construct a post-engraftment IFD risk score. The 1-year CI of IFD was 11%. The non-relapse mortality was 40% in those developing IFD and 16% in those who did not. The intent-to-treat analysis showed that 17% of patients abandoned the assigned prophylaxis. Age >40 years, ⩾1 previous SCT, pre-engraftment neutropenia >15 days, extensive chronic GVHD and CMV reactivation were independent risk factors. The post-engraftment IFD score stratified patients into low risk (0-1 factor, CI 0.7%), intermediate risk (2 factors, CI 9.9%) and high risk (3-5 factors, CI 24.7%) (P<0.0001). The antifungal prophylaxis strategy failed to prevent post-engraftment IFD in 11% of alloSCT. Our risk score could be useful to implement risk-adapted strategies using antifungal prophylaxis after engraftment.

Topics: Administration, Oral; Adult; Aged; Allografts; Amphotericin B; Antifungal Agents; Aspergillosis; Caspofungin; Cause of Death; Drug Therapy, Combination; Echinocandins; Female; Fungemia; Granulocyte Colony-Stimulating Factor; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Incidence; Lipopeptides; Male; Medication Adherence; Middle Aged; Mycoses; Neutropenia; Patient Compliance; Premedication; Retrospective Studies; Risk Assessment; Risk Factors; Survival Analysis; Transplantation Conditioning; Treatment Failure; Triazoles; Young Adult

We investigated the species distribution and amphotericin B (AMB) susceptibility of Korean clinical Aspergillus isolates by using two Etests and the CLSI broth microdilution method.. A total of 136 Aspergillus isolates obtained from 11 university hospitals were identified by sequencing the internal transcribed spacer (ITS) and β-tubulin genomic regions. Minimal inhibitory concentrations (MICs) of AMB were determined in Etests using Mueller-Hinton agar (Etest-MH) and RPMI agar (Etest-RPG), and categorical agreement with the CLSI method was assessed by using epidemiological cutoff values.. ITS sequencing identified the following six Aspergillus species complexes: Aspergillus fumigatus (42.6% of the isolates), A. niger (23.5%), A. flavus (17.6%), A. terreus (11.0%), A. versicolor (4.4%), and A. ustus (0.7%). Cryptic species identifiable by β-tubulin sequencing accounted for 25.7% (35/136) of the isolates. Of all 136 isolates, 36 (26.5%) had AMB MICs of ≥2 μg/mL by the CLSI method. The categorical agreement of Etest-RPG with the CLSI method was 98% for the A. fumigatus, A. niger, and A. versicolor complexes, 87% for the A. terreus complex, and 37.5% for the A. flavus complex. That of Etest-MH was ≤75% for the A. niger, A. flavus, A. terreus, and A. versicolor complexes but was higher for the A. fumigatus complex (98.3%).. Aspergillus species other than A. fumigatus constitute about 60% of clinical Aspergillus isolates, and reduced AMB susceptibility is common among clinical isolates of Aspergillus in Korea. Molecular identification and AMB susceptibility testing by Etest-RPG may be useful for characterizing Aspergillus isolates of clinical relevance.

Topics: Amphotericin B; Antifungal Agents; Aspergillus; DNA, Fungal; Hospitals; Humans; Microbial Sensitivity Tests; Mycoses; Republic of Korea; Sequence Analysis, DNA; Tubulin

In vitro susceptibilities of a worldwide collection of molecularly identified Phaeoacremonium strains (n = 43) belonging to seven species and originating from human and environmental sources were determined for eight antifungal drugs. Voriconazole had the lowest geometric mean MIC (0.35 μg/ml), followed by posaconazole (0.37 μg/ml), amphotericin B (0.4 μg/ml), and isavuconazole (1.16 μg/ml). Caspofungin, anidulafungin, fluconazole, and itraconazole had no activity.

Topics: Amphotericin B; Anidulafungin; Antifungal Agents; Ascomycota; Caspofungin; Echinocandins; Fluconazole; Humans; Itraconazole; Lipopeptides; Microbial Sensitivity Tests; Mycoses; Nitriles; Pyridines; Triazoles; Voriconazole

To evaluate antifungal combination strategy in children with hematologic diseases and invasive fungal disease( IFD).. A retrospective clinical study was performed based on 67 childhood patients with hematologic diseases and IFD who firstly accepted combination antifungal therapy for ≥ 7 days during January 2012 and December 2014. Of them, 11 cases received combination of echinocandin with azole, 10 cases received combination of echinocandin with amphotericin B, and 46 cases received combination of azole with amphotericin B.. Overall response rate was 79.1%. Univariate analysis revealed that granulocyte recovery (P=0.031), status of underling disease (P=0.023) and the duration of the therapy (P=0.046) were significantly associated with efficacy. Multivariate analysis showed that the independent prognostic factor was the duration of combination antifungal therapy (OR=0.229, 95% CI 0.061- 0.863, P=0.029). The response rates of echinocandin combined with azole, echinocandin combined with amphotericin B and azole combined with amphotericin B were 81.8%, 60.0% and 82.6%, respectively (P>0.05), and 12-week survival rates were 81.8%, 80.0% and 86.5%, respectively (P>0.05). The drug- related adverse reactions occurred 59 times in 34 patients. BUN increasing, hypokalemia and abnormal liver functions were considered the main side effects.. For IFD in children with hematologic disease, to extend the duration of treatment (≥ 14 days) could significantly improve the curative effect. Combinations of echinocandin with azole, echinocandin with amphotericin B and azole with amphotericin B can be used as a combination treatment options. Combination of Azole with amphotericin B is efficacious, safe and economic treatment option considering efficacy, survival rate, cost and dosage form.

Topics: Amphotericin B; Antifungal Agents; Child; Drug Therapy, Combination; Echinocandins; Hematologic Diseases; Humans; Mycoses; Retrospective Studies; Survival Rate; Treatment Outcome

The pharmacokinetic characteristics of liposomal amphotericin B (L-AMB; AmBisome(®)) in patients with invasive fungal infection were investigated. A population pharmacokinetic (PK) model in Japanese pediatric patients was developed based on 159 serum amphotericin B (AMPH-B) concentrations obtained in a post-marketing clinical study. The subjects were 39 patients with a mean age of 8.4 years (SD 4.5) and mean body weight of 27.1 kg (SD 14.1). A two-compartment PK model with zero-order input and first-order elimination was fitted to serum AMPH-B concentrations for L-AMB doses of 1.0, 2.5, and 5.0 mg/kg/day. Body weight showed significant correlations with PK parameters, such as clearance (CL) and distribution volume of the central compartment (Vc). The predicted Cmax/dose and AUC0-24/dose in Japanese pediatric patients were similar to those in non-Japanese pediatric patients and Japanese adult patients. Extremely large increases in Ctrough compared with predicted values were observed in some Japanese pediatric patients, but no relationships with demographic characteristics, clinical laboratory test values, or representative adverse drug reaction (decreased potassium) were found. The population PK parameters in this study are useful for simulating PK profiles of L-AMB and will be helpful for PK exposure comparisons among different populations and in investigations of pharmacokinetic-pharmacodynamic characteristics in patients.. Amphotericin B Deoxycholate (PubChem CID:23668620); amphotericin B (PubChem CID:5280965); 3-nitrophenol (PubChem CID:11137); methanol (PubChem CID:887).

Topics: Adolescent; Amphotericin B; Antifungal Agents; Area Under Curve; Asian People; Biomarkers; Child; Child, Preschool; Drug Monitoring; Female; Humans; Infant; Infant, Newborn; Japan; Male; Metabolic Clearance Rate; Models, Biological; Models, Statistical; Mycoses; Potassium; Product Surveillance, Postmarketing

In this paper we report the SAR studies of a series of N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)amide and N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)sulfonamide derivatives 6(a-o) and 7(a-o), were synthesized in good yields and characterized by (1)H NMR, (13)C NMR and mass spectral analyses. The preparation of the key intermediate highlights an optimized palladium catalyzed (Pd₂(dba)₃/RuPhos) Buchwald cross-coupling of intermediate 2 and 3. The newly synthesized compounds were evaluated for their in vitro antibacterial activity against Staphylococcus aureus, (Gram-positive), Escherichia coli and Klebsiella pneumoniae (Gram-negative), antifungal activity against Candida albicans, Aspergillus flavus and Rhizopus sp. and antitubercular activity against Mycobacterium tuberculosis H37Rv, Mycobacterium smegmatis, Mycobacterium fortuitum and MDR-TB strains. The synthesized compounds displayed interesting antimicrobial activity. The compounds 7d, 7f, 7h and 7n displayed significant activity against Mycobacterium tuberculosis H37Rv strain.

Topics: Amides; Anti-Infective Agents; Antitubercular Agents; Bacteria; Bacterial Infections; Fungi; Humans; Imidazoles; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Mycoses; Structure-Activity Relationship; Sulfonamides

Imidazolium salts (Im(+)-R(2)R(3)-Cl(-)) attached to the N,N'-bis(salicylidene)-(±)-trans-1,2-diaminocyclohexane (saldach) backbone (4a-f) have been designed and successfully applied for the synthesis of the corresponding mononuclear complexes with Mn(III) and Fe(III) ions. The molecular structures of the saldach ligands H2(R(1))2saldach(Im(+)-R(2)R(3)-Cl(-))2 (R(1) = H, tert-Bu, R(2) = H, Et, n-Bu, R(3) = H, Me) and their [M(III)Cl{(R(1))2saldach(Im(+)-R(2)R(3)-Cl(-))2}] (M = Mn, Fe) complexes have been established. The free ligands exist as the phenol-OH and not as the zwitterionic (imine)N-H(+)· · ·(-)O(phenol) tautomer. Antimicrobial activity of the target compounds revealed higher potent antibacterial activity against Salmonella aureus, B. subtilis while less effective against E. coli and C. albicans and inactivity against A. flavus. Compound (4d) and its Fe(III) complex (6d) exhibit remarkable extra-potent bactericidal activity.

Topics: Anti-Infective Agents; Bacteria; Bacterial Infections; Cyclohexylamines; Escherichia coli; Ferric Compounds; Fungi; Humans; Imidazoles; Mycoses; Salts

A patient with aplastic anaemia, successively treated with caspofungin then liposomal amphotericin, developed a disseminated infection due to Acremonium, further confirmed as resistant in vitro to these drugs. Successful treatment was achieved with voriconazole. Multiple antifungal treatments may expose to the risk of breakthrough of multi-resistant pathogens in haematology patients.

Topics: Acremonium; Adult; Amphotericin B; Anemia, Aplastic; Antifungal Agents; Caspofungin; Drug Resistance, Fungal; Echinocandins; Humans; Lipopeptides; Male; Mycoses; Opportunistic Infections; Pyrimidines; Triazoles; Voriconazole

The Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO) here presents its updated recommendations for the treatment of documented fungal infections. Invasive fungal infections are a main cause of morbidity and mortality in cancer patients undergoing intensive chemotherapy regimens. In recent years, new antifungal agents have been licensed, and agents already approved have been studied in new indications. The choice of the most appropriate antifungal treatment depends on the fungal species suspected or identified, the patient's risk factors (e.g., length and depth of neutropenia), and the expected side effects. This guideline reviews the clinical studies that served as a basis for the following recommendations. All recommendations including the levels of evidence are summarized in tables to give the reader rapid access to the information.

Topics: Amphotericin B; Antifungal Agents; Candidiasis, Invasive; Catheter-Related Infections; Chemotherapy-Induced Febrile Neutropenia; Clinical Trials as Topic; Combined Modality Therapy; Drug Monitoring; Drug Therapy, Combination; Echinocandins; Fungemia; Humans; Immunocompromised Host; Immunotherapy; Invasive Pulmonary Aspergillosis; Mycoses; Neoplasms; Salvage Therapy; Triazoles

This study was aimed at finding predictors of invasive fungal infection (IFI) after pediatric allogeneic hematopoietic SCT (HSCT). All children who received allogeneic HSCT in the Wilhelmina Children's Hospital Utrecht between 2004 and 2012 were included. HSCT data were prospectively collected. Patients were retrospectively classified into high- or low-risk groups for developing IFI using criteria based on available literature. Predictors for the occurrence of IFI were analyzed using Cox regression models. We used logistic regression models to analyze the association between other HSCT-related complications and IFI. Secondary outcomes were overall survival and treatment-related mortality (TRM). Two-hundred nine patients were included in the analysis; median age was 6.6 years. The cumulative incidence of IFI was 12%. In patients classified as 'low risk' (n=75), only 5.3% developed IFI (odds ratio (OR): 0.325; P=0.047). In multivariate analysis, a predictor for the occurrence of IFI was an a priori determined HSCT TRM risk >20% (based on EBMT-risk score). Post-HSCT, the administration of high-dose steroids was associated with IFI (OR: 4.458; P=0.010). Patients who developed IFI showed an increased risk of TRM (OR: 3.773; P=0.004). These results confirm that risk group stratification should guide intensity of monitoring for IFI and use of antifungal prophylaxis.

Topics: Adolescent; Adult; Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis; Caspofungin; Child; Child, Preschool; Echinocandins; Female; Fusariosis; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Infant; Lipopeptides; Logistic Models; Male; Mycoses; Neutrophils; Prospective Studies; Pyrimidines; Retrospective Studies; Risk; Treatment Outcome; Triazoles; Voriconazole; Young Adult

Liposomal amphotericin B (L-AMB) and amphotericin B lipid complex (ABLC) are both indicated for treating invasive fungal infections (IFIs) caused by Aspergillus, Candida and Cryptococcus spp. among patients who are refractory to or intolerant of conventional amphotericin B (CAB). Prior studies have suggested similar efficacies but differences in adverse event (AE) profiles between L-AMB and ABLC.. Our objective was to conduct a cost-minimisation and budget impact analysis for the treatment of IFIs with L-AMB and ABLC in a US hospital setting.. A Microsoft® Excel-based budget impact model was developed to estimate the costs associated with using L-AMB and ABLC for the treatment of adult patients with Aspergillus, Candida and Cryptococcus spp. infections, who are refractory to or intolerant of CAB, during a hospital stay. The model was built from a hospital perspective, and included drug costs of L-AMB and ABLC, and costs for treating drug-related AEs (i.e. nephrotoxicity with/without dialysis, infusion-related reactions, anaphylaxis, hypomagnesaemia and hypokalaemia). Average sales price was used as the drug cost estimate in the base-case analyses. The treatment duration and rates of AEs for L-AMB and ABLC were mainly obtained from a retrospective study of these two drugs in the target population using the Cerner Health Facts data. Treatment costs of AEs were obtained from the publicly available sources. The budget impact ($US, year 2011 values) was evaluated for a hypothetical hospital with 100 administrations where L-AMB and ABLC are used for the treatment of the target population by changing the market share of L-AMB and ABLC from 32/68% to an anticipated market share of 60/40% in the base-case analysis. Sensitivity analyses were conducted by varying drug costs, rates of AEs, costs of AEs and anticipated market shares of L-AMB and ABLC.. The estimated per-patient cost per hospital episode associated with L-AMB and ABLC use were $US14,563 and $US16,748, respectively. Cost of AEs accounted for 68.7% of the costs for L-AMB and 85.4% for ABLC. In a hypothetical hospital with 100 annual admissions of patients using these two drugs for IFIs, changing the market shares from 32/68% for L-AMB and ABLC, respectively, to 60/40% yielded a 3.8% cost reduction, which corresponded to an absolute cost savings of $US61,191. Sensitivity analyses indicated that the results were robust to changes in input parameter values in most cases.. This study suggests that hospitals can realize cost savings by substituting L-AMB for ABLC in the treatment of IFIs. The cost savings are driven by the lower rates of AEs associated with L-AMB use compared with ABLC.

Topics: Adult; Amphotericin B; Antifungal Agents; Aspergillus; Candida; Costs and Cost Analysis; Cryptococcus; Drug Costs; Drug Resistance, Fungal; Humans; Immunocompromised Host; Models, Biological; Mycoses; United States

Fluconazole prophylaxis of invasive fungal infections is a cornerstone of neonatal care, but in vitro studies have shown that it inhibits corticosteroid production. This study assessed whether preterm infants demonstrated an association between fluconazole administration, and its duration, and symptoms of adrenocortical insufficiency.. We compared two groups who were treated before and after we introduced the use of fluconazole to our neonatal intensive care unit. Infants with a gestational age of ≤27 weeks or with a birth weight of ≤750 g were considered for the retrospective analysis. In order to assess whether the duration of prophylaxis was related to adrenocortical insufficiency, regression models were performed in all preterm infants in the fluconazole group.. The fluconazole group (n = 37) and nonfluconazole group (n = 41) were compared. No differences were found in the percentage of infants with symptoms of adrenocortical insufficiency, such as hypotension or need of vasopressor therapy. The incidence of hypotension and the use of vasopressor therapy were not related to duration of fluconazole prophylaxis.. Fluconazole and it duration were not associated with the incidence of symptoms related to adrenocortical insufficiency. Further prospective trials are needed to better define the relationship between fluconazole and adrenocortical insufficiency.

Topics: Amphotericin B; Antifungal Agents; Antigens, Fungal; Apgar Score; Bronchoalveolar Lavage Fluid; Candida; Chemoprevention; Female; Fluconazole; Humans; Hypoaldosteronism; Infant, Extremely Low Birth Weight; Infant, Extremely Premature; Infant, Newborn; Infant, Premature, Diseases; Intensive Care Units, Neonatal; Logistic Models; Male; Mycoses; Outcome Assessment, Health Care; Retrospective Studies

Penicillium marneffei is a thermally dimorphic pathogenic fungus that causes systemic infection similar to disseminated cryptococcosis. P. marneffei is endemic in Southeast Asia, usually infecting HIV-infected individuals; infection of HIV-negative individuals is extremely rare. Here, we describe a disseminated P. marneffei infection within an osteolytic lesion in an HIV-negative patient. A 40-year-old Chinese woman presented with intermittent fever, generalized lymphadenopathy, and a skin rash. Following a sternum biopsy, the patient was diagnosed with P. marneffei infection. An emission computed tomography bone scan revealed the presence of increased radioactivity in the left clavicle and sternum, indicative of an osteolytic lesion. In addition to reporting this very rare case, we also present a brief review of the literature, highlighting the differences in clinical manifestations between HIV-positive and HIV-negative patients infected with P. marneffei as it applies to our case.

Topics: Adult; Amphotericin B; Antifungal Agents; Asia, Southeastern; Asian People; Female; HIV Infections; Humans; Mycoses; Osteolysis; Penicillium; Tomography, Emission-Computed

A 28-year-old man undergoing treatment for hemophagocytic syndrome developed Paecilomyces lilacinus infection in skin ulcers on the face and in the tracheotomy stoma. While his bone marrow was suppressed by chemotherapy with dexamethasone, cyclosporin and etoposide for hemophagocytic syndrome, dental infection led to subacute necrotizing fasciitis caused by Pseudomonas aeruginosa on the right side of the face, resulting in a large area of soft tissue defects. Etoposide was discontinued, and prophylactic treatment with itraconazole was initiated. The ulcers resulting from necrotizing fasciitis were treated conservatively using trafermin and alprostadil alfadex ointment 0.003 %, and near-complete re-epithelialization occurred, except on the right lower eyelid, right buccal mucosa and perioral area. However, 6 weeks later, pustules/crusts started to form and break down repeatedly, leading to expansion of tissue defects on the face. Direct microscopic examination revealed fungal elements, and fungal culture identified Paecilomyces lilacinus suspicious twice some other day. Based on DNA extraction from the isolated fungus, this fungal strain was identified as Paecilomyces lilacinus. Cyclosporin and itraconazole were discontinued, and treatment with liposomal amphotericin B and a tapering dose of steroids was initiated. Cure was achieved in approximately 2.5 months after treatment initiation, and no relapse has been observed. The most important factor that ultimately contributed to the resolution of fungal infection might have been release of immunosuppression by discontinuing cyclosporin and tapering steroids.

Topics: Adult; Amphotericin B; Antifungal Agents; Cyclosporine; Dexamethasone; Face; Fasciitis, Necrotizing; Humans; Immune Tolerance; Lymphohistiocytosis, Hemophagocytic; Male; Mycoses; Paecilomyces; Pseudomonas aeruginosa; Pseudomonas Infections; Skin Ulcer; Surgical Stomas; Tracheotomy; Treatment Outcome

We retrospectively analyzed the medical records and clinical characteristics of 15 patients diagnosed with Penicilliosis marneffei (PSM) between January 1, 1993, and December 31, 2012, at the Third Affiliated Hospital of Sun Yat-sen University. The most common symptoms of PSM were fever (14/15, 93 %), cough (13/15, 87 %), and sputum production (6/15, 40 %), weight loss (14/15, 60 %), lymph node enlargement (9/15, 60 %), hepatosplenomegaly (7/15, 47 %), anemia (7/15, 47 %), and hemoptysis (4/15, 26 %). The most common underlying diseases in patients diagnosed with PSM were AIDS (9/15, 60 %), post-organ transplantation (3/15, 20 %), rheumatic autoimmune disease (2/15, 13 %), and hematological malignancy (1/15, 7 %). All patients, except those with AIDS, were treated with immunosuppressant drugs. White blood cell counts were increased in 10/15 (67 %) patients, while hemoglobin concentrations were decreased in 8/15 (53 %) patients. The ratios of CD4(+)/total T lymphocytes and CD4(+)/CD8(+) T lymphocytes declined in all the 11 test cases. Nodular lesions or masses were the most common anomalies detected during computed tomography scans, but disseminated inflammation and interstitial changes were also seen. Clinical samples with positive culture results were obtained from sputum or secretions obtained by bronchoscopy, venous blood, percutaneous pulmonary puncture, bone marrow, or skin lesions. Between 1993 and 2003, only four cases of PSM, all connected with AIDS, were diagnosed, while 11 cases of PSM, with or without concurrent AIDS, were diagnosed between 2003 and 2012. Amphotericin B was used to control the disease in some cases. In conclusion, the occurrence of PSM, especially in patients without concurrent AIDS, has increased. The early culture of Penicillium marneffei from clinical samples is critical for correct diagnosis of PSM, and amphotericin B is recommended as the first choice for treatment.

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; China; Female; Hospitals; Humans; Male; Middle Aged; Mycoses; Penicillium; Retrospective Studies; Young Adult

Although amphotericin B (AmB) and its lipid formulations are used for the treatment of fungal infections of the CNS, the kinetics of AmB in the CSF after intravenous administration of liposomal amphotericin B (LAmB) are not well characterized.. From 14 paediatric haemato-oncological patients (aged 0.4-19.5 years, median 7.6 years), we obtained 30 CSF samples by means of routine punctures (performed for intrathecal treatment of the underlying diseases) at different timepoints after the prophylactic intravenous infusion of LAmB (AmBisome, 3 mg/kg/day). Concurrent serum samples were obtained to calculate the transfer rates. An HPLC method was used for AmB detection.. CSF levels of AmB 1-100 h after the intravenous infusion of LAmB were between 10 and 120 ng/mL, except in one case with a level of 529 ng/mL. Concurrent serum levels were about 1000-fold higher, ranging between 3 and 75 μg/mL. CSF levels did not show a clear time-dependent concentration profile, but remained at a steady-state for longer than 48 h after infusion. The transfer rate ranged from 0.02% to 0.92% (median 0.13%) and correlated significantly (r=0.801, P<0.001) with increasing time after infusion.. After the intravenous administration of LAmB, AmB CSF levels were low, confirming published animal data. CSF levels remained at a steady-state level for longer than 48 h. As indicated by published post mortem data, higher levels in brain tissue, which would be necessary for the successful treatment of CNS infections, might be possible.

Topics: Adolescent; Amphotericin B; Animals; Antifungal Agents; Cerebrospinal Fluid; Chemoprevention; Child; Child, Preschool; Female; Hematologic Neoplasms; Humans; Infant; Infusions, Intravenous; Male; Mycoses; Serum; Young Adult

Subcutaneous phaeohyphomycosis usually results from traumatic inoculation with the fungus and generally occurs in immunosuppressed men. Cladosporium, Exophiala, and Alternaria spp. are commonly implicated pathogens.. We present a case of subcutaneous phaeohyphomycosis caused by Rhytidhysteron sp. that was refractory to conventional antifungal therapy.. A 72-year-old man with hypertension and diabetes presented with a multiloculated, large cystic swelling over the right dorsal foot. Laboratory findings and x-rays of the chest and left foot were normal.. Adequate control of the patient's diabetes was achieved, and the swelling was excised under itraconazole/terbinafine coverage. Histology showed multiple areas of neutrophilic abscess, epithelioid cells, foreign body giant cells, and multiple septate hyphae and yeast-like cells. Dematiaceous fungus was cultured but failed to produce spores. Sequencing of the isolate showed a match of > 99% with Rhytidhysteron rufulum. The patient demonstrated no response after one year of therapy with itraconazole/terbinafine. Weekly infiltration of the lesion with liposomal amphotericin B resulted in its complete resolution within 15 weeks.. Lesions of phaeohyphomycosis appear morphologically similar regardless of the organism implicated. Hence, their diagnosis rests entirely on the clinicopathological and microbiological presentation. Molecular studies may be required to identify a fungus if attempts to grow it in artificial culture media fail. Rhytidhysteron spp. are not known as pathogens in humans, and no treatment protocol exists. Intralesional amphotericin was highly effective in our patient and caused no systemic adverse effects. Voriconazole and posaconazole are effective against disseminated/visceral phaeohyphomycotic infections, but their efficacy against Rhytidhysteron spp. remains unstudied.

Topics: Aged; Amphotericin B; Antifungal Agents; Ascomycota; Humans; Itraconazole; Liposomes; Male; Mycoses; Naphthalenes; Phaeohyphomycosis; Terbinafine

We have evaluated the efficacy of amphotericin B, posaconazole, and voriconazole in immunosuppressed murine models of disseminated infection by Curvularia spicifera and Curvularia hawaiiensis. The 3 antifungals improved survival of mice in comparison to controls; however, only the 2 azoles were able to reduce significantly the fungal load.

Topics: Amphotericin B; Animals; Antifungal Agents; Ascomycota; Disease Models, Animal; Immunocompromised Host; Male; Mice; Mycoses; Treatment Outcome; Triazoles; Voriconazole

Topics: Amphotericin B; Antifungal Agents; Humans; Mycoses; Neoplasms; Neutropenia; Opportunistic Infections; Pyrimidines; Triazoles

The aim of this study was to review a series of consecutive cases of corneal and scleral infection by Paecilomyces spp. and to identify features of clinical presentation and assess treatment modalities.. This retrospective review of a case series included 22 patients with nontraumatic Paecilomyces anterior segment infections who were seen in a tertiary referral practice. Outcome measures were the number of eyes that were lost and visual acuity in eyes that were saved.. Twenty-two patients with Paecilomyces corneal or scleral infection with no significant history of trauma or surgery were identified over a 20-year period. Two distinct clinical presentations were noted with 17 presenting with corneal infection and 5 initially presenting with scleral infection, and all demonstrated a classical endothelial plaque and deep stromal infiltrate. Almost all required single or multiple anterior segment reconstructive surgeries together with systemic and topical antifungal agents. The first 10 patients were treated with amphotericin B, whereas the remaining 12 patients were treated with voriconazole and 21 of 22 patients underwent surgery. Paecilomyces spp. was identified from most intraocular specimens although corneal fungal growth was noted only from deep corneal biopsies or corneal buttons removed during corneal transplantation. Outcomes were better in the last 12 patients treated with voriconazole.. Nontraumatic Paecilomyces anterior segment infection presents with a pathognomonic clinical picture when the cornea is the initial site of infection and later in scleral infections. Early identification and aggressive treatment with extirpative surgery and voriconazole may result in retention of the eye with useful vision.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Eye Infections, Fungal; Female; Humans; Keratitis; Male; Middle Aged; Mycoses; Paecilomyces; Retrospective Studies; Scleritis; Voriconazole; Young Adult

Cases of invasive mycosis due to Blastobotrys serpentis and B. proliferans identified by sequencing in a preterm patient and a rhabdomyosarcoma patient, respectively, are reported. Both species revealed elevated fluconazole and echinocandin MICs by the CLSI broth microdilution method. Additionally, B. serpentis exhibited high amphotericin B MICs, thus posing serious therapeutic challenges.

Topics: Adult; Amphotericin B; Antifungal Agents; Child; Drug Resistance, Fungal; Echinocandins; Female; Fluconazole; Humans; Immunocompromised Host; Infant, Newborn; Male; Microbial Sensitivity Tests; Molecular Sequence Data; Mycoses; Saccharomycetales; Sequence Analysis, DNA

We determined the in vitro antifungal activity of liposomal amphotericin B (L-AmB) against 604 clinical yeast isolates. Amphotericin B deoxycholate (D-AmB) was tested in parallel against all the isolates. Susceptibility testing was performed according to the Clinical and Laboratory Standards Institute (CLSI) M27-A3 method. Overall, L-AmB was highly active against the isolates (mean MIC, 0.42 µg ml(-1); MIC90, 1 µg ml(-1); 97.2 % of MICs were ≤1 µg ml(-1)) and comparable to D-AmB (mean MIC, 0.48 µg ml(-1); MIC90, 1 µg ml(-1); 97.3 % of MICs were ≤1 µg ml(-1)). The in vitro activity of D-AmB and L-AmB was correlated (R(2) = 0.61; exp(b), 2.3; 95 % CI, 2.19-2.44, P<0.001). Candida albicans (mean MICs of D-AmB and L-AmB, 0.39 µg ml(-1) and 0.31 µg ml(-1), respectively) and Candida parapsilosis (mean MICs of D-AmB and L-AmB, 0.38 µg ml(-1) and 0.35 µg ml(-1), respectively) were the species most susceptible to the agents tested, while Candida krusei (currently named Issatchenkia orientalis) (mean MICs of D-AmB and L-AmB, 1.27 µg ml(-1) and 1.13 µg ml(-1), respectively) was the least susceptible. The excellent in vitro activity of L-AmB may have important implications for empirical treatment approaches and support its role in treatment of a wide range of invasive infections due to yeasts.

Topics: Amphotericin B; Antifungal Agents; Candida albicans; Deoxycholic Acid; Drug Combinations; Humans; Microbial Sensitivity Tests; Mycoses; Pichia; Yeasts

Penicillium marneffei, one of the most important thermal dimorphic fungi, is a severe threat to the life of immunocompromised patients. However, the pathogenic mechanisms of P. marneffei remain largely unknown. In this work, we developed a model host by using nematode Caenorhabditis elegans to investigate the virulence of P. marneffei. Using two P. marneffei clinical isolate strains 570 and 486, we revealed that in both liquid and solid media, the ingestion of live P. marneffei was lethal to C. elegans (P<0.001). Meanwhile, our results showed that the strain 570, which can produce red pigment, had stronger pathogenicity in C. elegans than the strain 486, which can't produce red pigment (P<0.001). Microscopy showed the formation of red pigment and hyphae within C. elegans after incubation with P. marneffei for 4 h, which are supposed to be two contributors in nematodes killing. In addition, we used C. elegans as an in vivo model to evaluate different antifungal agents against P. marneffei, and found that antifungal agents including amphotericin B, terbinafine, fluconazole, itraconazole and voriconazole successfully prolonged the survival of nematodesinfected by P. marneffei. Overall, this alternative model host can provide us an easy tool to study the virulence of P. marneffei and screen antifungal agents.

Topics: Amphotericin B; Animals; Antifungal Agents; Caenorhabditis elegans; Disease Models, Animal; Fluconazole; Host-Pathogen Interactions; Hyphae; Itraconazole; Mycoses; Naphthalenes; Penicillium; Pigments, Biological; Survival Analysis; Terbinafine; Voriconazole

Topics: Adult; Amphotericin B; Antifungal Agents; Asia, Southeastern; Bone Marrow Examination; CD4 Lymphocyte Count; Diagnosis, Differential; Drug Administration Routes; Female; HIV; HIV Infections; Humans; Itraconazole; Mycoses; Penicillium; Travel; Treatment Outcome; Viral Load

Fusarium species are among the most common fungi present in the environment and some species have emerged as major opportunistic fungal infection in human. However, in immunocompromised hosts they can be virulent pathogens and can cause death. The pathogenesis of this infection relies on three factors: colonization, tissue damage, and immunosuppression. A novel Fusarium species is reported for the first time from keratitis in an agriculture worker who acquired the infection from plant material of maize. Maize plants are the natural host of this fungus where it causes stalk rot and seeding malformation under temperate and humid climatic conditions. The clinical manifestation, microbiological morphology, physiological features and molecular data are described.. Diagnosis was established by using polymerase chain reaction of fungal DNA followed by sequencing portions of translation elongation factor 1 alpha (TEF1 α) and beta-tubulin (BT2) genes. Susceptibility profiles of this fungus were evaluated using CLSI broth microdilution method.. The analyses of these two genes sequences support a novel opportunist with the designation Fusarium temperatum. Phylogenetic analyses showed that the reported clinical isolate was nested within the Fusarium fujikuroi species complex. Antifungal susceptibility testing demonstrated that the fungus had low MICs of micafungin (0.031 μg/ml), posaconazole (0.25 μg/ml) and amphotericin B (0.5 μg/ml).. The present case extends the significance of the genus Fusarium as agents of keratitis and underscores the utility of molecular verification of these emerging fungi in the human host.

Topics: Amphotericin B; Antifungal Agents; Base Sequence; DNA, Fungal; Echinocandins; Fungal Proteins; Fusarium; Humans; Keratitis; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Molecular Sequence Data; Multilocus Sequence Typing; Mycoses; Phylogeny; Sequence Analysis, DNA; Treatment Outcome; Triazoles; Tubulin; Zea mays

The study objective was to assess the lethality rates and the predictive factors for death in AIDS patients infected by Penicillium marneffei (Pm) in Hai Phong, Vietnam.. A retrospective cohort study was conducted by reviewing 103 medicals records of confirmed cases from June 2006 to August 2009.. Penicilliosis-related mortality was very high (33%). The majors risk factors of death were: (i) patient lacking complete treatment, a regimen with both of secondary prophylaxis by itraconazole and HAART (OR=52.2, P<0.001); (ii) patients having received only secondary prophylaxis (OR=21.2, P<0.001); (iii) patients coinfected by hepatitis C (OR=2.3, P=0.02) and tuberculosis (OR=1.97, P=0.04). Penicilliosis occurred in 28 cases after initiation of ART, probably caused by IRIS, with the same signs and symptoms as "common" penicilliosis. However, the diagnosis of IRIS was ruled out because the viral load could not be assessed.. Penicilliosis is very frequent in the North of Vietnam. A good compliance to a complete treatment with healing antifungal (Amphotericin B) then secondary prophylaxis (Itraconazole) associate with ART, prolongs survival, prevents relapse, and also allows discontinuing a secondary prophylaxis in a half of the cases.

Topics: Adult; AIDS-Related Opportunistic Infections; Amphotericin B; Antifungal Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Female; Follow-Up Studies; Hepatitis B; Hepatitis C; Humans; Immune Reconstitution Inflammatory Syndrome; Incidence; Itraconazole; Kaplan-Meier Estimate; Male; Mycoses; Penicillium; Recurrence; Retrospective Studies; Risk Factors; Tuberculosis; Vietnam

In this study the authors evaluated the efficacy of prophylaxis with liposomal amphotericin B (L-AmB) in the incidence of fungal infections (FI) during the first 3 months after liver transplant (LT). The study was retrospective and accessed a 4-year period from 2008 to 2011. All patients who died in the first 48 hours after LT were excluded. Patients were divided by the risk groups for FI: Group 1, high-risk (at least 1 of the following conditions: urgent LT; serum creatinine >2 mg/dL; early acute kidney injury [AKI] after LT; retransplantation; surgical exploration early post-LT; transfused cellular blood components [>40 U]); and Group 2, low-risk patients. Group 1 patients were further separated into those who received antifungal prophylaxis with L-AmB and those who did not. Prophylaxis with L-AmB consisted of intravenous administration of L-AmB, 100 mg daily for 14 days. Four hundred ninety-two patients underwent LT; 31 died in the first 48 hours after LT. From the remaining 461 patients, 104 presented with high-risk factors for FI (Group 1); of these, 66 patients received antifungal prophylaxis and 38 did not. In this group 8 FI were observed, 5 in patients without antifungal prophylaxis (P = .011). Three more FI were identified in Group 2. By logistic regression analysis, the categorical variable high-risk group was independently related to the occurrence of invasive FI (P = .006). We conclude that prophylaxis with L-AmB after LT was effective in reducing the incidence of FI. No influence on mortality was detected.

Topics: Amphotericin B; Antifungal Agents; Dose-Response Relationship, Drug; Female; Humans; Incidence; Infusions, Intravenous; Liver Transplantation; Male; Middle Aged; Mycoses; Reoperation; Retrospective Studies

Miltefosine is an alkylphosphocholine that shows broad-spectrum in vitro antifungal activities and limited in vivo efficacy in mouse models of cryptococcosis. To further explore the potential of this class of compounds for the treatment of systemic mycoses, nine analogs (3a-3i) were synthesized by modifying the choline structural moiety and the alkyl chain length of miltefosine. In vitro testing of these compounds against the opportunistic fungal pathogens Candida albicans, Candida glabrata, Candida krusei, Aspergillus fumigatus, and Cryptococcus neoformans revealed that N-benzyl-N,N-dimethyl-2-{[(hexadecyloxy)hydroxyphosphinyl]oxy}ethanaminium inner salt (3a), N,N-dimethyl-N-(4-nitrobenzyl)-2-{[(hexadecyloxy)hydroxyphosphinyl]oxy}ethanaminium inner salt (3d), and N-(4-methoxybenzyl)-N,N-dimethyl-2-{[(hexadecyloxy)hydroxyphosphinyl]oxy}ethanaminium inner salt (3e) exhibited minimum inhibitory concentrations (MIC) of 2.5-5.0 μg/mL against all tested pathogens, when compared to miltefosine with MICs of 2.5-3.3 μg/mL. Compound 3a showed low in vitro cytotoxicity against three mammalian cell lines similar to miltefosine. In vivo testing of 3a and miltefosine against C. albicans in a mouse model of systemic infection did not demonstrate efficacy. The results of this study indicate that further investigation will be required to determine the potential usefulness of the alkylphosphocholines in the treatment of invasive fungal infections.

Topics: Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Candida; Candidiasis; Cell Line; Cryptococcosis; Cryptococcus neoformans; Fungi; Humans; Mice; Mycoses; Phosphorylcholine

Two different series of N-substituted imidazolium oximes and their monoquaternary salts were synthesized and biologically tested with respect to their ability to inhibit growth a diverse panel of antibiotic susceptible Gram-positive and antibiotic resistant Gram-negative bacteria as well fungal strains. The newly synthesized compounds were analyzed by spectral studies to confirm their structure. The preliminary results showed that all compounds tested possess promising antimicrobial potential against both susceptible Gram-positive and antibiotic resistant Gram-negative isolates, exhibiting a wide range of MIC values from 0.14 to 100.0 μg/mL. The structure-activity relationship demonstrates that the p-methylphenyl and p-fluorophenyl groups in monoquaternary salts 6 and 7 attached directly to the imidazolium ring could be essential for observed remarkable inhibitory profiles against clinically important pathogens Pseudomonas aeruginosa (MIC=0.14 μg/mL) and Klebsiella pneumoniae (MIC=1.56 μg/mL). Furthermore, the broth microdilution assay was then used to investigate the antiresistance efficacy of compound 7 against fourteen extended-spectrum β-lactamase (ESBL)-producing strains in comparison to eight clinically relevant antibiotics. Compound 7 exhibited a remarkable antiresistance profiles ranging between 0.39 and 12.50 μg/mL against all of ESBL-producing strains, which leads to the suggestion that may be interesting candidate for development of new antimicrobials to combat multidrug resistant Gram-negative bacteria.

Topics: Anti-Infective Agents; Bacterial Infections; Drug Resistance, Multiple; Fungi; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Imidazoles; Microbial Sensitivity Tests; Mycoses; Oximes

Recommended doses of liposomal amphotericin B (L-AMB) range from 3 to 6 mg/kg/day, but 1mg/kg/day may be equally effective and a lower cost alternative for many indications. The objective of this analysis was to assess indications and clinical outcomes of patients who received low-dose (1mg/kg/day rounded up in 50-mg increments) and standard-dose (≥2 mg/kg/day) L-AMB.. This was a retrospective analysis of adult L-AMB recipients with suspected invasive fungal infections (IFI) at a single center from 2006 to 2011. The primary outcome was clinical response at the end of treatment. Secondary outcomes included survival and toxicity. Results were analyzed using Chi-square and descriptive statistics.. Of 89 adult L-AMB recipients included, 36 had proven or probable IFIs. Nineteen (53%) received low doses and 17 (47%) received standard doses. Median doses were 1.5 and 3.0mg/kg/day. Cryptococcus was the most common fungal pathogen in the low-dose group (37%), and Candida spp. in the standard-dose group (47%). Forty-seven percent of subjects in both groups improved clinically. Sixty-eight percent of low-dose recipients and 76% of standard-dose recipients survived to discharge. Rates of nephrotoxicity and hypokalemia were comparable.. Comparable rates of clinical improvement, survival to discharge, and toxicity were identified among low- and standard-dose L-AMB recipients.

Topics: Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Female; Hospitalization; Humans; Liposomes; Male; Middle Aged; Mycoses; Retrospective Studies; Treatment Outcome; Young Adult

Schizophyllum commune (n = 30) showed lowest geometric mean MICs of isavuconazole (0.19 μg/ml), itraconazole (0.2 μg/ml), voriconazole (0.24 μg/ml), and amphotericin B (0.29 μg/ml) and high geometric mean MICs of fluconazole (19.39 μg/ml) and flucytosine (17.28 μg/ml). Five cases (of 8) of allergic bronchopulmonary mycosis that were treated with itraconazole had no recrudescence after 6 to 24 months of follow-up. One case each of invasive pulmonary mycosis and fungal ball were treated successfully with voriconazole and itraconazole.

Topics: Amphotericin B; Antifungal Agents; Humans; Invasive Pulmonary Aspergillosis; Itraconazole; Microbial Sensitivity Tests; Molecular Sequence Data; Mycoses; Pyrimidines; Schizophyllum; Sequence Analysis, DNA; Treatment Outcome; Triazoles; Voriconazole

Schizophyllum commune is a globally distributed basidiomycete fungus that is known as a rare cause of sinusitis, for which no prompt treatment has been established. We describe the first report of S. commune sinusitis following unrelated cord blood transplantation for acute lymphoblastic leukemia. Thirteen days after transplantation, a 23-year-old female developed maxillary and ethmoid sinusitis. The sinusitis was antimicrobial-resistant, and the sinus aspirate culture revealed white wooly mold, which was identified as S. commune by nucleotide sequencing. The patient was successfully treated with intravenous administration of liposomal amphotericin B for 2 months, followed by oral voriconazole. This report suggests the effectiveness of liposomal amphotericin B and voriconazole for S. commune infection in immunocompromised patients. Given the difficulty in distinguishing S. commune infection from aspergillosis by standard culture methods, the incidence of S. commune infection following allogeneic hematopoietic stem cell transplantation may be underestimated. Nucleotide sequencing may be useful in the diagnosis of S. commune infection.

Topics: Adult; Allografts; Amphotericin B; Antifungal Agents; Cord Blood Stem Cell Transplantation; Ethmoid Sinusitis; Female; Humans; Maxillary Sinusitis; Mycoses; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Schizophyllum

Nephrotoxicity evaluations between liposomal amphotericin B (L-AMB) and amphotericin B lipid complex (ABLC) have provided mixed results. This retrospective study used an electronic medical record database of hospitalized patients with invasive fungal infections treated with either L-AMB or ABLC. Patients had renal insufficiency, clinical condition suggesting intolerance to amphotericin B deoxycholate (CAB), or recent CAB exposure. Baseline SCr, exposure to other nephrotoxic agents, and total amphotericin B exposure were similar between the groups. In 105 patients administered L-AMB, 10.6% had nephrotoxicity versus 22.6% of 222 patients administered ABLC (P = 0.020). A logistic regression model found ABLC patients had 3.48 higher odds (95% CI 1.05-11.52) than L-AMB of developing nephrotoxicity. Infusion reactions were more prevalent with ABLC (23.9% versus 9.5%, P = 0.002) as was hypomagnesemia (44.3% versus 28.1%, P = 0.033). This study demonstrated that L-AMB is associated with less nephrotoxicity, infusion reactions and hypomagnesemia than ABLC in patients at increased risk of nephrotoxicity.

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; Deoxycholic Acid; Drug Combinations; Female; Humans; Hypokalemia; Length of Stay; Male; Middle Aged; Multivariate Analysis; Mycoses; Renal Insufficiency; Retrospective Studies

Invasive fungal infections (IFIs) are a major concern within healthcare systems. This pharmacoeconomic study evaluated the use of caspofungin (CAS) versus liposomal amphotericin B (L-AmB) in the empirical treatment of IFIs within the Turkish healthcare system. A decision-analytic model was adopted, utilising data from a randomised, non-inferiority clinical trial and a panel of clinical experts in Turkey. A five-point composite outcome measure was used to evaluate both agents. Sensitivity analyses were performed. In the base-case scenario, CAS was preferred over L-AmB by Turkish Lira (TL) 3961 per patient treated, TL 12 904 per successfully treated patient and TL 3972 per death averted. One-way sensitivity analysis did not change the study outcome. Monte Carlo simulation concluded a 71.0% chance of the outcome favouring CAS. The results were most sensitive to changes in length of stay. This is the first economic evaluation of the empirical treatment of IFIs in Turkey and suggests that CAS is more cost effective than L-AmB.

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Cost-Benefit Analysis; Delivery of Health Care; Echinocandins; Febrile Neutropenia; Fever; Humans; Lipopeptides; Microbial Sensitivity Tests; Mycoses; Turkey

Limited data exist regarding echinocandins as antifungal prophylaxis in liver transplant recipients.. The efficacy and safety of targeted prophylaxis with micafungin or amphotericin B lipid complex (ABLC) was assessed in a sequential cohort of high-risk patients (posttransplantation dialysis, retransplantation, or reoperation) and compared with those without high risk who did not receive prophylaxis. Outcomes were assessed at 90 days.. Micafungin versus ABLC recipients were older (P=0.0065) and more likely to have hepatocellular carcinoma (P=0.025). High-risks, that is, dialysis (55.6% vs. 79.2%), retransplantation (5.6% vs. 12.5%), and reoperation (38.9% vs. 20.8%) did not differ between the two groups. Invasive fungal infections developed in 11.1% (2 of 18) of micafungin recipients, 8.3% (2 of 24) of ABLC recipients, and 3% (7 of 234) of patients without high risks (P=0.12). In nondialyzed patients, ABLC versus micafungin recipients had significantly higher serum creatinine on day 14 (P=0.04). However, renal and hepatic function, rejection, graft loss, and mortality did not differ for the two groups on day 90.. Targeted prophylaxis with micafungin or ABLC decreased the risk of mycoses in high-risk recipients compared with that in low-risk recipients. Compared with ABLC, however, micafungin appeared to be associated with lower early-renal dysfunction and no additional risk of hepatic dysfunction.

Topics: Amphotericin B; Antifungal Agents; Chi-Square Distribution; Drug Administration Schedule; Echinocandins; Female; Graft Rejection; Humans; Immunocompromised Host; Kidney Diseases; Lipopeptides; Liver Transplantation; Male; Micafungin; Middle Aged; Mycoses; Premedication; Renal Dialysis; Reoperation; Risk Factors; Time Factors; Treatment Outcome

To investigate the risk factors, clinical features, efficacy and adverse reactions in patients of hematologic diseases with invasive fungal infections (IFI).. The risk factors and clinical features were retrospectively analyzed to compare the efficacy and safety of itraconazole with amphotericin B in treatment of IFI in 76 patients with hematologic diseases.. Of the 76 patients, 68 (89.5%) used broad-spectrum antibiotics, 64 (84.2%) were treated with more than 2 courses chemotherapy, 43 (56.6%) were under agranulocytosis, 34 (44.7%) were using glucocorticoid for long terms, 27 (35.5%) were with peripheral or central venous catheter. The overall effective rates of itraconazole and amphotericin B were 60.5% and 61.5% respectively (P = 0.929). There was a significant difference between itraconazole and amphotericin B in hypokalemia (14.0% vs 42.4%, P = 0.005) while no other differences in adverse reactions were found.. The risk factors of patients in hematologic diseases with IFI include chemotherapy, using broad septum antibiotics and agranulocysis. The therapeutic effect of itraconazole and amphotericin B in treatment of IFI is similar. The adverse reactions of itraconazole is less and slighter than amphotericin B.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Female; Hematologic Diseases; Humans; Itraconazole; Male; Middle Aged; Mycoses; Retrospective Studies; Risk Factors; Treatment Outcome; Young Adult

Topics: Amphotericin B; Antifungal Agents; Child; Child, Preschool; Fluconazole; Humans; Mycoses; Practice Guidelines as Topic

We evaluated and compared the efficacies of different antifungal drugs against Sarocladium kiliense (formerly Acremonium kiliense), a clinically relevant opportunistic fungus, in a murine model of systemic infection. Three clinical strains of this fungus were tested, and the therapy administered was as follows: posaconazole at 20 mg/kg of body weight (twice daily), voriconazole at 40 mg/kg, anidulafungin at 10 mg/kg, or amphotericin B at 0.8 mg/kg. The efficacy was evaluated by prolonged animal survival, tissue burden reduction, and (1→3)-β-d-glucan serum levels. In general, the four antifungal drugs showed high MICs and poor in vitro activity. The efficacy of the different treatments was only modest, since survival rates were never higher than 40% and no drug was able to reduce fungal load in all the organs for the three strains tested. Posaconazole, in spite of its high MICs (≥16 μg/ml), showed the highest efficacy. The (1→3)-β-d-glucan serum levels were equally reduced by all drugs evaluated.

Topics: Acremonium; Amphotericin B; Anidulafungin; Animals; Antifungal Agents; Echinocandins; Male; Mice; Mycoses; Pyrimidines; Triazoles; Voriconazole

Invasive fungal infections (IFI) are associated with considerable expense and mortality on healthcare systems. There is a need to provide evidence of both clinical efficacy and value for money with any health technology. The current pharmacoeconomic evaluation investigated the use of liposomal amphotericin B (LAmB) and voriconazole for the empiric treatment of IFI in the Turkish setting.. Decision analytic modelling was used to create a pathway for patient treatment with a 5-point composite outcome measure. The data was obtained from a major non-inferiority multicentre randomised controlled study, with an expert panel of clinicians in Turkey providing transition probabilities and cost not available in the literature. Sensitivity analyses were performed on the inputs from the clinical trial and the expert panel.. As per the base case analysis, voriconazole was preferred by Turkish Lira (TL) 2,523 per patient treated and TL2,520 per surviving patient. LAmB was the preferred alternative by TL5,362 per successfully treated patient. Removing fever resolution as part of the composite outcome measure resulted in voriconazole being the preferred alternative per successfully treated patient. Univariate sensitivity analysis highlighted that increasing the duration of voriconazole by >1.2 days or decreasing LAmB by >1.0 days changes the result. Monte Carlo Simulation resulted in 69.4% of simulations favouring voriconazole per patient treated.. There is a strong likelihood that voriconazole is economically more favourable than LAmB in the empiric treatment of IFI in Turkey.

Topics: Amphotericin B; Antifungal Agents; Cost-Benefit Analysis; Economics, Pharmaceutical; Humans; Mycoses; Pyrimidines; Treatment Outcome; Triazoles; Turkey; Voriconazole

To summarize the clinical datas of thepatients with invasive laryngeal fungal infections in, discuss pathogenesis and treatment methods.. Eleven cases of invasive laryngeal fmycosis who were collected from September 2006 to February 2010 with electronic laryngoscopy, aspirate smear and culture and tissue biopsy for pathological diagnosis, were restrospectively analyzed. Those patients were received iv fluconazole, treatment of Oxygen Atomization of amphotericin B solution and taking itraconazole orally. The hepatic and renal functions of the patients were monitored in the course of treatment.. All the cases were diagnosed of invasive laryngeal mycosis. 1 patient showed liver dysfunction in the second week during treatment. And continuing the treatment after using liver protection drugs. All symptoms of the patients were improved and no recurrence happened during the 1-6 years of follow-up.. Invasive laryngeal fmycosis was correlated with occupation exposure, abusing of antibiotics and low immunity. Laryngeal mycosis was Diagnosised mainly depended on the pathological examination. The positive rates of the secretion smear was low. The effects of iv fluconazole, Oxygen Atomization of amphotericin B 2-4 weeks, and 4 weeks of taking itraconazole orally were safety and reliable.

Topics: Administration, Oral; Amphotericin B; Antifungal Agents; Chemical and Drug Induced Liver Injury; Fluconazole; Humans; Itraconazole; Laryngeal Diseases; Mycoses

Sinonasal polyposis is considered to be the end-result of a chronic inflammatory process in the sinonasal mucosa. Its underlying mechanisms are still unclear, but the involvement of fungi has been suggested for many years. In the present study, we retrospectively evaluated the clinical and mycological profile of 161 patients with chronic rhinosinusitis (CRS) and nasal polyps who were undergoing surgery at our tertiary care facility during 2002 to 2010. CT scan findings and per-operative presence of allergic mucin were provisionally suggestive of fungal rhinosinusitis (FRS) in all the patients. Total serum IgE and peripheral eosinophilia were noted. Histological examination of polyp tissue showed eosinophilic mucin in 100% of the cases and the incidence of allergic fungal rhinosinusitis (AFRS) was 83.9% in the patient population. KOH and/or culture were positive for fungal hyphae or yeast in 93% (150/161) of the patients. Aspergillus spp. were the most commonly recovered isolates (70%). MICs of all A. flavus and A. fumigatus isolates were within the susceptible zone for itraconazole, voriconazole, and amphoterecin B. In conclusion, allergic fungal rhinosinusitis (FRS) is a common disorder in patients with sinonasal polyposis and due to its recurrent and intractable nature, a high degree of clinical suspicion for the presence of FRS in nasal polyposis should be considered.

Topics: Adult; Amphotericin B; Antifungal Agents; Aspergillosis; Chronic Disease; Female; Fungi; Humans; Immunoglobulin E; Incidence; India; Itraconazole; Male; Middle Aged; Mucins; Mycoses; Nasal Polyps; Pyrimidines; Retrospective Studies; Rhinitis, Allergic, Perennial; Sinusitis; Tertiary Healthcare; Tomography, X-Ray Computed; Triazoles; Voriconazole

Antifungal prophylaxis with liposomal amphotericin B in high-risk liver transplant recipients is recommended, but experience with amphotericin B lipid complex (ABLC, Abelcet(®)) in this setting is limited. Data from 615 liver transplants performed during 1999-2005 were analyzed retrospectively. High-risk patients (n = 146) received a mean cumulative ABLC dose of 955 ± 609 mg (mean duration of 23.3 ± 11.9 days). Low-risk patients (n = 469) received no prophylaxis. During a mean follow-up of 43.8 ± 29.2 months, fungal infections occurred in 32.2% of ABLC patients versus 43.5% of non-prophylaxis patients (P = 0.015). The overall rate of invasive fungal infection was 12.3% in the ABLC group versus 15.6% in the non-prophylaxis patients (P = 0.34). Any Candida infection (ABLC 29.5%, non-prophylaxis 41.2%, P = 0.011), probable or proven invasive Candida infection requiring systemic antifungal treatment (ABLC 18.5%, non-prophylaxis 32.4%, P = 0.001) and invasive abdominal candidiasis during the first 3 months (ABLC 4.1%, non-prophylaxis 9.2%, P = 0.049) were significantly less frequent in the ABLC group. There was no significant difference between groups in the incidence of Aspergillus infections. The ABLC group showed no evidence of nephrotoxicity. In conclusion, the marked and significant differences in infection rates and requirement for systemic treatment in this large population suggest that targeted use of low-dose ABLC therapy to high-risk patients is a valid prophylactic strategy following liver transplantation.

Topics: Adult; Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis, Invasive; Cyclosporine; Female; Follow-Up Studies; France; Humans; Immunosuppressive Agents; Kidney; Liposomes; Liver Transplantation; Male; Middle Aged; Mycoses; Postoperative Complications; Retrospective Studies; Safety; Tacrolimus; Treatment Outcome

Topics: Amphotericin B; Antifungal Agents; Humans; Infant, Premature, Diseases; Kidney Diseases; Mycoses

Topics: Amphotericin B; Antifungal Agents; Humans; Infant, Premature, Diseases; Kidney Diseases; Mycoses

Deoxycholate amphotericin B (DAB) is a nephrotoxic drug and the incidence of acute kidney injury (AKI) is high.. The aim of this study was to describe the incidence of AKI in patients under DAB therapy and determine risk factor to predict the AKI.. The data of this retrospective study included previously hospitalized patients treated with intravenous DAB for at least five days. Clinical and laboratorial data were evaluated and AKI was classified in stages using Acute Kidney Injury Network criteria. Univariated test followed by a multivariable analysis was performed to determine risk factor and Kaplan-Meier survival estimates were calculated to evaluate the role of AKI in the outcome.. One hundred six patients were included in the final analysis. AKI occurred in 51.9% and dialysis was necessary in 4.7%. The occurrence of AKI was not associated with any risk factor. The mortality of the patients was neither associated with AKI nor with dialysis. Other nephrotoxic drugs were not risk factors for AKI.. The incidence of AKI in patients using DAB is high and we cannot predict the chance of AKI using clinical or laboratorial data.

Topics: Acute Kidney Injury; Adult; Aged; Amphotericin B; Antifungal Agents; Brazil; Comorbidity; Deoxycholic Acid; Drug Combinations; Female; Humans; Incidence; Inpatients; Kaplan-Meier Estimate; Male; Middle Aged; Mycoses; Polypharmacy; Postoperative Complications; Renal Dialysis; Retrospective Studies; Risk Factors; Treatment Outcome; Young Adult

In the attempt to establish key therapy definitions and provide shared approaches to invasive fungal diseases in neutropenic patients, trials of empiric, preeemptive and targeted antifungal therapy (EAT, PAT and TAT) were reviewed, and a Consensus Development Conference Project was convened. The Expert-Panel concurred that all antifungal treatments, including EAT, should always follow an adequate diagnostic strategy and that the standard definition of PAT may be misleading: being PAT guided by the results of a diagnostic work-up, it should better be termed diagnostic-driven antifungal therapy (DDAT). The Expert-Panel agreed that radiological findings alone are insufficient for the choice of a TAT and that the identification of the etiologic pathogen is needed. The Consensus Agreement proceeded identifying which clinical and microbiological findings were sufficient to start a DDAT and which were not. Finally, an algorithm to rationalize the choice of antifungal drugs on the basis of clinical manifestations, antifungal prophylaxis, instrumental and laboratory findings was drawn up.

Topics: Amphotericin B; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Chemotherapy-Induced Febrile Neutropenia; Clinical Trials as Topic; Drug Administration Schedule; Drug Resistance, Fungal; Drug Therapy, Combination; Febrile Neutropenia; Fungi; Hematologic Neoplasms; Humans; Immunocompromised Host; Multicenter Studies as Topic; Mycoses; Premedication; Prospective Studies; Randomized Controlled Trials as Topic; Transplantation Conditioning; Triazoles

Liposomal amphotericin B (L-AmB) is recommended as an empirical antifungal treatment for patients at increased risk of fungal infections although renal toxicity remains a clinical problem. We therefore conducted a pilot study to evaluate the safety and efficacy of low-dose L-AmB as an empirical antifungal therapy for patients with prolonged neutropenia.. High-risk patients with hematological malignancies were eligible to enroll in this study provided they had: exhibited neutropenia for at least 1 week; suffered from high-grade fever for 4 days despite treatment with a broad-spectrum antibacterial; and no identified fever-causing pathogen. Low-dose L-AmB (1 mg/kg) was administrated as empirical antifungal therapy.. Sixteen patients were registered and, of these, data from the13 patients who did not receive allogeneic stem cell transplantation were analyzed. The median duration of low-dose L-AmB treatment was 8 days. Hypokalemia was seen in one patient: administration of potassium supplements for 10 days restored potassium levels to the normal range. A two-fold increase in creatinine levels was not found in any patients even those taking concomitant nephrotoxic drugs (e.g., amynoglycoside) during the study. One patient stopped receiving the drug due to an infusion-related adverse event. No patients showed breakthrough fungal infections or died during therapy or within 7 days after the end of the study. Increase in the L-AmB dose was necessary due to persistent fever in three patients who withdrew from the study. The satisfactory response rate for low-dose L-AmB was 69 %.. This study suggests that low-dose L-AmB may be an effective option as empirical antifungal therapy for high-risk patients with febrile neutropenia.

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; Female; Fever; Hematologic Neoplasms; Humans; Liposomes; Male; Middle Aged; Mycoses; Neutropenia

Because published reports indicate that the antibiotic colistin (COL) has antifungal properties, this study investigated the antifungal in vitro activity of COL as single agent and in combination with the antifungal compounds voriconazole (VRC), caspofungin (CAS) and amphotericin B (AMB) against Scedosporium/Pseudallescheria spp., Exophiala dermatitidis and Geosmithia argillacea. In total, susceptibility was determined for 77 Scedosporium/Pseudallescheria spp., 82 E. dermatitidis and 17 G. argillacea isolates. The minimal inhibitory concentrations (MICs) of COL and the antifungals as single compound and in combination were determined with MIC test strips. Drug interactions were detected by crossing the MIC test strips at a 90º angle. The fractional inhibitory concentration index was used to categorise the drugs' interaction. The MIC50 value of COL was 12 μg ml(-1) for S. prolificans, 16 μg ml(-1) for P. apiosperma, 16 μg ml(-1) for P. boydii, 12 μg ml(-1) for E. dermatiditis and 6 μg ml(-1) for G. argillacea. VRC was the most active drug in combination without any antagonism with the exception of few P. boydii isolates. COL as single agent and in most combinations with antifungals exhibits in vitro antifungal activity against filamentous ascomycetes occurring in cystic fibrosis patients and may offer a novel therapeutic option, especially for multidrug-resistant S. prolificans.

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Colistin; Cystic Fibrosis; Drug Evaluation, Preclinical; Drug Synergism; Echinocandins; Exophiala; Humans; Lipopeptides; Microbial Sensitivity Tests; Mitosporic Fungi; Mycoses; Pyrimidines; Scedosporium; Triazoles; Voriconazole

A yeast strain was isolated from the sputum sample of a leukaemia patient in the Spirito Santo Hospital of Pescara, Italy. The fungus produced a pigment that formed a reddish halo around colonies, and was identified and deposited as a Metschnikowia spp. (accession number IHEM 25107-GenBank accession number JQ921016) in the BCCM/IHEM collection of biomedical fungi and yeasts (Bruxelles, Belgium). Although the physiology of the strain was close to that of Metschnikowia sinensis, the D1/D2 sequence did not correspond to any previously described Metschnikowia species. Phylogeny of the genus Metschnikowia is complex and requires far more analysis. We present the first non-M. pulcherrima Metschnikowia spp. isolate recovered from a human, and emphasize the role of man as a transient carrier of environmental yeasts, the pathogenicity of which still needs to be defined.

Topics: Amphotericin B; Antifungal Agents; Base Sequence; DNA, Fungal; DNA, Ribosomal; Fluconazole; Humans; Italy; Leukemia; Male; Metschnikowia; Microbial Sensitivity Tests; Molecular Sequence Data; Mycoses; Phylogeny; Pigments, Biological; Pyrazines; Sequence Analysis, DNA; Sputum; Voriconazole

The efficacy and safety of liposomal amphotericin B (L-AMB) in the treatment of invasive fungal infections (IFIs) were retrospectively evaluated for patients with connective tissue diseases (CTDs) during treatment with immunosuppressive therapy. Subjects were 13 patients with CTDs complicated by IFI, on the basis of clinical symptoms, imaging findings, and microbiological and histological examinations. All patients were treated with L-AMB. Efficacy and safety were evaluated before and after administration of L-AMB. Underlying diseases were systemic lupus erythematosus for 4 patients, rheumatoid arthritis for 3, microscopic polyangiitis for 2, adult-onset Still disease for 1, dermatomyositis for 1, and mixed connective tissue disease for 1. Eight patients were resistant to other antifungal drugs. Prednisolone was given to 11 patients and the median dose was 10 mg/day. Immunosuppressants were used for 8 patients. The median duration of administration of L-AMB was 8.5 days (range 4-38 days). In proven and probable diagnosis patients (n = 5), the treatment was effective for 3 patients and ineffective for 2 (efficacy rate 60 %). Serum 1,3-β-D-glucan antigenemia (BG) levels decreased after treatment in the 2 patients who were positive for BG. Serum Aspergillus galactomannan antigen levels decreased in 3 of 4 patients with Aspergillus infection. No patient died of IFI. Regarding potential adverse reactions, there were no significant changes in serum creatinine and potassium levels. L-AMB is effective and well-tolerated for treatment of IFI in patients with CTDs.

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; Connective Tissue Diseases; Creatinine; Female; Humans; Male; Middle Aged; Mycoses; Potassium; Prognosis; Retrospective Studies; Treatment Outcome

To report a case of accidental amphotericin B overdose that was treated with plasmapheresis.. A 60-year-old woman with a history of kidney transplant 4 years prior to presentation for a congenital abnormality was admitted for a suspected systemic fungal infection. The patient inadvertently received intravenous amphotericin B deoxycholate 250 mg (4.3 mg/kg) over 2 hours instead of prescribed liposomal amphotericin B. The medication error was discovered 16 hours after administration. She had normal vital signs at that time and reported abdominal pain and general malaise. Results of a metabolic panel were significant for a creatinine level of 2.1 mg/dL and CO₂ of 17 mg/dL. Her serum amphotericin B concentration 33 hours after the initial dose was 4.9 μg/mL. She subsequently received 5 courses of plasmapheresis and 3 courses of hemodialysis and ultimately did not develop any further renal injury, as well as hemolysis, cardiovascular collapse, dysrhythmias, or severe electrolyte abnormalities.. The dosing differences between nonliposomal and liposomal preparations of amphotericin B can be as high as 50-fold. Reported adverse events from overdose in both animal models and human case reports include renal insufficiency, hemolysis, thrombocytopenia, electrolyte abnormality, and cardiac dysrhythmias. There have been previous reports of similar errors that have led to death. Furthermore, amphotericin B has been shown to be poorly dialyzable. Our patient's serum amphotericin B concentration decreased after she received plasmapheresis, and she did not develop severe complications.. We describe a patient who survived a 4-fold overdose of amphotericin B because of a medication error. The use of plasmapheresis may have enhanced the elimination of amphotericin B and may have contributed to the positive outcome. However, the role of plasmapheresis in amphotericin overdose is not fully understood.

Topics: Amphotericin B; Antifungal Agents; Deoxycholic Acid; Drug Combinations; Drug Overdose; Female; Humans; Immunocompromised Host; Infusions, Intravenous; Kidney Transplantation; Medication Errors; Middle Aged; Mycoses; Plasmapheresis; Renal Dialysis; Treatment Outcome

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillus fumigatus; Cladosporium; Humans; Mucormycosis; Mycoses; Pyrimidines; Rhizopus; Rhodotorula; Triazoles; Voriconazole

We report a case of mycotic keratitis caused by a rare fungus Schizophyllum commune.. Clinical examination, slit-lamp examination, and microbiological evaluation of the corneal ulcer were done, and its treatment outcome was studied. The fungal etiology was established by conventional microbiological techniques, polymerase chain reaction and speciation by DNA sequencing.. Corneal scraping showed the presence of fungal filaments. The fungus was identified as S. commune based on DNA sequence analysis of the internal transcribed spacer region. The organism was susceptible to amphotericin B and voriconazole and demonstrated resistance to anidulafungin, itraconazole, and fluconazole. Therapeutic keratoplasty was performed but there was recurrence of the infection in the graft, which was controlled with topical voriconazole and intracameral amphotericin B. At the end of 3 months, the affected eye had developed phthisis bulbi.. The best of our knowledge, this is the first reported case of keratitis caused by the rare fungus S. commune. Management of these cases is difficult, and surgical procedures may be needed.

Topics: Administration, Topical; Adult; Amphotericin B; Antifungal Agents; Cornea; Corneal Transplantation; DNA, Fungal; DNA, Ribosomal Spacer; Humans; Keratitis; Male; Molecular Sequence Data; Mycoses; Polymerase Chain Reaction; Pyrimidines; Schizophyllum; Sequence Analysis, DNA; Treatment Outcome; Triazoles; Voriconazole

Benzoyl phenyl urea, a class of insect growth regulator's acts by inhibiting chitin synthesis. Carvacrol, a naturally occurring monoterpenoid is an effective antifungal agent. We have structurally modified carvacrol (2-methyl-5-[1-methylethyl] phenol) by introducing benzoylphenyl urea linkage. Two series of benzoylcarvacryl thiourea (BCTU, 4a-f) and benzoylcarvacryl urea (BCU, 5a-f) derivatives were prepared and characterized by elemental analysis, IR, (1)H and (13)C NMR and Mass spectroscopy. Derivatives 4b, 4d, 4e, 4f and 5d, 5f showed comparable insecticidal activity with the standard BPU lufenuron against Dysdercus koenigii. BCTU derivatives 4c, 4e and BCU 5c showed good antifungal activity against phytopathogenic fungi viz. Magnaporthe grisae, Fusarium oxysporum, Dreschlera oryzae; food spoilage yeasts viz. Debaromyces hansenii, Pichia membranifaciens; and human pathogens viz. Candida albicans and Cryptococcus neoformans. Compounds 5d, 5e and 5f showed potent activity against human pathogens. Moderate and selective activity was observed for other compounds. All the synthesized compounds were non-haemolytic. These compounds have potential application in agriculture and medicine.

Topics: Animals; Antifungal Agents; Cymenes; Fungi; Humans; Insecta; Insecticides; Microbial Sensitivity Tests; Monoterpenes; Mycoses; Phenylurea Compounds; Thiourea

In an attempt to identify new potential lead as antimicrobial agent, twenty hybrids of marine bromopyrrole alkaloids with 1,3,4-oxadiazole were designed based on molecular hybridization technique and synthesized. Synthesized molecules were evaluated for their antibacterial, antifungal and antitubercular activities. Hybrids 5d, 5i, 5j and 5k exhibited equivalent antibacterial activity (MIC of 1.56 μg/mL) compared with standard drug ciprofloxacin against Staphylococcus aureus and Escherichia coli. Equal antifungal activity (MIC of 1.56 μg/mL) was shown by of hybrids 5j, 5k and 7d compared with standard Amphotericin-B. The inhibition of Mycobacterium tuberculosis at concentrations as low as 1.6 and 1.5 μg/mL by compounds 5f and 7d respectively indicates that these compounds can act as leads for development of newer anti-TB compounds.

Topics: Alkaloids; Anti-Infective Agents; Antitubercular Agents; Bacteria; Bacterial Infections; Fungi; Halogenation; Humans; Microbial Sensitivity Tests; Mycoses; Oxadiazoles; Pyrroles

Topics: Adult; Amphotericin B; Antifungal Agents; Buprenorphine; Candidiasis; Endocarditis; Endophthalmitis; Eye Infections, Fungal; Fatal Outcome; Flucytosine; Hepatitis C, Chronic; Heroin Dependence; Humans; Male; Mycoses; Pneumonia, Staphylococcal; Recurrence; Shock, Cardiogenic; Substance Abuse, Intravenous; Tricuspid Valve; Ultrasonography

Yeasts occur as part of the normal human microbiota. Nevertheless, some species are opportunistic, affecting immunocompromised patients such as those undergoing oncologic treatment.. To detect the presence of yeasts in patients suffering from head and neck cancer who are receiving radiation therapy and display lesions in the oral cavity, compatible with candidiasis; and to evaluate the antifungal susceptibility of the isolates recovered.. Sixty samples from patients were obtained by swabbing the oral mucosa. Identification of isolates were performed by classical taxonomic, morphological and biochemical methods as well as by using commercial identification kits. Susceptibility to antifungal drugs was determined by the agar diffusion method with Neosensitabs(®) disks.. Forty-six samples (77%) yielded positive findings, and species recovered were: Candida albicans (22 isolates), Candida tropicalis (13 isolates), Candida parapsilosis (six strains), Candida krusei (three strains), Candida dubliniensis and Saccharomyces cerevisiae (one each). All strains were susceptible to itraconazole, clotrimazole, voriconazole, nystatin and amphotericin B. On the other hand, 65% of strains were miconazole-susceptible while 35%, showed intermediate susceptibility. With regard to ketoconazole, only three strains (7%) corresponding to C. albicans (one isolate) and C. krusei (two isolates) displayed intermediate susceptibility. Only C. krusei strains were resistant to fluconazole while all the other species were susceptible. Eventually, only six isolates (13%) were susceptible to terbinafine while the remaining strains were resistant in vitro.. Early detection of etiological agents causing lesions, as well as the evaluation of their susceptibility to commonly used drugs, are crucial in order to choose the appropriate treatment that will minimize complications while improving the quality of patients' lives.

Topics: Amphotericin B; Antifungal Agents; Candidiasis, Oral; Drug Resistance, Fungal; Head and Neck Neoplasms; Humans; Microbial Sensitivity Tests; Mycoses; Naphthalenes; Nystatin; Opportunistic Infections; Saccharomyces cerevisiae; Species Specificity; Terbinafine; Triazoles

A six-year-old female entire German shepherd dog was investigated for polyuria, polydipsia and lethargy. Investigations revealed a mild azotaemia and abdominal ultrasound revealed marked bilateral dilation of the renal pelves with echogenic material and proximal left hydroureter. Urine cytological examination and aspirates from the right renal pelvis revealed mats of fungal hyphae consistent with fungal bezoar formation. Fungal cultures revealed a profuse growth of Paecilomyces variotii. Initial treatment with oral itraconazole was unsuccessful, leading to bilateral nephrotomies to remove the fungal material. Postoperatively the Paecilomyces infection persisted despite continued itraconazole therapy. Treatment was commenced with amphotericin B, leading to resolution of the dog's clinical signs. To the authors' knowledge this is the first report of canine Paecilomyces pyelonephritis, without disseminated systemic disease, which documents its successful treatment.

Topics: Amphotericin B; Animals; Antifungal Agents; Dog Diseases; Dogs; Female; Itraconazole; Kidney; Mycoses; Paecilomyces; Pyelonephritis

Topics: Amphotericin B; Antifungal Agents; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Mycoses

The purpose of this investigation was to describe the characteristics of the use of systemic antifungal agents (AFAs) and to evaluate their appropriateness of use. A prospective drug-utilisation study was conducted in intensive-care areas: haematology-oncology services and transplant units. Data were collected in three periods over 9 months. The required sample size was determined to be 113 patients (margin of error ±7%, 95% confidence interval [CI]), assuming a variability of 50%. Two different investigator groups evaluated the appropriateness of use separately; Cohen's Kappa index was used to calculate the degree of agreement between groups. A total of 114 patients we included, of which 62 (54.4%) were children. A total of 150 prescriptions were administered; fluconazole was the most frequently prescribed (38%), followed by liposomal amphotericin B (22.7%) and caspofungin (18.7%). The indications were: (1) pre-emptive treatment of Candida in non-neutropaenic critically ill patients (35.1%), (2) treatment of systemic fungal infection (24.6%), (3) prophylaxis for systemic fungal infection (SFI) in immunocompromised patients (16.7%), (4) prophylaxis of SFI in transplant recipients (12.3%), (5) prophylaxis of SFI in preterm infants (5.3%), (6) treatment of SFI in neonates (6.1%). The Kappa index showed a substantial agreement (Kappa = 0.73). The indications were considered to be inappropriate in 71 (47.3%) episodes. The indications or dosages were inappropriate in 79 cases (52.7%). The indications, dosages or duration of treatment were inappropriate in 83 cases (55.3%). We conclude that AFAs are prescribed for a significant number of inappropriate indications.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus; Candida; Candidiasis; Caspofungin; Child; Child, Preschool; Drug Utilization; Echinocandins; Female; Fluconazole; Humans; Immunocompromised Host; Inappropriate Prescribing; Infant; Intensive Care Units; Lipopeptides; Male; Middle Aged; Mycoses; Prospective Studies; Transplantation; Young Adult

Literature provides much evidence regarding liposomal amphotericin B treatment for fungal infections in neonates and infants. Relevant data regarding critically ill paediatric patients of older age are scarce. We aimed to present our experience regarding liposomal amphotericin B use in critically ill paediatric patients from a tertiary-care paediatric hospital in Athens, Greece.. We prospectively identified all paediatric patients who received treatment with liposomal amphotericin B in the intensive care unit of a tertiary-care paediatric hospital during a 3-year period (2005-2008). Data were retrieved from the evaluation of the available medical records.. Twenty-three (nine females, mean age: 26·4 months, range: 5-39 months) critically ill paediatric patients were included; 12 had malignancy. In 16 of the 23 included children, liposomal amphotericin B was administered for the treatment of confirmed fungal infections (all but one were invasive), whereas in seven patients, it was used as pre-emptive treatment. One patient received voriconazole concomitantly. Eleven of the 16 children with documented infections were cured; five improved. Six of the seven children who received pre-emptive treatment also showed clinical improvement. Nine deaths were noted, all attributed to underlying diseases. Two cases of hepatotoxicity and one case of nephrotoxicity (all leading to drug-discontinuation) occurred. Seven and five cases of mild reversible hypokalaemia and hyponatraemia, respectively, were also noted.. According to the findings of our small case series, liposomal amphotericin B may provide a useful treatment option for fungal infections of vulnerable critically ill paediatric patients with considerable comorbidity.

Topics: Amphotericin B; Antifungal Agents; Chemical and Drug Induced Liver Injury; Child, Preschool; Comorbidity; Drug Monitoring; Female; Greece; Hospitals, Pediatric; Humans; Hypokalemia; Hyponatremia; Infant; Intensive Care Units, Pediatric; Liposomes; Male; Mycoses; Neoplasms; Prospective Studies; Renal Insufficiency

Many natural broad-spectrum cationic antimicrobial peptides (AMPs) possess a general mode of action that is dependent on lipophilicity and charge. Modulating the lipophilicity of AMPs by the addition of a fatty acid has been an effective strategy to increase the lytic activity and can further broaden the spectrum of AMPs. However, lipophilic modifications that narrow the spectrum of activity and exclusively direct peptides to fungi are less common. Here, we show that short peptide sequences can be targeted to fungi with structured lipophilic biomolecules, such as vitamin E and cholesterol. The conjugates were active against Aspergillus fumigatus, Cryptococcus neoformans, and Candida albicans but not against bacteria and were observed to cause membrane perturbation by transmission electron microscopy and in membrane permeability studies. However, for C. albicans, selected compounds were effective without the perturbation of the cell membrane, and synergism was seen with a vitamin E conjugate and amphotericin B. Moreover, in combination with β-cyclodextrin, antibacterial activity emerged in selected compounds. Biocompatibility for selected active compounds was tested in vitro and in vivo using toxicity assays on erythrocytes, macrophages, and mice. In vitro cytotoxicity experiments led to selective toxicity ratios (50% lethal concentration/MIC) of up to 64 for highly active antifungal compounds, and no in vivo murine toxicity was seen. Taken together, these results highlight the importance of the conjugated lipophilic structure and suggest that the modulation of other biologically relevant peptides with hydrophobic moieties, such as cholesterol and vitamin E, generate compounds with unique bioactivity.

Topics: Amphotericin B; Animals; Antimicrobial Cationic Peptides; Aspergillus fumigatus; Bacteria; beta-Cyclodextrins; Candida albicans; Cell Membrane; Cell Membrane Permeability; Cholesterol; Cryptococcus neoformans; Drug Synergism; Erythrocytes; Hemolysis; Hydrophobic and Hydrophilic Interactions; Macrophages; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Microscopy, Electron, Transmission; Mycoses; Species Specificity; Static Electricity; Vitamin E

There have been no published studies evaluating the efficacy and safety of weekly liposomal amphotericin B as secondary prophylaxis in leukemic patients with invasive fungal infections (IFIs). We found in a retrospective review of our experience with 14 such patients admitted from 2003-2009 that the use of this approach was associated with frequent relapse of IFIs (36%) and kidney injury (36%).

Topics: Adult; Aged; Amphotericin B; Antibiotic Prophylaxis; Antifungal Agents; Female; Hematologic Neoplasms; Humans; Leukemia; Male; Middle Aged; Mycoses; Treatment Outcome; Young Adult

Penicillium marneffei is a thermally dimorphic fungus that causes severe human immunodeficiency virus-related opportunistic infection in endemic areas of Southeast Asia and has rarely been reported in solid organ transplant (SOT) recipients. We report here the case of an Australian renal transplant patient who presented with disseminated P. marneffei infection shortly after a 10-day holiday to Vietnam, and review all previously published cases of penicilliosis associated with renal transplantation. This is the first reported case, to our knowledge, of P. marneffei infection in an SOT recipient acquired during travel to an endemic country, and highlights the importance of an accurate travel history when opportunistic infection is suspected, as well as giving appropriate health advice to transplant patients who travel.

Topics: Aged; Amphotericin B; Antifungal Agents; Australia; Humans; Immunocompromised Host; Itraconazole; Kidney Transplantation; Male; Mycoses; Penicillium; Travel; Treatment Outcome; Vietnam

Invasive fungal infections continue to be a major cause of morbidity and mortality in immunocompromised or severely ill patients. This report highlights new research data presented at the 51st Interscience Conference on Antimicrobial Agents and Chemotherapy on invasive fungal disease and its treatment. A number of important clinical trials were reported, and there were also interesting presentations on the use of new diagnostic tools, further studies on therapeutic drug monitoring for azoles and updates on several of the emerging fungal pathogens.

Topics: Amphotericin B; Antibiotic Prophylaxis; Azoles; Biomarkers; Clinical Trials as Topic; Communicable Diseases, Emerging; Congresses as Topic; Diagnostic Techniques and Procedures; Drug Monitoring; Drug Resistance, Fungal; Humans; Immunocompromised Host; Mycoses

There are limited data about the use of antifungal agents (AF) in critically ill patients and treatment trends since the inclusion of the new generation AF. The use of these agents may have a significant influence on the development of new resistances.. Observational prospective study of the systemic use of AF in patients admitted to Spanish intensive care units (ICU) participating in the ENVIN-HELICS register, from 2006 to 2010. The annual use, the indications that led to that use and, the intra-ICU infections, the AF employment related to the hospital size, and per 1000 patients/day, were compared.. Of the 8240 prescriptions for AF, fluconazole and caspofungin were the most often employed (55% and 19.5%, respectively). An increase in use was observed to the year 2008, with subsequent stabilisation. A decrease in the use of fluconazole and an increase in echinocandins consumption was observed over time. As regards the intra-ICU infections, the AF were ordered empirically in 47.9% of the indications. Fluconazole was more frequently used in medium size hospitals than in the large ones (60.4% versus 53.3%; P=.036) and the opposite occurred in the case of caspofungin (15.8% versus 21.8%; P<.001). Fluconazole was more prematurely employed (median 12 days since ICU admission) and the duration of the therapy was similar to the other AF (median 8 days). The total therapy days were 39.51 per 1000 patient/day, with predominance in fluconazole use (21.48 per 1000 patients/day).. Fluconazole is the most used antifungal agent in critically ill patients in any of the indications, although a progressive decrease in its use is observed, with a proportional increase in the use of echinocandins.

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Community-Acquired Infections; Critical Illness; Cross Infection; Drug Prescriptions; Drug Utilization; Echinocandins; Female; Fluconazole; Hospital Bed Capacity; Humans; Immunocompromised Host; Intensive Care Units; Lipopeptides; Male; Middle Aged; Mycoses; Neutropenia; Prospective Studies; Registries; Spain

Mucormycetes (formerly known as zygomycetes of the order Mucorales) and hyaline moulds such as those of the genus Fusarium or Paecilomyces are emerging as significant human pathogens. The aim of the study was to determine the in vitro antifungal susceptibility of these fungi to older and newer antifungals and to investigate the antifungal activity of amphotericin B, posaconazole and anidulafungin in dual combinations.. Twenty-one clinical isolates of mucormycetes and 16 of rare hyaline moulds were tested. MICs were determined by EUCAST methodology for conidia-forming moulds and Etesting. For antifungal combinations a chequerboard method based on EUCAST methodology was used.. Against mucormycetes, amphotericin B exhibited the lowest MICs, followed by posaconazole. Ravuconazole was active against eight of the Rhizopus isolates (MIC 1 mg/L). Resistance to amphotericin B (MIC ≥ 2 mg/L) and posaconazole (MICs ≥ 4 mg/L) was observed in five and three Rhizopus isolates, respectively. Among Fusarium species variable susceptibility patterns were detected. Amphotericin B exhibited the lowest MICs, followed by voriconazole. Etesting for amphotericin B and posaconazole had excellent agreement with EUCAST methodology (78.6%-100%). Synergy between amphotericin B and anidulafungin was observed against two isolates (one Mucor circinelloides and one Fusarium proliferatum). Synergy or antagonism was not detected in any other combination.. The study showed that mucormycetes and other rare hyaline moulds exhibit variable susceptibilities to antifungals, and hence antifungal testing is valuable. The fact that the combination of amphotericin B with anidulafungin was found synergistic in some cases merits further investigation.

Topics: Amphotericin B; Anidulafungin; Antifungal Agents; Drug Synergism; Echinocandins; Fungi; Humans; Microbial Sensitivity Tests; Mycoses; Triazoles

Transplant recipients require immunosuppression to prevent allograft rejection, placing them at risk of opportunistic infections including fungal infection. Difficulties in managing fungal infections include: establishing diagnosis, poor treatment response, drug interactions and toxicity. We report our single centre experience of treating fungal infections using systemic non-Amphotericin current generation antifungals. Patients receiving inpatient antifungal therapy from September 2005 to December 2010 were identified from pharmacy records. Fungal infections were retrospectively classified according to European Organization for Research and Treatment of Cancer (EORTC) criteria. Treatment outcomes were classified in a manner similar to those used in clinical trials. Two hundred and forty-nine recipients received antifungal treatment, 204 lungs and 45 hearts. One hundred and one patients received Voriconazole, 82 Caspofungin and 65 received both agents. One patient was unsuccessfully treated with additional Amphotericin. Treatment duration varied from 1.5 to 12 weeks. One hundred and sixty-five patients had a complete response, 24 had a partial response and in 60 patients treatment was unsuccessful. The response to systemic non-Amphotericin based antifungal therapy was high. We propose that diagnostic criteria without positive identification of a fungus allow treatment to be started early with few clinically relevant side effects.

Topics: Adolescent; Adult; Aged; Amphotericin B; Anti-Infective Agents; Antifungal Agents; Cohort Studies; Drug Interactions; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Lung Transplantation; Male; Middle Aged; Mycoses; Time Factors; Treatment Outcome

Liposomal amphotericin B (LAMB) is frequently administered in NICU to preterm infants <1500 g at birth (VLBW) for treatment of systemic fungal infections (SFI). Concerns exist on safety and tolerability of such drug in patients who are at risk for renal function impairment due to their prematurity.. To assess the occurrence of renal function impairment related to LAMB in a 10-year cohort of VLBW neonates treated with this drug.. Through database search of clinical charts, all VLBW neonates admitted to a 3(rd) level NICU in the years 1998-2007 and undergoing treatment with LAMB were identified. The occurrence of LAMB-attributable renal toxicity was investigated; infants withdrawn from treatment for development of adverse effects or toxicity were identified.. In the study period, 71 of 792 admitted VLBW neonates (8.9%) underwent antifungal treatment with LAMB administered at the recommended dosages (3-to-5 mg/kg/day). Mean duration of treatment was 14 (±9) days, mean cumulative dose given was 58 (±25) mg/kg per infant. Renal compromise, defined as hypokalaemia, and/or elevated creatinine serum levels, and/or decreased urine output, occurred in 2 of 71 (2.8%) treated patients, by 5 (±3) mean days after treatment initiation. In both patients LAMB was withdrawn; renal function impairment was only mild and transient, and normal renal function was restored at discharge. No other significant adverse effects were recorded in any treated neonate.. LAMB is generally safe and well tolerated in VLBW neonates. The occurrence of LAMB-related nephrotoxicity appears to be uncommon, mild and transient.

Topics: Amphotericin B; Antifungal Agents; Candidiasis; Cohort Studies; Creatinine; Fluconazole; Humans; Hypokalemia; Infant, Newborn; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Kidney; Kidney Diseases; Kidney Function Tests; Mycoses; Premature Birth; Retrospective Studies; Sepsis

Topics: Amphotericin B; Antifungal Agents; Ascomycota; Cornea; Corneal Injuries; Endophthalmitis; Eye Foreign Bodies; Eye Infections, Fungal; Eye Injuries, Penetrating; Humans; Keratoplasty, Penetrating; Male; Middle Aged; Mycoses; Sclera; Ultrasonography; Visual Acuity; Vitreous Body; Young Adult

Topics: Airway Obstruction; Amphotericin B; Antifungal Agents; Bronchoscopy; C-Reactive Protein; Eosinophilia; Humans; Itraconazole; Lung Diseases, Fungal; Male; Middle Aged; Mycoses; Penicillium; Treatment Outcome

Lung transplant recipients are at high risk of invasive fungal disease (IFD), particularly invasive aspergillosis and candidiasis. The antifungal strategy that optimally balances effective reduction of IFD with a minimum of toxicity remains undefined; universal triazole prophylaxis is common at lung transplantation (LT) centers, despite the well-known toxicities and costs of this approach.. We implemented an antifungal strategy in March 2007 targeted at LT recipients at highest risk for IFD based on our institutional epidemiology. All patients received inhaled amphotericin B during their initial LT hospitalization, bilateral lung transplant recipients received 7 to 10 days of micafungin, and only patients with growth of yeast or mold in their day-of-transplant cultures received further oral antifungal therapy tailored to their fungal isolate.. IFD events were assessed in sequential cohorts composed of 82 lung transplant recipients before and 83 patients after the implementation of this targeted antifungal strategy. We observed a sharp decline in IFD; in the second cohort, 87%, 91%, and 96% of patients were free of IFD, invasive candidiasis, and invasive aspergillosis at 1 year. Only 19% of patients in the second cohort received systemic antifungal therapy beyond the initial LT hospitalization, and no patients experienced antifungal drug-related toxicity or IFD-associated mortality.. The targeted antifungal strategy studied seems to be a reasonable approach to reducing post-LT IFD events while limiting treatment-related toxicities and costs.

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis; Cohort Studies; Echinocandins; Female; Humans; Lipopeptides; Lung Transplantation; Male; Micafungin; Middle Aged; Mycoses; Risk; Time Factors; Triazoles

To assess the tolerability of liposomal amphotericin B (L-AmB) in critically ill patients with elevated serum creatinine concentrations (Cr) (> 1.5 mg/dL) at starting L-AmB therapy.. Retrospective, multicenter, comparative study of two cohorts of critically ill patients treated with L-AmB during 3 or more days, the difference between them was the level of Cr at the beginning of treatment. A cutoff value of Cr of 1.5 mg/dL was established. Patients undergoing extrarenal depuration procedures before or 48 hours after starting L-AmB were excluded. The primary endpoint was the difference between Cr values at the end of treatment as compared with Cr at starting L-AmB. Secondary endpoints were treatment-related withdrawals, need of extrarenal depuration techniques, and treatment-related severe adverse events. Demographic data, underlying illness, indication of L-AmB therapy, concomitant risk factors of nephrotoxicity, and vital status at ICU and hospital discharge were recorded.. A total of 122 patients admitted to 26 ICUs (16 with Cr > 1.5 g/dL; 106 with normal Cr levels) were recruited. Main reasons for the use of L-AmB in both groups were the broad spectrum of the drug and the presence of hemodynamic instability. L-AmB was administered as first-line treatment in 68.8% of patients with elevated Cr and in 52.8% with normal Cr. The APACHE II score on ICU admission was 25 in patients with elevated Cr and 17 in those with normal Cr values (p < 0.001). Duration of treatment with L-AmB was 16 and 12 days in patients with elevate and normal Cr values, respectively, with a mean dose of 3.5 vs 3.9 mg/kg/day. The use of concomitant nephrotoxic drugs, mortality rate, and ICU and hospital length of stay were similar in both cohorts. In patients with renal function impairment at the initiation of L-AmB treatment, an absolute decrease of Cf-Ci of 1.08 mg/dL was observed (P < 0.001). A decrease of Cr levels to normal limits was observed in 50% of the patients; in 37.5% of patients there was a decrease but normal levels were not achieved, whereas a Cr increased occurred in only one (6.25%) patient. None of the patients required withdrawal of L-AmB or use of extrarenal depuration procedures. Treatment-related severe adverse events were not reported.. In critically ill patients with impaired renal function, the impact of L-AmB on renal function was minimal. L-AmB can be used for the treatment of fungal infections in critically ill patients independently of renal function at the initiation of treatment.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Child; Child, Preschool; Cohort Studies; Creatinine; Critical Illness; Female; Humans; Infant; Kidney; Kidney Diseases; Kidney Function Tests; Male; Middle Aged; Mycoses; Retrospective Studies; Young Adult

Penicillium marneffei (P. marneffei) infection usually occurs with skin, bone marrow, lung or hepatic involvement. However, no cases of P. marneffei infection with chylous ascites have been reported thus far. In this report, we describe the first case of acquired immune deficiency syndrome (AIDS) which has been complicated by a P. marneffei infection causing chylous ascites. We describe the details of the case, with an emphasis on treatment regimen. This patient was treated with amphotericin B for 3 mo, while receiving concomitant therapy with an efavirenz-containing antiretroviral regimen, but cultures in ascitic fluid were persistently positive for P. marneffei. The infection resolved after treatment with high-dose voriconazole (400 mg every 12 h) for 3 mo. P. marneffei should be considered in the differential diagnosis of chylous ascites in human immunodeficiency virus patients. High-dose voriconazole is an effective, well-tolerated and convenient option for the treatment of systemic infections with P. marneffei in AIDS patients on an efavirenz-containing antiretroviral regimen.

Topics: Acquired Immunodeficiency Syndrome; AIDS-Related Opportunistic Infections; Alkynes; Amphotericin B; Anti-Retroviral Agents; Antifungal Agents; Benzoxazines; Chylous Ascites; Cyclopropanes; Diagnosis, Differential; Humans; Male; Middle Aged; Mycoses; Penicillium; Pyrimidines; Sepsis; Triazoles; Voriconazole

Antifungal prophylaxis in the haematological patient is currently regarded as the gold standard in situations with a high risk of infection, such as acute leukaemias, myelodysplastic syndromes and autologous or allogenic hematopoietic stem cell transplantation. Over the years, different scientific societies have established a series of recommendations on antifungal prophylaxis based on prospective studies performed with different drugs. However, the prescription of each one of the agents must be personalised, adapted to the characteristics of each patient and to possible interactions with concomitant medication.

Topics: Algorithms; Amphotericin B; Antifungal Agents; Antineoplastic Agents; Biological Availability; Decision Trees; Drug Interactions; Echinocandins; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Immunosuppressive Agents; Liver Diseases; Mycoses; Myelodysplastic Syndromes; Postoperative Complications; Practice Guidelines as Topic; Premedication; Triazoles

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Echinocandins; Humans; Itraconazole; Lipopeptides; Micafungin; Mycoses; Pyrimidines; Triazoles; Voriconazole

The synthesis of some natural and synthetic biflavonoids was performed in good overall yields starting from readily available materials via high yielding aldol and Ullmann condensations. Some of these compounds, especially bichalcones, display an interesting activity against fungi, higher than that of the corresponding monomers.

Topics: Antifungal Agents; Biflavonoids; Fungi; Humans; Microbial Sensitivity Tests; Molecular Structure; Mycoses

Fusarium species are common hyaline soil saprophytes and plant pathogens that are opportunistic fungal pathogens of immunocompromised patients. The treatment for fusariosis remains uncertain with an unfavourable prognosis; new possibilities for treatment, such as various synergistic drug interactions, must be uncovered. In this study, we evaluated the in vitro interactions of amphotericin B with caspofungin, ketoconazole, 5-flucytosine, itraconazole, miconazole, rifampin, fluconazole, terbinafine and voriconazole against isolates of Fusarium spp. using the chequerboard method with interactions evaluated by fractional inhibitory concentration indices. The highest percentages of synergistic interactions were observed for the combinations of amphotericin B and caspofungin (68.7%), amphotericin B and rifampin (68.7%), amphotericin B plus 5-flucytosine (59.3%) and amphotericin B with voriconazole (37.5%). The pattern of susceptibility to antifungal agents among Fusarium species and their consequence on the effects of drug combinations are also discussed.

Topics: Amphotericin B; Antifungal Agents; Drug Interactions; Fusarium; Humans; Mycoses; Rifampin

Combination treatment of paediatric invasive fungal infections (IFIs) has rarely been reported. A total of 17 children with 19 IFI episodes were enrolled in the study. The median age of the patients was 5.3 (range 0.5-17) years. IFI was classified as proven in 4, probable in 12 and possible in 3 episodes. These patients received empiric antifungal treatment, which consisted of liposomal amphotericin B (LAmB) monotherapy for a median duration of 12 days (range 3-69 days). All patients were refractory to LAmB; therefore, caspofungin was added to the therapy in 11 patients. In the remaining six patients, LAmB was ceased and a combination of caspofungin and voriconazole was started. Among the patients who received caspofungin + LAmB, four did not show favourable response and the combination was switched to caspofungin + voriconazole. The median (range) and total duration of the therapy were 7 (3-14) days and 91 patient days for LAmB + caspofungin combination and 49 (7-126) days and 516 patient days for caspofungin + voriconazole combination. We found a favourable response rate of 68.4% in 16 proven or probable IFI episodes. Twelve-week survival rate of these patients was 75%. No serious side effect was observed among the patients. Our data suggest that combination antifungal therapy is safe and effective in children with haematological malignancies.

Topics: Adolescent; Amphotericin B; Antifungal Agents; Caspofungin; Child; Child, Preschool; Drug Resistance, Fungal; Drug Therapy, Combination; Echinocandins; Female; Fungi; Hematologic Neoplasms; Humans; Infant; Lipopeptides; Male; Mycoses; Pyrimidines; Salvage Therapy; Treatment Outcome; Triazoles; Voriconazole

Invasive fungal infections (IFIs) still pose major challenges in allogeneic hematopoietic SCT (HSCT), and effective antifungal prophylaxis remains a matter of debate. The aim of this retrospective study was to evaluate the toxicity and the impact of aerosolized deoxycholate amphotericin B (aero-d-AmB) on respiratory tract IFIs (airways IFIs) in a homogeneous cohort of allogeneic HSCT patients, transplanted at one institution. Since 1999, 102 consecutive patients were transplanted from matched related (N = 71) or unrelated donor (MUD). Aero-d-AmB was administered for a median time of 16 days (range 2-45), in addition to systemic antifungal prophylaxis. Prolonged administration was neither associated with increased severe bacterial infections, nor with severe adverse events. In 16 patients in whom aero-d-AmB was delivered for less than 8 days, due to worsened clinical conditions or poor compliance, proven or probable airways IFIs were diagnosed in three cases (one mucormycosis and one fusariosis and one probable aspergillosis), whereas in 84 patients receiving aero-d-AmB for ≥ 8 days, one possible and one probable aspergillosis were diagnosed. A shortened administration (< 8 days) of aero-d-AmB was therefore associated with an increased risk of both total airways IFIs (P = 0.027) and proven/probable IFIs (P = 0.012). At multivariate analysis prolonged aero-d-AmB administration retained an independent protective effect on airways IFIs (P = 0.026) whereas a MUD transplant was associated with a borderline increase of IFIs risk (P=0.052). Overall, 95.1% of patients did not experience airways IFIs and no patient died due to IFIs. In this cohort of patients, prolonged aero-d-AmB seems to have a role in preventing respiratory tract IFIs, but a randomized controlled trial is recommended to verify the impact of this prophylaxis in the setting of allogeneic HSCT.

Topics: Adolescent; Adult; Aerosols; Aged; Amphotericin B; Antifungal Agents; Cohort Studies; Deoxycholic Acid; Drug Combinations; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppression Therapy; Incidence; Italy; Lymphoproliferative Disorders; Male; Middle Aged; Mycoses; Respiratory System; Respiratory Tract Infections; Retrospective Studies; Risk Factors; Transplantation, Homologous; Young Adult

Topics: Adult; Amphotericin B; Antifungal Agents; Dipodascus; Female; Humans; Leukemia, Myeloid, Acute; Liver; Middle Aged; Mycoses; Portal Vein; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Radiography, Abdominal; Tomography, X-Ray Computed; Treatment Outcome

This report describes a chronically ill child who presented with high fever and was diagnosed with catheter-related sepsis. Aureobasidium pullulans variety melanigenum, a dematiaceous fungus that rarely causes opportunistic infections, was recovered from multiple blood cultures. Antifungal susceptibilities were performed and the minimum inhibitory concentration (MIC) for fluconazole was 64 mg/l, suggestive of fluconazole resistance. The patient made a full recovery after removal of the catheter line and treatment with liposomal amphotericin B. This is the first case report of an elevated in vitro fluconazole MIC of an A. pullulans isolate and only the third case of successful treatment of A. pullulans fungemia.

Topics: Amphotericin B; Antifungal Agents; Ascomycota; Blood; Catheter-Related Infections; Child; DNA, Fungal; DNA, Ribosomal Spacer; Drug Resistance, Fungal; Fluconazole; Fungemia; Humans; Male; Microbial Sensitivity Tests; Molecular Sequence Data; Mycoses; Sequence Analysis, DNA

Twenty-eight clinical fungal isolates were characterised by morphological (macro- and micro-features and growth response at 25, 30 and 37°C) and molecular (nuclear rDNA-internal transcriber spacer, calmodulin, cytochrome c oxidase 1 and the largest subunit of RNA polymerase II) analyses. The clinical fungal isolates were ascribed to the following taxa: Penicillium chrysogenum, Verticillium sp., Aspergillus tubingensis, Aspergillus minutus, Beauveria bassiana and Microsporum gypseum. In addition, in vitro susceptibility testing of the isolates to conventional antifungal agents and to two chemically well-defined chemotypes of Thymus schimperi essential oil was performed. Most of the isolates were resistant to amphotericin B (except A. minutus), and itraconazole, while terbinafine was quite active on these fungi. T. schimperi essential oil showed antifungal activity against all of the tested fungal isolates with minimal inhibitory concentration values similar or lower than those of terbinafine. Transmission electron microscopy analyses revealed that fungal growth inhibition by essential oil was accompanied by marked morphological and cytological changes.

Topics: Amphotericin B; Antifungal Agents; DNA, Fungal; DNA, Ribosomal Spacer; Drug Resistance, Fungal; Fungal Proteins; Fungi; Humans; Itraconazole; Microbial Sensitivity Tests; Microscopy, Electron, Transmission; Molecular Sequence Data; Mycoses; Naphthalenes; Oils, Volatile; Sequence Analysis, DNA; Terbinafine; Thymus Plant

Batrachochytrium dendrobatidis is one of the most pathogenic microorganisms affecting amphibians in both captivity and in nature. The establishment of B. dendrobatidis free, stable, amphibian captive breeding colonies is one of the emergency measures that is being taken to save threatened amphibian species from extinction. For this purpose, in vitro antifungal susceptibility testing and the development of efficient and safe treatment protocols are required. In this study, we evaluated the use of amphotericin B and voriconazole to treat chytridiomycosis in amphibians. The concentration at which the growth of five tested B. dendrobatidis strains was inhibited was 0.8 μg/ml for amphotericin B and 0.0125 μg/ml for voriconazole. To completely eliminate a mixture of sporangia and zoospores of strain IA042 required 48 h of exposure to 8 μg/ml of amphotericin B or 10 days to 1.25 μg/ml of voriconazole. Zoospores were killed within 0.5 h by 0.8 μg/ml of amphotericin B, but even after 24 h exposure to 1.25 μg/ml of voriconazole they remained viable. Amphotericin B was acutely toxic for Alytes muletensis tadpoles at 8 μg/ml, whereas toxic side effects were not noticed during a seven-day exposure to voriconazole at concentrations as high as 12.5 μg/ml. The voriconazole concentrations remained stable in water during this exposure period. On the basis of this data, experimentally inoculated postmetamorphic Alytes cisternasii were sprayed once daily for 7 days with a 1.25 μg/ml solution of voriconazole in water which eliminated the B. dendrobatidis infection from all treated animals. Finally, treatment of a naturally infected colony of poison dart frogs (Dendrobatidae) using this protocol, combined with environmental disinfection, cleared the infection from the colony.

Topics: Amphotericin B; Animals; Antifungal Agents; Anura; Chytridiomycota; Clinical Protocols; Microbial Sensitivity Tests; Mycoses; Pyrimidines; Triazoles; Voriconazole

Using a murine model of disseminated infection by two strains of Fusarium verticillioides, we have evaluated the efficacy of high doses of amphotericin B (AMB) (3 mg/kg of body weight/day), voriconazole (VRC) (60 mg/kg of body weight/day), posaconazole (PSC) (100 mg/kg of body weight/day), and the combinations of AMB plus VRC or PSC. In general, our results were very modest. Neither combination was superior to the respective monotherapies. VRC alone and in combination with AMB was able to prolong survival but not to reduce tissue burden, and AMB plus PSC was able to reduce fungal load in organs but not to prolong survival.

Topics: Amphotericin B; Animals; Antifungal Agents; Drug Therapy, Combination; Fusarium; Mice; Mycoses; Pyrimidines; Survival Rate; Triazoles; Voriconazole

Topics: Amphotericin B; Antifungal Agents; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Mycoses

Topics: Amphotericin B; Antifungal Agents; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Mycoses

Using a murine model of disseminated infection by Fusarium verticillioides, the efficacy of liposomal amphotericin (L-AmB) B at 10mg/kg body weight once daily and terbinafine (TRB) at 150 mg/kg body weight twice daily, alone and in combination, was evaluated. The combination of L-AmB with TRB was the only treatment able to prolong survival and to reduce fungal loads in the spleen and kidneys of mice infected with either strain of F. verticillioides used. The results suggest that this combination may have a role in the treatment of F. verticillioides infection.

Topics: Amphotericin B; Animals; Antifungal Agents; Colony Count, Microbial; Disease Models, Animal; Drug Therapy, Combination; Fusarium; Kidney; Male; Mice; Mycoses; Naphthalenes; Spleen; Survival Analysis; Terbinafine; Treatment Outcome

Hormographiella aspergillata, a filamentous basidiomycete, has rarely been involved in human infections. We describe 2 febrile neutropenic patients who developed a severe pulmonary infection due to H. aspergillata while receiving empirical caspofungin therapy for presumed fungal pneumonia. After introduction of liposomal amphotericin B, one patient, who had neutrophil recovery, presented a favorable outcome, while the other, who remained neutropenic throughout the course of infection, died. Resistant fungi, including basidiomycetes, may emerge during empirical treatment with caspofungin in febrile neutropenic patients. A rapid switch to any other potent antifungal should be rapidly considered in case of failure of caspofungin in this setting.

Topics: Adult; Amphotericin B; Antifungal Agents; Basidiomycota; Caspofungin; DNA, Fungal; Echinocandins; Female; Fever of Unknown Origin; Fungi; Humans; Lipopeptides; Lung Diseases, Fungal; Male; Molecular Sequence Data; Mycoses; Neutropenia; Sequence Analysis, DNA; Treatment Outcome

To report the beneficial properties of subconjunctival amphotericin B as an adjunctive therapy in patients with severe fungal keratitis.. Case reports and review of medical literature. Four patients with advanced fungal keratitis were treated with repeated injections of subconjunctival amphotericin B in addition to topical and systemic antifungal treatment.. Two to 8 injections were given to each patient. All patients showed rapid clinical improvement after the injections. No serious adverse effects were observed. However, all patients experienced pain during the injections.. Subconjunctival injections of amphotericin B are useful as an adjunctive treatment of advanced fungal keratitis. This treatment assures compliance and may be an alternative to avoid a surgical intervention in an acute stage of advanced fungal keratitis. More cases are needed to validate our findings.

Topics: Acremonium; Adult; Aged, 80 and over; Amphotericin B; Antifungal Agents; Candida; Conjunctiva; Corneal Ulcer; Eye Infections, Fungal; Female; Fusarium; Humans; Injections, Intraocular; Male; Mycoses

Treatment of disseminated trichosporosis is still challenging. Itraconazole is a widely used broad-spectrum antifungal drug. In vitro interactions of itraconazole (ICZ) with amphotericin B (AMB), caspofungin (CAS), and terbinafine (TBF) against 18 clinical isolates of Trichosporon asahii were assessed by chequerboard microdilution method. ICZ combined with CAS showed the highest percentage of synergistic effect (72.2%), followed by ICZ/AMB (11%) and ICZ/TBF (11%) combination. Antagonistic effect was not observed. This study demonstrates that itraconazole can enhance the antifungal activity of CAS against T. asahii, suggesting that this combination may be a potential strategy for treating disseminated trichosporosis.

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Drug Interactions; Echinocandins; Humans; Lipopeptides; Microbial Sensitivity Tests; Mycoses; Naphthalenes; Terbinafine; Trichosporon

Topics: Amphotericin B; Antifungal Agents; Combined Modality Therapy; Corneal Transplantation; Corneal Ulcer; Drug Therapy, Combination; Endophthalmitis; Eye Infections, Fungal; Female; Humans; Microscopy, Acoustic; Middle Aged; Mycoses; Phialophora; Pyrimidines; Recurrence; Triazoles; Voriconazole

Two German Shepherd dogs with sequential opportunistic infections are described. The first was a 2-year-old male with cryptococcal rhinitis that spread to involve the optic nerves and brain. It was successfully treated with combination therapy utilising amphotericin B administered for 2 years, but the dog developed a disseminated Aspergillus deflectus infection 5 years later and was euthanased. The second case was a 4-year-old male that presented for a severe, deep-seated infection of the right antebrachium, with gradual extension to contiguous tissues. Neosartorya fischeri (anamorph; Aspergillus fischerianus) was isolated in pure culture and detected in histological sections. The infection was refractory to itraconazole, but resolved after amputation of the affected limb. Five months later, the dog developed a localised cutaneous lesion on the proximal pelvic limb, from which Pythium insidiosum was isolated and then visualised in tissue sections, together with a structure thought to be grass seed. This lesion was treated by wide surgical resection, although it was reported that the dog died of disseminated disease some months later. These cases provide further circumstantial evidence that young adult German Shepherd dogs have a predilection to developing invasive infections with fungi and other saprophytic pathogens.

Topics: Amphotericin B; Animals; Antifungal Agents; Dog Diseases; Dogs; Drug Therapy, Combination; Fatal Outcome; Itraconazole; Male; Mycoses; Opportunistic Infections

Small-angle neutron scattering (SANS) studies have been performed to study the structural changes induced in the membranes of vesicles prepared (by thin film evaporation) from phospholipid and mixed phospholipid-sterol mixtures, in the presence of different concentrations and different aggregation states of the anti-fungal drug, amphotericin B (AmB). In the majority of the experiments reported, the lipid vesicles were prepared with the drug added directly to the lipid dispersions dissolved in solvents favouring either AmB monomers or aggregates, and the vesicles then sonicated to a mean size of ~100 nm. Experiments were also performed, however, in which micellar dispersions of the drug were added to pre-formed lipid and lipid-sterol vesicles. The vesicles were prepared using the phospholipid palmitoyloleoylphosphatidylcholine (POPC), or mixtures of this lipid with either 30 mol% cholesterol or 30 mol% ergosterol. Analyses of the SANS data show that irrespective of the AmB concentration or aggregation state, there is an increase in the membrane thickness of both the pure POPC and the mixed POPC-sterol vesicles-in all cases amounting to ~4 Å. The structural changes induced by the drug's insertion into the model fungal cell membranes (as mimicked by POPC-ergosterol vesicles) are thus the same as those resulting from its insertion into the model mammalian cell membranes (as mimicked by POPC-cholesterol vesicles). It is concluded that the specificity of AmB for fungal versus human cells does not arise because of (static) structural differences between lipid-cholesterol-AmB and lipid-ergosterol-AmB membranes, but more likely results from differences in the kinetics of their transmembrane pore formation and/or because of enthalpic differences between the two types of sterol-AmB complexes.

Topics: Amphotericin B; Antifungal Agents; Cell Membrane; Cholesterol; Ergosterol; Humans; Kinetics; Lipid Bilayers; Models, Molecular; Molecular Structure; Mycoses; Neutron Diffraction; Phosphatidylcholines; Phospholipids; Scattering, Small Angle; Sterols; Temperature

Studies using patient-level data to determine the attributable cost of invasive fungal diseases (IFDs) are few. Using a case-control study with activity-based costing of patients admitted to a quaternary hospital from 2002 to 2007, we determined attributable hospitalization cost (and 12 weeks thereafter), length of stay (LOS), and costly antifungal treatment (C-AT; liposomal amphotericin B, voriconazole, posaconazole, caspofungin), expressed as defined daily doses (DDDs) per IFD episode, in patients with hematological malignancies and hematopoietic stem cell recipients. Matching criteria and median regression modeling controlled for confounding variables, including LOS prior to IFD onset. Multiple mycoses were identified in 43 matched case-control pairs (n=86). A separate sensitivity analysis included 22 unmatched patients. IFD status was associated with a median excess cost of AU$30,957 (95% confidence interval [CI]=AU$2,368 to AU$59,546; P=0.034), approximating at purchasing power parity US$21,203 (95% CI=US$1,622 to US$40,784) and €15,788 (95% CI=€1,208 to €30,368), increasing to AU$80,291 (95% CI=AU$33,636 to AU$126,946; P=0.001), i.e., US$54,993 (95% CI=US$23,038 to US$86,948) and €40,948 (95% CI=€17,154 to €64,742), with intensive care unit (ICU) requirement. Cost determinants were pharmacy costs (64%; P<0.001) inclusive of antifungal treatment (27%; P<0.001) and ward costs (27%; P=0.091), with proportions persisting through 12 weeks for 25 surviving matched pairs (pharmacy, 60% [P=0.12]; ward, 31% [P=0.21]). Median LOS was not significantly increased unless unmatched patients were included (8 days, 95% CI=1.8 to 14 days; P=0.012). Excess C-ATs were 17 DDDs (95% CI=15 to 19 DDDs; P<0.001) per case patient and 19 DDDs (95% CI=16 to 22 DDDs; P<0.001) per ICU patient. The sensitivity analysis was confirmatory (for median cost, AU$29,441, 95% CI=AU$5,571 to AU$53,310, P=0.016; for C-AT, 17 DDDs, 95% CI=16 to 18 DDDs, P<0.001). IFD results in increased hospital and ICU costs, with pharmacy costs, including antifungal treatment, being major determinants. Consumption of costly antifungal drugs may be a novel resource metric with wider generalizability than cost alone.

Topics: Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Caspofungin; Echinocandins; Female; Hematology; Hospital Costs; Humans; Length of Stay; Lipopeptides; Male; Middle Aged; Models, Economic; Mycoses; Pyrimidines; Retrospective Studies; Triazoles; Voriconazole

Sporopachydermia cereana is a cactophilic yeast, which is not recognised as a human pathogen. We describe two fatal infections with this fungus in profoundly neutropenic patients. S. cereana escapes detection by conventional mycological identification methods. This organism may be an under-recognised cause of fatal fungal sepsis among immunocompromised patients.

Topics: Adult; Amphotericin B; Antifungal Agents; Fatal Outcome; Humans; Immunocompromised Host; Male; Middle Aged; Mycoses; Neutropenia; Saccharomycetales

Liver transplantation is the most effective treatment for end-stage liver diseases; however, infections after transplantation can seriously affect the patient's health. The aim of this research was to investigate the diagnosis and treatment of fungal infection following liver transplantation.. Clinical data for 232 liver transplant patients at risk of fungal infection were examined for the presence of fungus in the blood, fluid, sputum, urine and stools of patients and by chest or abdominal CT scans. Patients diagnosed with a fungal infection were treated with Fluconazole or, if this was not effective, Voriconazole or Amphotericin B. Immunosuppressive therapy was also reviewed.. Thirty-seven of 232 (15.9%) patients were diagnosed with a fungal infection, which occurred 4 to 34 days post-transplantation. Candida infections were diagnosed in 23 cases (62.2%) and Aspergillus infections in 12 cases (32.4%). Twenty-one cases were effectively treated with Fluconazole, 11 cases with Voriconazole, and two cases with Amphotericin B; however, three cases were not effectively treated with any of the antifungal agents. Overall, treatment was effective in 91.9% of patients.. Fungal infection has a significant influence on survival rate after liver transplantation. Imaging studies, and pathogenic and biopsy examinations can diagnose fungal infections, which can be effectively treated with antifungal agents such as Fluconazole, Voriconazole or Amphotericin B.

Topics: Adult; Amphotericin B; Antifungal Agents; Female; Fluconazole; Humans; Liver Transplantation; Male; Mycoses; Pyrimidines; Triazoles; Voriconazole

Subcutaneous mycoses are chronic infections caused by slow growing environmental fungi. Latin American plants are used in folk medicine to treat these afflictions. Moreover, the potential of the rich Latin American biodiversity for this purpose has not been fully explored.. The aim of the study was to screen Latin American plant extracts against two species of subcutaneous fungi: Sporothrix schenckii and Fonsecaea pedrosoi.. One hundred ninety-five organic extracts from 151 Latin American plants were screened against two subcutaneous fungi by the agar dilution method at a concentration of 100 µg/mL, and minimum inhibitory concentrations (MICs) of active extracts were determined. Positive (amphothericin B) and negative (50% ethanol) controls were used.. Twenty eight extracts showed activity at ≤100 µg/mL. Of these, four extracts from Gnaphalium gaudichaudianum DC (Asteraceae), Plumeria rubra L (Apocynaceae), Tecoma stans (L.) Juss. ex Kunth. (Bignoniaceae), and Trichostigma octandum (L.), H. Walter showed activity against F. pedrosoi at MIC 12.5 µg/mL; and, four extracts from Bourreria huanita (Lex.) Hemsl. (Boraginaceae), Phytolacca bogotensis Kunth (Phytolaccaceae), Monnina xalapensis Kunth (Polygalaceae) and Crataegus pubescens (C. Presl) C. Presl (Rosaceae) against S. schenckii. This is the first report on antifungal activity of the Latin American plants against these two subcutaneous fungi.. S. schenkii and F. pedrosoi were inhibited by B. huanita (MIC: 12.5 and 25 µg/mL), G. gaudichaudianum (MIC: 50 and 12.5 µg/mL) and T. triflora (MIC: 25 µg/mL).

Topics: Amphotericin B; Antifungal Agents; Ascomycota; Drug Evaluation, Preclinical; Ethanol; Fungi; Humans; Latin America; Medicine, Traditional; Microbial Sensitivity Tests; Mitosporic Fungi; Mycoses; Phytotherapy; Plant Extracts; Sporothrix; Terminalia

Topics: Amphotericin B; Antifungal Agents; Candidiasis; Child; Echinocandins; Humans; Ketoconazole; Mycoses; Prognosis; Treatment Outcome

Intensified chemotherapy and hematopoietic stem cell transplantation result in severe and prolonged granulocytopenia with an increased risk of invasive fungal infections. The major fungal species that cause serious infections in cancer patients are Candida species and Aspergillus species. The main features of Candida infection in this context are oropharyngeal candidiasis and Candida esophagitis, chronic disseminated candidiasis, also known as hepatosplenic candidiasis, and candidemia. Aspergillus can cause severe lung infection but also sinusal or CNS infection. Because invasive fungal infections are severe and often life-threatening, preventive and empirical managements have become standard practice. An increasing number of antifungal drugs is now available, notably lipid formulations of amphotericin B (liposomal amphotericin B), new azoles with broad spectrum of activity and echinocandin.

Topics: Agranulocytosis; Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus; Azoles; Candidiasis; Child; Cryptococcosis; Echinocandins; Humans; Mycoses; Neoplasms; Opportunistic Infections; Risk Factors; Stem Cell Transplantation; Treatment Outcome

Albumin dialysis (AD) is a therapeutic option in severe cholestatic liver failure. However, it can significantly enhance drug elimination. Pharmacokinetic data on antimicrobial agents--in particular on antimycotics--administered under this clinical condition are very sparse. Therefore, amphotericin B (AMB) plasma concentrations were measured in two critically ill patients who were treated with AD because of severe cholestatic liver failure and were prescribed lipid formulated AMB--either AMB colloidal dispersion (ABCD) or AMB lipid complex (ABLC)--for suspected invasive fungal infection. AD was performed with the molecular adsorbent recirculating system (MARS). Lipid-associated and liberated AMB were separately quantified on and off AD. The clearance of the liberated AMB fraction was not essentially affected (ABLC) or moderately enhanced during AD by a factor of 2.5 (ABCD). The clearance of the lipid-formulated fraction was increased by a factor of 4 during AD (ABCD) or was similar (ABLC) on and off AD. Despite the fact that there was a four-fold higher clearance of the lipid-formulated fraction of ABCD, the clinically relevant area under the concentration time curve of the liberated AMB fraction was only moderately changed (by 37% in ABCD, 70% in ABLC) during AD. Thus, the effect of AD on lipid formulated AMB appears to be moderate. A daily dose of 5 mg/kg will probably lead to adequate plasma levels in patients on AD.

Topics: Aged; Albumins; Amphotericin B; Antifungal Agents; Critical Illness; Female; Humans; Lipid Metabolism; Liver Failure; Male; Middle Aged; Mycoses; Renal Dialysis

Invasive pulmonary infection by Scedosporium apiospermum (IPSA) and invasive pulmonary aspergillosis (IPA) are clinically similar. Our objective was to identify clinical parameters that may differentiate IPSA from IPA. Ours was a prospective cohort study that included patients with different degrees of immunosuppression and respiratory isolation of S. apiospermum (SCA). Episodes of invasive infection were classified according to the EORTC and MSG criteria. Clinical variables corresponding to patients with IPSA were compared with those collected from patients with a diagnosis of IPA during the same period. Twenty-seven patients with positive culture for SCA from respiratory samples were evaluated. Of the 27 positive cultures, nine were classified as IPSA. When compared with the 89 patients with IPA, patients with IPSA were most likely to have received prophylaxis with either aerosolised (14.6% vs. 66.7%; P < 0.001) or intravenous amphotericin B (AMB; 4.5% vs. 44.4%; P = 0.002), to have prior episode of acute rejection (19% vs. 66.7%; P = 0.005), to have a later onset of infection after transplantation (251 days vs. 404 days; P = 0.009), and to have higher CD4(+) lymphocyte count (207.6 vs. 289.4; P = 0.005). Late-onset disease after transplantation and prophylaxis with AMB are more frequent in patients with IPSA compared with IPA.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Aspergillus; Chemoprevention; Child; Child, Preschool; Cohort Studies; Diagnosis, Differential; Female; Humans; Lung Diseases, Fungal; Male; Middle Aged; Mycoses; Organ Transplantation; Prospective Studies; Risk Factors; Scedosporium; Young Adult

Topics: Amphotericin B; Biopsy, Needle; Follow-Up Studies; Foot Dermatoses; Fungemia; Fusarium; Humans; Immunocompromised Host; Immunohistochemistry; Leukemia, Myeloid; Magnetic Resonance Imaging; Male; Middle Aged; Muscular Diseases; Mycoses; Opportunistic Infections; Risk Assessment; Severity of Illness Index; Toes; Treatment Outcome

Topics: Abscess; Aged; Amphotericin B; Ascomycota; Cataract Extraction; Combined Modality Therapy; Drug Therapy, Combination; Endophthalmitis; Eye Enucleation; Eye Infections, Fungal; Female; Humans; Mycoses; Pyrimidines; Recurrence; Triazoles; Vitrectomy; Vitreous Body; Voriconazole

Trichoderma longibrachiatum is an emerging pathogen in immunocompromised patients. We report a case of Trichoderma post-operative mediastinitis and peritonitis in a child with complex congenital cardiac disease and functional asplenia. The patient was treated unsuccessfully, initially with caspofungin alone followed by a combination of voriconazole (systemic and topical), caspofungin and intraperitoneal amphotericin B.

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Child, Preschool; Echinocandins; Fatal Outcome; Female; Heart Defects, Congenital; Humans; Immunocompromised Host; Lipopeptides; Mediastinitis; Mycoses; Peritoneal Dialysis; Peritonitis; Postoperative Complications; Pyrimidines; Spleen; Triazoles; Trichoderma; Voriconazole

Data on antifungal prophylaxis in paediatric cancer patients at high risk for invasive fungal disease (IFD) are scant. Intermittent administration of liposomal amphotericin B (LAMB) has been shown to be safe and effective in adult patients with haematological malignancies. We prospectively evaluated the safety and efficacy of prophylactic LAMB at a dosage of 2.5 mg/kg twice weekly in children at high risk for IFD. Efficacy was compared with that in a historical control group of patients with similar demographic characteristics not receiving LAMB prophylaxis. A total of 46 high-risk patients (24 boys; mean age, 7.7 years) with 187 episodes of antifungal prophylaxis were analysed. The median duration of neutropenia (<500/μL) was 10 days. LAMB was discontinued in four patients because of acute allergic reactions. Median values for creatinine and liver enzymes at end of treatment did not differ significantly from those at baseline. Hypokalaemia (<3.0 mmol/L) occurred with 13.5% of the prophylactic episodes, but was usually mild and always reversible. No proven/probable IFD occurred in patients receiving LAMB prophylaxis. In comparison, five proven and two probable IFDs were observed in 45 historical controls not receiving LAMB prophylaxis (p 0.01). LAMB prophylaxis had no impact on the use of empirical antifungal therapy. Systemic antifungal prophylaxis with LAMB 2.5 mg/kg twice weekly is feasible and safe, and seems to be an effective approach for antifungal prophylaxis in high-risk paediatric cancer patients.

Topics: Adolescent; Amphotericin B; Antifungal Agents; Chemoprevention; Child; Child, Preschool; Creatinine; Enzymes; Female; Hematologic Neoplasms; Humans; Infant; Liver; Liver Function Tests; Male; Mycoses; Prospective Studies; Siphoviridae; Treatment Outcome; Young Adult

The synthesis, in vitro evaluation, and conformational study of a new series of small-size peptides acting as antifungal agents are reported. In a first step of our study we performed a conformational analysis using Molecular Mechanics calculations. The electronic study was carried out using Molecular electrostatic potentials (MEPs) obtained from RHF/6-31G calculations. On the basis of the theoretical predictions three small-size peptides, RQWKKWWQWRR-NH(2), RQIRRWWQWRR-NH(2), and RQIRRWWQW-NH(2) were synthesized and tested. These peptides displayed a significant antifungal activity against human pathogenic strains including Candida albicans and Cryptococcus neoformans. Our experimental and theoretical results allow the identification of a topographical template which can serve as a guide for the design of new compounds with antifungal properties for potential therapeutic applications against these pathogenic fungi.

Topics: Amino Acid Sequence; Animals; Antifungal Agents; Candida albicans; Candidiasis; Cryptococcosis; Cryptococcus neoformans; Models, Molecular; Mycoses; Peptides; Poecilia; Toxicity Tests, Acute

We have evaluated the efficacy of posaconazole, amphotericin B, and itraconazole in a murine model of disseminated infection by Fonsecaea monophora. Of these three antifungal drugs tested, posaconazole prolonged survival significantly and reduced the fungal load in most of the organs tested. Bioassay studies demonstrated the relationship between posaconazole levels and dose escalation in serum and brain tissue. Posaconazole may have a clinical role in the treatment of disseminated infections by F. monophora.

Topics: Animals; Antifungal Agents; Ascomycota; Brain; Disease Models, Animal; Kidney; Liver; Lung; Male; Mice; Mycoses; Triazoles

Ten bis(alkylpyridinium)alkane compounds were tested for antifungal activity against 19 species (26 isolates) of yeasts and molds. We then determined the MICs and minimum fungicidal concentrations (MFCs) of four of the most active compounds (compounds 1, 4, 5, and 8) against 80 Candida and 20 cryptococcal isolates, in comparison with the MICs of amphotericin B, fluconazole, itraconazole, voriconazole, posaconazole, and caspofungin, using Clinical Laboratory and Standards Institutes broth microdulition M27-A3 (yeasts) or M38-A2 (filamentous fungi) susceptibility protocols. The compounds were more potent against Candida and Cryptococcus spp. (MIC range, 0.74 to 27.9 microg/ml) than molds (0.74 to 59.7 microg/ml). MICs against Exophiala were 0.37 to 5.9 microg/ml and as low as 1.48 microg/ml for Scedosporium but >or=25 microg/ml for zygomycetes, Aspergillus, and Fusarium spp. Compounds 1, 4, 5, and 8 exhibited good fungicidal activity against Candida and Cryptococcus, except for Candida parapsilosis (MICs of >44 mug/ml). Geometric mean (GM) MICs were similar to those of amphotericin B and lower than or comparable to fluconazole GM MICs but 10- to 100-fold greater than those for the other azoles. GM MICs against Candida glabrata were <1 microg/ml, significantly lower than fluconazole GM MICs (P<0.001) and similar to those of itraconazole, posaconazole, and voriconazole (GM MIC range of 0.4 to 1.23 microg/ml). The GM MIC of compound 4 against Candida guilliermondii was lower than that of fluconazole (1.69 microg/ml versus 7.48 microg/ml; P=0.012). MICs against Cryptococcus neoformans and Cryptococcus gattii were similar to those of fluconazole. The GM MIC of compound 4 was significantly higher for C. neoformans (3.83 mug/ml versus 1.81 microg/ml for C. gattii; P=0.015). This study has identified clinically relevant in vitro antifungal activities of novel bisalkypyridinium alkane compounds.

Topics: Antifungal Agents; Fungi; Humans; Microbial Sensitivity Tests; Mycoses; Pyridinium Compounds; Yeasts

A series of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-substituted-2-propanols (1a-v, 2a-w), which are analogues of fluconazole, have been designed and synthesized as the potential antifungal agents by the click reaction. Click reaction approach toward the synthesis of two sets of novel 1,2,3-triazolyl linked triazole antifungal derivatives 1a-v, 2a-w was achieved by Cu(I)-catalyzed 1,3-dipolar cycloaddition of propargylated intermediate 8 with substituted azidomethyl benzene. The 1,2,3-triazolyl group was inserted into the side chain of the target molecule which can increase the antifungal activity of compounds.

Topics: 14-alpha Demethylase Inhibitors; Antifungal Agents; Fungi; Humans; Models, Molecular; Mycoses; Sterol 14-Demethylase; Triazoles

Post-sternotomy infectious complications, including superficial and deep wound infections, sternal osteomyelitis and mediastinitis, are rarely caused by fungi. Trichosporon asahii is the main Trichosporon species that causes systemic infection in humans. Most cases involved neutropenic patients with hematologic malignancies. We report a unique case of a non-cancer, non-neutropenic but severely ill patient who developed an ultimately lethal T. asahii infection after sternotomy. We speculate that our patient had been colonized with the fungus and his surgical site infection may have been related to his emergency revascularization surgery. Therapy with liposomal amphotericin failed to sterilize the bloodstream despite in vitro susceptibility results. The addition of voriconazole helped sterilizing the bloodstream without changing the outcome. Physicians must be aware of the continuously expanding spectrum of infections with this emerging difficult-to-treat fungal pathogen.

Topics: Aged, 80 and over; Amphotericin B; Antifungal Agents; Fatal Outcome; Humans; Male; Mediastinitis; Mycoses; Osteomyelitis; Sepsis; Sternotomy; Surgical Wound Infection; Trichosporon

The clinical and microbiological characteristics of 103 patients with cultures positive for non-Aspergillus moulds in the period 2000 to 2008 were described. Among these patients, 27 had proven or probable invasive infections caused by Fusarium (n = 12), Paecilomyces (n = 7), Zygomycetes (n = 5) and Scedopsorium species (n = 3). The incidence of invasive infections caused by these moulds has not increased during the study period. Lung was the most common infection site and disseminated disease was observed in three leukaemic patients. The overall mortality rate was 40.7%, and was highest in cases zygomycosis. Antifungal susceptibility varied considerably among species. Amphotericin B and posaconazole demonstrated greatest activity against these moulds.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Child; Child, Preschool; Female; Fungi; Hospitals; Humans; Incidence; Infant; Infant, Newborn; Male; Microbial Sensitivity Tests; Middle Aged; Mycology; Mycoses; Sequence Analysis, DNA; Taiwan; Young Adult

Topics: Adolescent; Alternaria; Amphotericin B; Antifungal Agents; Child, Preschool; Female; Humans; Leukemia, Myeloid, Acute; Male; Mycoses; Pyrimidines; Sinusitis; Triazoles; Voriconazole

We evaluated the efficacy of amphotericin B (1.5mg/kg/day), voriconazole (60mg/kg/day) and posaconazole (60mg/kg/day) in a murine model of systemic infection caused by Neoscytalidium dimidiatum. All the treatments were able to prolong survival and to reduce the tissue burden in the spleen and kidneys of infected mice. Neither voriconazole nor posaconazole improved the results achieved with amphotericin B.

Topics: Amphotericin B; Animals; Antifungal Agents; Ascomycota; Colony Count, Microbial; Disease Models, Animal; Kidney; Male; Mice; Mycoses; Neutropenia; Pyrimidines; Sepsis; Spleen; Survival Analysis; Treatment Outcome; Triazoles; Voriconazole

Topics: Adrenal Cortex Hormones; Adult; Amphotericin B; Antifungal Agents; Diagnosis, Differential; Humans; Itraconazole; Magnetic Resonance Imaging; Male; Mycoses; Schizophyllum; Sella Turcica; Sphenoid Sinusitis; Tomography, X-Ray Computed

Topics: Adult; Amphotericin B; Antifungal Agents; Cadaver; Female; Humans; Infusions, Intravenous; Itraconazole; Kidney Transplantation; Mycoses; Osteolysis; Penicillium; Tissue Donors; Treatment Outcome

We studied the efficacy of voriconazole (VRC) and amphotericin B (AMB) in an immunosuppressed murine model of disseminated infection by two strains of Paecilomyces lilacinus. Mice were treated with VRC 60 mg/kg/day orally or AMB 3mg/kg/day intraperitoneally, beginning 1 day after infection and continuing for 9 days. To avoid rapid clearance of VRC, animals receiving VRC and the control group were given grapefruit juice instead of water. VRC significantly prolonged survival with respect to the group treated with AMB and the control group for both strains (P=0.005 and P<0.0001, respectively, for strain FMR 5522; and P=0.0002 and P<0.0001, respectively, for strain FMR 8252). VRC reduced the fungal load in the spleen, kidneys and liver of infected mice for both strains tested. Survival of mice challenged with strain FMR 8252 treated with AMB did not differ from that of the control group (P=0.223), being worse than that of the mice treated with VRC (P=0.0002). AMB was not able to reduce the tissue burden in any organ with respect to the control group for both strains studied.

Topics: Amphotericin B; Animals; Antifungal Agents; Citrus paradisi; Colony Count, Microbial; Diet; Immunocompromised Host; Kidney; Liver; Male; Mice; Mycoses; Paecilomyces; Pyrimidines; Spleen; Survival Analysis; Treatment Outcome; Triazoles; Voriconazole

Amphotericin B deoxycholate is associated with infusion-related toxicity and renal toxicity.. To evaluate medical indications of this compound in a tertiary care center, analyze adverse reactions, infusion protocols and outcome of treated patients.. Retrospective analysis of 39 treatments indicated in 33 patients during 2007, exploring indications, infusion protocols and renal protective measures, infusion-related adverse reactions, nephrotoxicity, hypokalemia and outcomes.. On average, therapy lasted 12 days (2 to 39) and reached 600 mg of accumulated dose (100 to 1950) respectively. 24-hours infusions were applied in 63.2% of prescriptions and 35.9% received a 4-6 hour infusion schedule. In addition, 36.8% received daily a saline infusion before amphotericin. Adverse reactions were observed in 40% of treatments, predominating fever (25%). Nonetheless, nephrotoxicity was infrequent (9.4%), of low magnitude, only affecting patients without previous renal disease, and not requiring dialysis. Hypokalemia developed in 21.6% of treatments. More than half of medical indications were empirical (59%), for presumed infections by either filamentous fungi or yeasts. In the subgroup with microbiological information, main indications were invasive aspergillosis (15.4% of total), systemic candidiasis (12.8%) or meningeal cryptococcosis (10.3%). A favorable response was registered in 41%, and only 48.5% of patients survived. In a multivariate analysis, only age > 60 years remained as an independent factor for developing infusion-related adverse reactions. In the same manner, a SOFA score > 3 and corticosteroids administration at the same time than amphotericin B, were independently associated to a fatal outcome.. infusion-related adverse reactions are frequent during amphotericin B deoxycholate therapy, but renal toxicity is occasionally observed. Amphotercin B was used mainly as empirical therapy in this study.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Chile; Deoxycholic Acid; Drug Combinations; Female; Hospitals, University; Humans; Kidney Diseases; Male; Middle Aged; Mycoses; Retrospective Studies; Time Factors; Young Adult

Hansenula anomala (H. anomaly) is part of the normal flora in the alimentary tract and throat. It has been reported to be an organism causing opportunistic infections in immunocompromised patients. However, cases of fungal arthritis caused by H. anomala are rare. We encountered a case of H. anomala arthritis in a 70-year-old man who was treated with an empirical antibiotic treatment and surgery under the impression of septic arthritis. However, the patient did not improve after antibiotic therapy and surgery. Consequently, knee joint aspiration was performed again, which identified fungal arthritis caused by H. anomala. It was treated successfully with amphotericin B and fluconazole. When treating arthritis patients with diabetes, it is important to consider the possibility of septic arthritis by H. anomala and provide the appropriate treatment.

Topics: Aged; Amphotericin B; Antifungal Agents; Arthritis, Infectious; Fluconazole; Humans; Knee Joint; Male; Mycoses; Pichia

Disseminated infections caused by Trichosporon asahii are difficult to resolve. Combination regimens with synergistic drugs could provide additional options for treating trichosporonosis. The aim of this study was to evaluate the antifungal activities of voriconazole (VCZ), caspofungin (CAS) and amphotericin B (AMB) alone or in combination in vitro against clinical isolates of T. asahii. The combined antifungal activities of VCZ, CAS and AMB against 18 clinical isolates were assessed by a chequerboard microdilution method. CAS combined with AMB showed the highest percentage of synergistic effects (89%), much higher than those of the other two combinations (AMB/VCZ and CAS/VCZ both 17%). No antagonistic effect was observed in any case. This study demonstrates that the activity of two combined antifungals, especially the combination of CAS and AMB, against T. asahii is more effective than that of a drug alone against this fungus, suggesting that combined antifungal therapy may be a potential strategy for treating disseminated trichosporonosis.

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Drug Synergism; Echinocandins; Humans; Lipopeptides; Microbial Sensitivity Tests; Mycoses; Pyrimidines; Triazoles; Trichosporon; Voriconazole

Fusariosis is one of the emerging invasive fungal infections over the last decade. However, its recent rise has been in its ability to produce disseminated infection in severely immunosuppressed patients with neutropenia. In solid organ transplantation, fusariosis remains an uncommon picture mainly with nodules, subcutaneous abscesses, ulcers, or necrotic skin lesions resembling erthyma gangrenosum. Herein, we have reported a case of cellulitis, subcutaneous nodules, and abscesses due to Fusarium spp in a liver transplantation patient who was successfully treated with polyenes and surgical resection.

Topics: Amphotericin B; Biopsy; Cellulitis; Fusarium; Graft Rejection; Hepatitis C; Humans; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Mycoses; Pyrimidines; Skin; Treatment Outcome; Triazoles; Voriconazole

Since the advent of combination antiretroviral therapy, the incidence of opportunistic infections has declined and the life expectancy of HIV-infected people has significantly increased. However, opportunistic infections, including fungal diseases, remain a leading cause of hospitalizations and mortality in HIV-infected people. With the availability of several new antiretroviral and antifungal agents, drug-drug interactions emerge as a potential safety concern.. Relevant literature was identified using a Medline search of articles published up to March 2010 and a review of conference abstracts. Search terms included HIV, antifungal agents and drug interactions. Original papers and relevant citations were considered for this review.. Readers will gain an understanding of the pharmacokinetic properties of antiretroviral and antifungal agents, and insight into significant drug-drug interactions which may require dosage adjustments or a change in therapy.. Azole antifungal drugs, with the exception of fluconazole, pose the greatest risk of two-way interactions with antiretroviral drugs through CYP450 enzymes effects. Limited studies suggest the risk of interactions between antiretroviral drugs and echinocandins is much lower. The combination of tenofovir and amphotericin B should be used with caution and close monitoring of renal function is required.

Topics: Amphotericin B; Anti-Retroviral Agents; Antifungal Agents; Azoles; Biotransformation; Cytochrome P-450 Enzyme System; Drug Interactions; Echinocandins; HIV Infections; Humans; Kidney; Microsomes, Liver; Mycoses

The incidence of invasive fungal infections (IFIs) in nonneutropenic solid organ transplant patients is increasing. We report our clinical experience with the use of interferon-gamma (IFN-gamma) immunotherapy in seven renal transplant patients who developed life threatening, disseminated IFIs refractory to conventional antifungal drug therapy. The infections were all microbiologically and histologically proven. The rapid cure of these disseminated infections with exogenous IFN-gamma injections was not associated with impaired kidney allograft function despite the use of liposomal amphotericin B in all cases. No clinical toxicity from the IFN-gamma immunotherapy was seen and no IFI relapsed during long-term follow-up. Our experience is both uncontrolled and in patients with unpredictable fungal infection-related outcomes. However, compared to standard approaches, the accelerated cure of life threatening, disseminated IFIs with 6 weeks of combination antifungal drug therapy and IFN-gamma immunotherapy saved lives, retained allograft function and led to substantial cost savings in this small patient group.

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; Drug Therapy, Combination; Fatal Outcome; Female; Humans; Immunotherapy; Interferon-gamma; Kidney Transplantation; Male; Middle Aged; Mycoses

We have evaluated the efficacy of posaconazole, itraconazole and amphotericin B in murine models of disseminated infection caused by Exophiala spp.. Immunosuppressed mice were treated with posaconazole at 10, 20 or 40 mg/kg/day orally (po), amphotericin B at 1.5 mg/kg/day intraperitoneally (ip) or itraconazole at 50 mg/kg/day po. Treatment began 1 day after infection and continued for 7 days post-infection. Two strains of each of the three most relevant clinical species, i.e. Exophiala dermatitidis, Exophiala oligosperma and Exophiala xenobiotica, were tested.. Posaconazole showed the highest efficacy in mice infected with E. dermatitidis, the only species that showed a high neurotropism, while the three drugs showed a similarly good activity against E. oligosperma and E. xenobiotica infections.. The results suggest that posaconazole may have a clinical role in the treatment of disseminated infections caused by Exophiala species, especially in those with CNS invasion.

Topics: Administration, Oral; Amphotericin B; Animals; Antifungal Agents; Exophiala; Injections, Intraperitoneal; Itraconazole; Male; Mice; Mycoses; Treatment Outcome; Triazoles

Two hundred fungal isolates (Aspergillus and Fusarium species) from mycotic keratitis were tested for in vitro susceptibilities to amphotericin B and proteinase production. Geometric mean MICs for all fungal species increased fourfold with thousandfold increase in the inoculum. The MIC(50) and MIC(90) values ranged between 3.12-6.25 and 3.12-12.5 microg/ml, respectively. Proteinase production was noted in 113 (56.5%) isolates. Ninety-eight (49%) showed MICs of > or =1.56 microg/ml that was above the criteria of > or =1 microg/ml for amphotericin B resistance (CLSI). Seventy-three (74.5%) of these 98 isolates were proteinase producers, whereas only 40 (39.2%) of the remaining 102 with low MICs (<1.56 microg/ml) were proteinase producers (p < 0.001). Proteinase seems to be an important virulence marker of filamentous fungi in mycotic keratitis, correlating significantly with amphotericin B resistance.

Topics: Amphotericin B; Antifungal Agents; Aspergillus; Corneal Ulcer; Drug Resistance, Fungal; Fusarium; Humans; Microbial Sensitivity Tests; Mycoses; Peptide Hydrolases

Paecilomyces variotii is a commonly occurring species in air and food, but it is also associated with many types of human infections and is among the emerging causative agents of opportunistic mycoses in immunocompromised hosts. Paecilomyces can cause hyalohyphomycosis, and two species, Paecilomyces lilacinus and P. variotii, are the most frequently encountered organisms. In the present study, a set of 34 clinical isolates morphologically identified as P. variotii or P. lilacinus were formally identified by sequencing intergenic transcribed spacer regions 1 and 2 (including 5.8S rDNA) and a part of the beta-tubulin gene. Three isolates were identified as P. lilacinus, and five of the presumptive P. variotii isolates did not belong to the genus Paecilomyces but were identified as Talaromyces eburneus (anamorph, Geosmithia argillacea) or Hamigera avellanea (anamorph, Merimbla ingelheimense). Applying the most recent taxonomy, we found that the clinical P. variotii isolates could be identified as P. variotii sensu stricto (14 strains), P. formosus (11 strains), and P. dactylethromorphus (1 strain). These data indicate that P. formosus occurs in clinical samples as commonly as P. variotii. Susceptibility tests showed that the antifungal susceptibility profiles of P. variotii, P. formosus, and P. dactylethromorphus are similar and that all strains tested were susceptible to amphotericin B in vitro. P. lilanicus, T. eburneus, and H. avellanea had different susceptibility profiles; and flucytosine and voriconazole were the least active of the antifungal drugs tested against these species. Our results indicate that correct species identification is important to help guide appropriate antifungal therapy.

Topics: Amphotericin B; Antifungal Agents; DNA, Fungal; DNA, Ribosomal; DNA, Ribosomal Spacer; Flucytosine; Fungal Proteins; Genes, rRNA; Humans; Microbial Sensitivity Tests; Molecular Sequence Data; Mycoses; Paecilomyces; Pyrimidines; RNA, Fungal; RNA, Ribosomal, 5.8S; Sequence Analysis, DNA; Triazoles; Tubulin; Voriconazole

Rhino-orbital-cerebral disease is a significant manifestation of zygomycosis in solid organ transplant (SOT) recipients. However, its characteristics and outcome are not well addressed.. SOT recipients with zygomycosis as per the European Organization for Research and Treatment in Cancer and the Mycoses Study Group criteria in a cohort study at our centers published previously and those identified with a PubMed search from the 1950s to November 2009 were studied. Patients with mycosis involving the sinuses, orbits, or central nervous system (CNS) were included.. Patients comprised a total of 90 SOT recipients with rhino-orbital-cerebral zygomycosis, including 13 in our cohort and 77 in the literature. CNS disease occurred in 57% (51 of 90). Overall mortality was 52.3% (46 of 88), and the mortality in patients with CNS disease was 73.5% (36 of 49). In logistic regression analysis, older age (odds ratio [OR] 1.12, 95% confidence interval [CI] 1.04-1.21, P=0.002) was associated with a higher mortality rate, whereas lipid formulations of amphotericin B compared with amphotericin B deoxycholate (OR 0.09, 95% CI 0.02-0.50, P=0.006) and surgery (OR 0.12, 95% CI 0.01-0.94, P=0.043) were independently associated with an improved survival even when controlled for CNS involvement and the era of diagnosis of disease.. Rhino-orbital-cerebral zygomycosis, particularly CNS disease, is associated with substantial mortality rate in SOT recipients. Older age is a significant risk factor for mortality, whereas lipid formulations of amphotericin B and surgery improved outcomes.

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; Brain Diseases; Cohort Studies; Debridement; Female; Humans; Kidney Transplantation; Liver Transplantation; Male; Middle Aged; Mycoses; Organ Transplantation; Regression Analysis; Sinusitis; Zygomycosis

The newly available AST-YS01 Vitek 2 cards were evaluated, and the results were compared with those obtained by the CLSI M27-A2 microdilution reference method. Clinical fungal isolates, including 614 isolates of Candida spp., 10 Cryptococcus neoformans isolates, 1 Geotrichum capitatum isolate, and 2 quality control strains, were tested for their susceptibilities to amphotericin B, fluconazole, and voriconazole using both methods. The majority of fungal isolates were susceptible to all antifungal agents tested: the MIC(90) values determined by the Vitek 2 and CLSI methods were 0.5 and 1 microg/ml, respectively, for amphotericin B; 8 and 16 microg/ml, respectively, for fluconazole; and <0.12 and 0.25 microg/ml, respectively, for voriconazole. Overall there was excellent categorical agreement (CA) between the methods (99.5% for amphotericin B, 92% for fluconazole, 98.2% for voriconazole), but discrepancies were observed within species. The CAs for fluconazole were low for Candida glabrata and Candida krusei when the results of the CLSI method at 48 h were considered. Moreover, the fully automated commercial system did not detect the susceptibility of Cryptococcus neoformans to voriconazole. The Vitek 2 system can be considered a valid support for antifungal susceptibility testing of fungi, but testing of susceptibility to agents not included in the system (e.g., echinocandins and posaconazole) should be performed with other methods.

Topics: Amphotericin B; Antifungal Agents; Candida; Cryptococcus neoformans; Fluconazole; Geotrichum; Humans; Italy; Microbial Sensitivity Tests; Mycoses; Pyrimidines; Triazoles; Voriconazole

Acetone leaf extracts of Combretaceae species Combretum imberbe Wawra, Combretum nelsonii Duemmer, Combretum albopunctatum Suesseng, and Terminalia sericea Burch ex DC and a mixture of asiatic acid and arjunolic acid isolated from C. nelsonii were tested for antifungal activity against Candida albicans, Cryptococcus neoformans, Microsporum canis, and Sporothrix schenckii on wounds of immunocompromised Wistar rats. The therapeutic agents were selected based on low MIC values ranging 0.02-2.5 mg/mL and low toxicity (LC50) ranging 75.7-168.6 microg/mL. Seven circular, full-thickness wounds were made on the back skin of 24 Wistar rats, under general anesthetic and using an aseptic technique. Rats were infected with different fungal pathogens in groups of six. The treatments were administered topically using 20% concentrations of each extract in aqueous cream. Amphotericin B was used as positive control. Erythema, exudate, crust formation, swelling, and ulceration were used to determine the wound healing process. Throughout the experiment, body temperature, measured using a subcutaneous probe, and weight of the rats were found to be within normal ranges. Epithelial closure in all rats occurred by 17 days. There was no significant difference in contraction of the lesion areas treated with different extracts. The variability in erythema at each lesion in rats infected with different fungal pathogens differed with treatments; the lesion without treatment took a longer time to heal in all cases. Exudate formation was observed until day 12 in rats infected with C. albicans and day 8 in rats infected with C. neoformans. In lesions infected with M. canis and S. schenckii, exudate formation was observed until day 10. The treated group presented a rigid, dark, and thick crust formation after day 3 until day 15. During histopathological evaluations, scant fungi were noted in all the wounds, indicating that infection had occurred but had generally cleared. The antifungal potential of crude extracts of selected plants and a mixture of asiatic acid and arjunolic acid on the wounds of immunocompromised rats was confirmed. The extracts of these plants may possibly be further developed into drugs for topical treatment of fungally infected wounds.

Topics: Administration, Topical; Amphotericin B; Animals; Antifungal Agents; Combretum; Fungi; Immunocompromised Host; Male; Microbial Sensitivity Tests; Mycoses; Plant Extracts; Plant Leaves; Rats; Rats, Wistar; Species Specificity; Terminalia; Time Factors; Toxicity Tests; Wound Healing

The in vitro susceptibilities of 140 laboratory reference strains of fungi, including type strains, and 165 clinical yeast isolates from Japan towards isavuconazole compared with fluconazole (FLC), itraconazole (ITC), voriconazole and amphotericin B were measured. Broth microdilution methods based on Clinical and Laboratory Standards Institute (CLSI) methods were used for yeasts, and RPMI-MOPS medium semi-solidified with 0.2% low-melting-point agarose based on CLSI guidelines was used for moulds. The range of isavuconazole minimum inhibitory concentrations (MICs) was 0.0004-0.21 mg/L for Candida albicans, 0.0036-0.4 mg/L for Candida glabrata, 0.023-0.058 mg/L for Candida krusei, 0.0026-0.032 mg/L for Cryptococcus neoformans, 0.1-0.39mg/L for Aspergillus fumigatus and 0.2-0.39 mg/L for Aspergillus terreus. Isavuconazole was as active as ITC against the dimorphic true pathogenic fungi, with a range of MICs from <0.0004 mg/L to 0.0063 mg/L for Blastomyces dermatitidis and Histoplasma capsulatum. It was also active against uncommon dematiaceous fungi such as Exophiala spp. and Phialophora spp. as well as against dermatophytic species. Isavuconazole showed very good in vitro antifungal activity with a broad spectrum, including against FLC-resistant Candida spp., Aspergillus spp. and uncommon opportunistic fungal species. This is the first report of the in vitro susceptibility of Japanese clinical yeast isolates to isavuconazole. No cross-resistance was found to isavuconazole amongst FLC-resistant strains.

Topics: Amphotericin B; Antifungal Agents; Azoles; Fungi; Humans; Japan; Microbial Sensitivity Tests; Mycoses; Nitriles; Pyridines; Reference Standards; Triazoles; Yeasts

Topics: Amphotericin B; Antifungal Agents; Creatinine; Female; Humans; Kidney; Kidney Diseases; Male; Middle Aged; Mycoses; Retrospective Studies

Haiphong is the second city of Vietnam most affected by HIV infection. Penicilliosis represents the third leading cause of opportunistic infection. However, this systemic fungal infection remains poorly knew by practitioners. This study aimed to clarify the clinical, diagnostic and therapeutic aspects of penicilliosis.. It is a descriptive study, prospective and retrospective, conducted over a 3-year period in Viet Tiep hospital, Haiphong.. With 94 cases, penicilliosis represented 11% of opportunistic infections. The patients were young (mean: 33 years) and male (87%). The main symptoms were persistent fever (99%), weight loss (88%), skin lesions (86%), hepatomegaly (69%) and lymphadenopathy (68%). Anemia was noted in 77% of cases. The average CD4 count was 29/μL. The culture of skin biopsies and blood culture were positive for Penicillium marneffei in 94% and 90% of cases, respectively. Despite antiretroviral and antifungal therapy, the mortality rate was 18%. Itraconazole monotherapy, administered in 53 patients due to the unavailability of amphotericin B, did not significantly affect the survival compared to the recommended treatment received by the 41 other patients.. In Haiphong, penicilliosis is one of the most frequent and severe opportunistic infections of AIDS. The diagnosis should be considered in all febrile and immunocompromised patients having spent time in Vietnam. The prognosis can be improved by early diagnosis through the blood culture and a good adherence to an appropriate antifungal therapy.

Topics: Adolescent; Adult; AIDS-Related Opportunistic Infections; Amphotericin B; Antifungal Agents; Antiretroviral Therapy, Highly Active; Early Diagnosis; Female; Hospitalization; Humans; Immunocompromised Host; Itraconazole; Male; Middle Aged; Mycoses; Penicillium; Prognosis; Prospective Studies; Retrospective Studies; Survival Analysis; Treatment Outcome; Vietnam

To describe the clinical courses of patients who received intravitreal injections of highly concentrated amphotericin B deoxycholate for suspected fungal endophthalmitis.. Retrospective medical record review of 3 cases of intraocular toxicity from highly concentrated amphotericin B.. The first patient developed posttraumatic endophthalmitis and received an undiluted dose (500 μg) of amphotericin B. He developed severe intraocular inflammation and required a pars plana lensectomy, vitrectomy, and scleral buckle after developing a cataract and retinal detachment. Six years later, his visual acuity stabilized at 20/30. The second patient developed endogenous endophthalmitis and was treated with 5 intravitreal injections of amphotericin B and underwent 3 surgical procedures. The surgeon later discovered that the patient had received 55 μg of amphotericin B during the second injection. Three months after the injection, the patient's visual acuity was 20/60. The third patient developed chronic postoperative endophthalmitis following cataract extraction. He received 160 μg of amphotericin B and was immediately treated with a vitreous washout. Two years later, his visual acuity improved to 20/30. The vitreous culture results were negative in each case. A key finding was that the amphotericin B solution appeared to be yellow instead of nearly colorless.. We present 3 cases of intraocular toxicity from highly concentrated amphotericin B. In every case, the overly concentrated amphotericin B solution was yellow in color. Although severe noninfectious panophthalmitis resulted in every case, the visual acuity outcomes were good. Physicians should examine the color of amphotericin B solution prior to intraocular administration. If the solution appears to be yellow, the medication should not be injected.

Topics: Aged; Amphotericin B; Antifungal Agents; Cataract; Child; Deoxycholic Acid; Drug Combinations; Endophthalmitis; Eye Infections, Fungal; Humans; Intravitreal Injections; Male; Middle Aged; Mycoses; Retinal Detachment; Retrospective Studies; Visual Acuity; Vitreous Body

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Drug Combinations; Female; Humans; Kidney Function Tests; Liver Function Tests; Male; Middle Aged; Mycoses; Pyrimidines; Survival Analysis; Triazoles; Voriconazole; Young Adult

Disseminated penicilliosis-an AIDS-indicator disease in Southeast Asian countries -but not Japan- is a systemic fungal infection caused by Penicillium marneffei. A 30-year-old HIV-positive Japanese man visiting Southeast Asia three months before admission and reporting fever, general fatigue, and enlarged lymph nodes lasting over one month was admitted for detailed tests. Blood culture and fine-needle aspiration lymph node biopsy a led to a diagnosis of disseminated penicillioisis, later cured by several anti-fungal agents. Caution is thus recommended regarding the possibility of this disease, given the large number of travelers visiting overseas, geographical proximity to Southeast Asia, and increasing numbers of HIV patients in Japan.

Topics: Adult; AIDS-Related Opportunistic Infections; Amphotericin B; Asian People; HIV Infections; Humans; Male; Mycoses; Penicillium; Thailand; Travel

We have retrospectively investigated clinical profile, efficacy, and safety in 41 patients who were treated with liposomal amphotericin B (L-AMB) in Aichi Medical University Hospital between January 2008 and June 2009. It turned out that L-AMB was used for severe infectious diseases and 31.7% cases discontinued L-AMB therapy because of death. L-AMB was administered as the second-line therapy in 56.1% (23/41), and was not effective in 48.8% (20/41). L-AMB was administered as the first-line therapy in 43.9% (18/41); (1) 1 for cryptotoccal infection, (2) 7 for severe sepsis or septic shock, (3) 2 for the case which cannot remove medical device and might have biofilm formation, (4) 6 for the induction of step-down therapy concept, (5) 2 for febrile neutropenic patients who have needed aggressive empiric therapy. There was no significant difference in serum potassium level (p = 0.10) and serum creatinine level (p = 0.05) between pretreatment and posttreatment with L-AMB. The serum creatinine level before initial treatment with L-AMB was 1.31 +/- 1.30 mg/dL. The patients for 7.3% (3 cases) had dialyzed before initial treatment with L-AMB, however, there was no case who need dialysis after administration of L-AMB. As for the highest creatinine level in L-AMB administered cases, 29.3% (12/41) and 24.4% (10/41) were normal to abnormal, and abnormal to abnormal, respectively. This is the first investigational report when the serum creatinine level before initial administration of LAMB had been abnormal. The other antimicrobial agents, which might have influenced renal function, were administered to 51.2% cases (21/41). That means the cases administered L-AMB might have other bacterial infections. As for the serum creatinine level, we observed the changing cases and the cases which did not cause the change at all regardless of the administering period of LAMB. The serum potassium level before initial administration of L-AMB was 4.1 +/- 0.8 mEq/L, concomitant use of furosemide etc. was 31.7% (13/41), the lowest serum potassium level was 3.4 +/- 0.9 (1.9-6.2)mEq/L in during using L-AMB, the serum potassium was 34.1% (14/41) in replenish potassium during administration of L-AMB, and the total replenished potassium was 131.25 mEq. We did not observe the case who had died because of the low potassium. Since L-AMB was the only fungicidal drug, when we use L-AMB for the serious infectious diseases to make the best use of the characteristic, we have to pay attention to the

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Child; Child, Preschool; Creatinine; Female; Humans; Male; Middle Aged; Monitoring, Physiologic; Mycoses; Potassium; Retrospective Studies; Risk Assessment; Severity of Illness Index; Young Adult

We have evaluated and compared the efficacies of high doses of amphotericin B (AMB; 3 mg/kg of body weight/day), voriconazole (60 mg/kg), and posaconazole (PSC; 100 mg/kg) alone and combined in a murine model of disseminated infection by Fusarium oxysporum. The combination of AMB with PSC showed the best results, prolonging the survival of mice and reducing their organ fungal loads. This combination might constitute a therapeutic option for those infections where monotherapies fail.

Topics: Amphotericin B; Animals; Antifungal Agents; Drug Therapy, Combination; Fusarium; Male; Mice; Mycoses; Pyrimidines; Triazoles; Voriconazole

A collection of 2,278 isolates belonging to 86 different fungal species was tested with micafungin and eight other drugs using the EUCAST procedures. Micafungin was active against species of Candida and Aspergillus (even azole-resistant species) as well as Penicillium spp., Scedosporium apiospermum, and Acremonium spp. It was inactive for species of Basidiomycota and Mucorales and for multiresistant species such as those of Fusarium.

Topics: Acremonium; Antifungal Agents; Aspergillus; Candida; Drug Resistance, Fungal; Echinocandins; Fungi; Humans; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Mycoses; Penicillium; Scedosporium; Spain

Fusarium species are saprophytic molds which cause disseminated or localized infections in humans. Disseminated Fusarium infection can cause significant morbidity and mortality in immunocompromised patients. We present a case of disseminated fusariosis caused by Fusarium verticillioides in a patient with acute lymphoblastic leukemia and successfully treated using both liposomal amphotericin B and voriconazole.

Topics: Amphotericin B; Antifungal Agents; Child; Fusarium; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Male; Mycoses; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrimidines; Triazoles; Voriconazole

We have compared the efficacy of posaconazole and amphotericin B in an experimental murine model of paecilomycosis.. Immunosuppressed mice were treated with posaconazole at 25, 50, 75 or 100 mg/kg/day orally, amphotericin B at 1.5 or 3 mg/kg/day intraperitoneally or liposomal amphotericin B at 5 mg/kg/day intravenously. Treatment began 1 day after infection and continued for 10 days post-infection. Two strains of Paecilomyces lilacinus were tested.. Posaconazole at 50 mg/kg/day was the only treatment able to significantly reduce fungal loads in the spleens, kidneys and livers of the mice infected by each of the two strains.. The results suggest that posaconazole may have a clinical role in the treatment of disseminated paecilomycosis.

Topics: Amphotericin B; Animals; Antifungal Agents; Colony Count, Microbial; Kidney; Liver; Male; Mice; Mycoses; Paecilomyces; Spleen; Triazoles

We tested ten day courses of amphotericin B (AMB), micafungin (MFG), voriconazole (VRC), flucytosine (5FC) and posaconazole (PSC) alone and in double or triple combinations in the treatment of disseminated infections caused by Cladophialophora bantiana in a murine model. Animals were monitored for survival for 40 days. We found that PSC at 100 mg/kg or 5FC at 180 mg/kg prolonged survival over controls. The combinations PSC+MFG and PSC+5FC improved survival compared to MFG and 5FC alone, but were not superior to PSC alone. The triple combination of PSC+MFG+5FC improved the survival with respect to both the control group and the component monotherapies, but all the animals died during the experiment. When treatment with this triple therapy was extended up to 30 days, half of the animals survived for at least 10 months. Combination therapy with the three drugs (PSC, MFG and 5FC) appears to be a promising option for the treatment of C. bantiana infections.

Topics: Amphotericin B; Animals; Antifungal Agents; Ascomycota; Disease Models, Animal; Drug Therapy, Combination; Echinocandins; Flucytosine; Humans; Lipopeptides; Male; Micafungin; Mice; Mycoses; Treatment Outcome; Triazoles

The in vitro activity of isavuconazole was compared to those of amphotericin B, fluconazole, itraconazole, voriconazole, posaconazole, and ravuconazole against 300 clinical isolates of Pseudallescheria boydii, Paecilomyces lilacinus, Fusarium spp., Bipolaris spicifera, Curvularia lunata, Alternaria alternata, Exophiala spp., Rhizopus arrhizus, Mucor circillenoides, Absidia corymbifera, Blastomyces dermatitidis, Histoplasma capsulatum and Coccidioides posadasii. MICs were determined by a broth macrodilution method based on the CLSI M38-A procedure. The triazoles were relatively uniform in that they showed strong in vitro inhibitory activity against most of the tested fungi. In vitro activity was variable with strains of P. lilacinus while with Fusarium spp., the triazoles were found to have limited in vitro activity and amphotericin B was moderately active. The results suggest that isavuconazole is a broad-spectrum antifungal agent, effective against a wide range of moulds in vitro.

Topics: Amphotericin B; Antifungal Agents; Fungi; Humans; Microbial Sensitivity Tests; Mycoses; Nitriles; Opportunistic Infections; Pyridines; Triazoles

Frequently, diseases caused by black yeasts are chronic in nature with a high morbidity. In addition, these infections are often fatal and relapse is common, even after prolonged treatment. Although the CLSI Document M38-A outlines methods for antifungal susceptibility testing of moulds, Exophiala spp. are not directly discussed. In an effort to determine the antifungal susceptibility patterns of Exophiala spp. we tested 160 clinical isolates against amphotericin B, itraconazole, posaconazole, and voriconazole in a head-to-head comparison. Posaconazole and itraconazole were the most active in vitro with MICs falling well below the achievable serum levels typically observed with standard dosing regimens.

Topics: Amphotericin B; Antifungal Agents; Exophiala; Humans; Itraconazole; Microbial Sensitivity Tests; Mycoses; Pyrimidines; Triazoles; Voriconazole

With use of data from the Prospective Antifungal Therapy (PATH) Alliance registry, we performed this multicenter, prospective, observational study to assess the epidemiologic characters and outcomes of invasive fungal infection (IFI) in hematopoietic stem cell transplant (HSCT) recipients.. Sixteen medical centers from North America reported data on adult HSCT recipients with proven or probable IFI during the period July 2004 through September 2007. The distribution of IFIs and rates of survival at 6 and 12 weeks after diagnosis were studied. We used logistic regression models to determine risk factors associated with 6-week mortality for allogeneic HSCT recipients with invasive aspergillosis (IA).. Two hundred thirty-four adult HSCT recipients with a total of 250 IFIs were included in this study. IA (59.2%) was the most frequent IFI, followed by invasive candidiasis (24.8%), zygomycosis (7.2%), and IFI due to other molds (6.8%). Voriconazole was the most frequently administered agent (68.4%); amphotericin B deoxycholate was administered to a few patients (2.1%). Ninety-three (46.7%) of 199 HSCT recipients with known outcome had died by week 12. The 6-week survival rate was significantly greater for patients with IA than for those with invasive candidiasis and for those with IFI due to the Zygomycetes or other molds (P < .07). The 6-week mortality rate for HSCT recipients with IA was 21.5%. At 6 weeks, there was a trend toward a worse outcome among allogeneic HSCT recipients with IA who received myeloablative conditioning (P = .07); absence of mechanical ventilation or/and hemodialysis (P = .01) were associated with improved survival.. IA remains the most commonly identified IFI among HSCT recipients, but rates of survival in persons with IA appear to have improved, compared with previously reported data. Invasive candidiasis and IFI due to molds other than Aspergillus species remain a significant problem in HSCT recipients.

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; Aspergillus; Candida; Deoxycholic Acid; Drug Combinations; Female; Fungi; Hematopoietic Stem Cell Transplantation; Humans; Logistic Models; Male; Middle Aged; Mucorales; Mycoses; North America; Prevalence; Prospective Studies; Pyrimidines; Risk Factors; Treatment Outcome; Triazoles; Voriconazole

Scytalidium dimidiatum is mainly responsible for human skin and nail infections but the mould has also been reported for invasive infections in immunocompromised individuals. We report a young immunocompetent individual diagnosed with invasive non-traumatic Scytalidium dimidiatum infection involving the left orbital cavity and maxillary sinus.

Topics: Amphotericin B; Antifungal Agents; Ascomycota; Diagnosis, Differential; Exophthalmos; Humans; Immunocompetence; Magnetic Resonance Imaging; Male; Mycoses; Sinusitis; Tomography, X-Ray Computed; Young Adult

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Deoxycholic Acid; Drug Combinations; Female; Humans; Male; Middle Aged; Mycoses; Retrospective Studies; Stem Cell Transplantation; Young Adult

To examine the clinical pathology and management of Paecilomyces lilacinus keratitis.. Observational case series, literature review, and laboratory study.. Characteristics and outcome of 17 patients with laboratory-confirmed Paecilomyces keratitis treated at 2 referral centers were combined with 25 previously reported cases. Experimental models were developed by topically inoculating a human corneal isolate of P. lilacinus onto murine eyes and onto human donor corneas.. Of 42 reported eyes with Paecilomyces keratitis, 13 (31%) were associated with chronic keratopathy or previous ocular surgery, 11 (26%) followed corneal trauma, and 10 (24%) occurred in soft contact lens wearers. Medical cure occurred in 13 (31%), including 9 of 31 eyes (29%) treated with natamycin or amphotericin B. Penetrating keratoplasty or other surgery was performed in 29 (69%). In vitro testing of P. lilacinus indicated resistance to natamycin and amphotericin B but susceptibility to ketoconazole and voriconazole. Experimental inoculation after superficial scarification established moderately severe corneal paecilomycosis by hyphae and conidia in immunosuppressed mice and in explanted donor corneas.. P. lilacinus is an emerging fungal pathogen that infects corneal tissue by filamentous invasion with occasional intrastromal sporulation. P. lilacinus keratitis does not reliably respond to natamycin or amphotericin B and has often required therapeutic keratoplasty, but topical azole antifungal agents such as voriconazole appear promising.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Animals; Anti-Bacterial Agents; Combined Modality Therapy; Cornea; Corneal Ulcer; Disease Models, Animal; Eye Infections, Fungal; Female; Humans; Keratoplasty, Penetrating; Male; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Middle Aged; Mycoses; Natamycin; Paecilomyces; Tissue Donors; Treatment Outcome

The role of fungi in chronic rhinosinusitis (CRS) is not clear. Fungi can be detected in the nose and paranasal sinuses of virtually all CRS patients; however, they also appear to be present in healthy controls. Various theories attempt to explain the mechanisms by which fungi can exert an effect on sinus mucosa in susceptible individuals. Further studies are necessary to clarify the role of fungi in CRS, which fungal organisms (if any) are pathogenic, and what exactly characterizes the immunologic response to fungi that may result in the development of disease. However, in the absence of convincing immunologic data and evidence of clinical improvement of CRS after antifungal therapy, the case against the fungus remains unproven.

Topics: Amphotericin B; Antifungal Agents; Antimicrobial Cationic Peptides; Chronic Disease; Cytokines; Fungi; Humans; Hyperplasia; Hypersensitivity; Immunotherapy; Mycoses; Pulmonary Surfactant-Associated Protein D; Sinusitis

To study the prevalence of risk factors and outcome of fungal infections in patients with severe acute pancreatitis.. Fifty consecutive patients with severe acute pancreatitis were investigated for evidence of fungal infection by weekly culture of body fluids and aspirate from pancreatic/peripancreatic tissue and samples collected at necrosectomy. All patients were managed as per a standard protocol. Patients with documented fungal infection were treated with intravenous amphotericin or fluconazole. Data were analyzed using SPSS software (version 13), and risk factors for fungal infection and mortality were determined.. Fungal infection was documented in 18 (36%) of 50 patients with Candida albicans (the commonest species). The incidence of fungal infection steadily increased with increasing duration of hospital stay. Those with fungal infection more often had evidence of respiratory failure (P = 0.031) and hypotension (P = 0.031) at admission, prolonged hospital stay > 4 weeks (P = 0.034), longer duration of antibiotics (P = 0.003), received total parenteral nutrition (P = 0.005), and required mechanical ventilation (P = 0.001) in contrast to those without fungal infection. The logistic regression analysis found the independent risk factors for fungal infection to be antibiotic therapy for > 4 weeks and hypotension at hospitalization. Of the 18 patients with fungal infection, 13 were administered intravenous antifungals; eight of these patients survived, while the five who did not receive antifungals died.. Fungal infection was detected in 36% of our patients. The independent risk factors associated with it were hypotension at hospitalization and prolonged antibiotic therapy. Antifungal therapy improved their chances of survival.

Topics: Adult; Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Female; Fluconazole; Humans; Hypotension; Length of Stay; Logistic Models; Male; Middle Aged; Mycoses; Odds Ratio; Pancreatectomy; Pancreatitis, Acute Necrotizing; Parenteral Nutrition, Total; Prevalence; Prospective Studies; Respiration, Artificial; Respiratory Insufficiency; Risk Assessment; Risk Factors; Severity of Illness Index; Time Factors; Treatment Outcome

This is a case study of Fusarium keratitis progressing to endophthatmitis that was successfully treated with a tiposomal formulation of amphotericin B (AmBisome] and local natamycin 5%.. A 41-year-old man presented with a clinical picture of endophthalmitis following deep Fusarium solani keratitis. Treatment with natamycin 5% drops and intravenous amphotericin B 150 mg per day caused renal failure and did not alleviate the endophthalmitis. Therefore, intravenous amphotericin B was replaced with intravenous AmBisome, 300 mg per day, to a cumulative dosage of 5.4 g.. Both the endophthalmitis and keratitis were alleviated within several weeks after starting AmBisome treatment. No systemic toxicity was noted. The final ophthalmoLogic examination showed a paracentral corneal scar, and a satisfactory best corrected visual acuity of 20/40.. Due to their relatively low systemic toxicity, liposomal formulations of amphotericin B can be administered in higher doses than traditional unencapsulated ntravenous amphotericin B achieving higher concentrations in the target organ.

Topics: Acute Kidney Injury; Adult; Amphotericin B; Antifungal Agents; Endophthalmitis; Fusarium; Humans; Injections, Intravenous; Keratitis; Male; Mycoses; Natamycin; Visual Acuity

Forty-eight Fusarium isolates morphologically identified as belonging to seven species of clinical interest (i.e., Fusarium chlamydosporum, Fusarium dimerum, Fusarium incarnatum, Fusarium napiforme, Fusarium nygamai, Fusarium proliferatum, and Fusarium sacchari) were characterized molecularly by the analysis of the sequences of the TUB region of the beta-tubulin gene. F. chlamydosporum and F. dimerum were the most genetically heterogeneous species. A high degree of correlation between the morphological and molecular identification was shown among the isolates studied. A table with the key morphological features for the identification of these Fusarium species is provided. The antifungal susceptibilities of the Fusarium isolates to 11 antifungal drugs were tested; terbinafine was the most active drug against all the species tested with the exception of F. incarnatum, for which amphotericin B was the most active.

Topics: Amphotericin B; Antifungal Agents; DNA, Fungal; Fungal Proteins; Fusarium; Humans; Microbial Sensitivity Tests; Molecular Sequence Data; Mycoses; Naphthalenes; Polymorphism, Genetic; Sequence Analysis, DNA; Terbinafine; Tubulin

Chronic rhinosinusitis (CRS) is an inflammatory disease with a multifactorial etiology. Antifungal therapy is not routinely used to treat it. However, evidence implicating fungi in some forms of CRS recently has been published. Controversy exists as to whether fungi identified in sinonasal cultures are always pathogenic. Immunologic evidence supporting the role of fungi in the pathogenesis of CRS is also debated. Topical antifungal therapy is more widely used than oral therapy, with amphotericin B irrigation being the most common. Although some studies show benefit from this irrigation, others refute the efficacy. Although oral antifungal agents are used uncommonly, itraconazole is the most commonly used drug. The efficacy of oral itraconazole in CRS has never been assessed in a clinical trial. Given the current evidence, the use of antifungals to treat CRS is controversial and has limited indications.

Topics: Administration, Intranasal; Administration, Oral; Administration, Topical; Amphotericin B; Antifungal Agents; Chronic Disease; Humans; Itraconazole; Mycoses; Rhinitis; Sinusitis

Topics: Adolescent; Amphotericin B; Antifungal Agents; Caspofungin; Child; Child, Preschool; Drug Therapy, Combination; Echinocandins; Female; Humans; Immunocompromised Host; Infant; Infant, Newborn; Lipopeptides; Male; Mycoses; Neutropenia; Pyrimidines; Retrospective Studies; Salvage Therapy; Triazoles; Voriconazole

To assess safety, tolerance and efficacy of liposomal amphotericin B (LAMB) in a large unselected series of paediatric cancer/haematopoietic stem cell transplantation (HSCT) patients requiring LAMB therapy.. The study included 84 children and adolescents (median age: 11 years) who received 141 consecutive courses of LAMB for prophylaxis (32), empirical therapy (83), possible (19) or probable/proven (7) invasive infections. LAMB was administered until intolerance or maximum efficacy at dosages individually determined by the responsible physician.. Fifty-nine courses were post-HSCT (42%, 49 allogeneic), and 92 courses were started during granulocytopenia (65%). The median duration of LAMB therapy was 13 days (range 1-79), and the median maximum dosage was 2.8 mg/kg (range 0.93-5.10). Mild-to-moderate adverse events were noted during 109 courses (77%; hepatic, 58.8%; electrolyte wasting, 52.5%; renal, 31.9%; infusion-related reactions, 8.5%); adverse events necessitating discontinuation of LAMB occurred in 6 courses (4.3%; renal, 3; anaphylaxis, 2; hepatic, 1). While median hepatic transaminase, alkaline phosphatase and blood urea nitrogen values were slightly (P < 0.01) higher at end of treatment (EOT), bilirubin and creatinine values were not different from baseline. Complete or partial responses were observed in 16/19 and 2/7 courses for possible and probable/proven invasive infections. Thirty-two of 33 courses of prophylaxis and 74 of 83 courses of empirical therapy were completed with success. Overall survival was 90.8% at 3 months post-EOT.. LAMB had acceptable safety and tolerance and was useful in prevention and treatment in unselected, mostly granulocytopenic paediatric patients undergoing treatment for cancer or HSCT.

Topics: Adolescent; Amphotericin B; Antifungal Agents; Child; Child, Preschool; Female; Humans; Immunocompromised Host; Infant; Male; Mycoses; Neoplasms; Stem Cell Transplantation; Treatment Outcome; Young Adult

Invasive fungal infection (IFI) caused by Lecythophora mutabilis occasionally occurs in patients with impaired host immunity; such patients had eosinophilia at onset, and surviving patients were treated with fungal cell-membrane-targeted drugs. An 18-year-old man with mitochondrial encephalomyopathy accompanied with refractory anaemia and chronic renal failure developed septic shock caused by L. mutabilis, which was detected from a blood culture, and was identified morphologically and genetically. During the course of the infection, he had eosinophilia, although beta-d-glucan levels were within the normal range. He was treated with micafungin, but deteriorated and died, despite his treatment being changed to liposomal amphotericin B. On the basis of this we suggest that IFI caused by L. mutabilis should be suspected when a compromised host develops infection and eosinophilia, and that antifungal drugs that target beta-d-glucan are not advisable.

Topics: Adolescent; Amphotericin B; Antifungal Agents; Ascomycota; Echinocandins; Humans; Insomnia, Fatal Familial; Lipopeptides; Male; Micafungin; Mitochondrial Encephalomyopathies; Mycoses; Pneumonia, Aspiration; Shock, Septic

Exophiala dermatitidis, one of the saprophytic dematiaceous fungi, is a cause of local and disseminated phaeohyphomycosis. We report a case of systemic phaeohyphomycosis resembling sclerosing cholangitis caused by E. dermatitidis in a 24-year-old woman.

Topics: Amphotericin B; Antifungal Agents; Cholangitis, Sclerosing; Diagnosis, Differential; Exophiala; Female; Humans; Lymph Nodes; Mycoses; Pyrimidines; Triazoles; Voriconazole; Young Adult

The clinical use of liposomal amphotericin B in 179 patients admitted to 30 medical-surgical intensive Care Units (ICUs) treated with this agent in 2006 was analyzed. Invasive fungal infections were proven, probable and possible in 44%, 16%, and 25% of cases, respectively. Fungi isolated were Candida albicans (38%), non-albicans Candida spp. (15%) and Aspergillus spp. (7%). The mean duration of treatment was 15 days (mean dose 3.7 mg/kg/day). The drug was used as rescue treatment after fluconazole or caspofungin in 47% of patients and as first line in 52% with a satisfactory clinical response in 54% of cases (72.6% with proven infection). Microbiological eradication was achieved in 68% of cases. Adverse events occurred in 51 patients but were severe in only 4. The use of liposomal amphotericin B both as first line and rescue treatment and mainly for proven invasive fungal infection was associated with a high rate of satisfactory clinical response.

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; APACHE; Critical Illness; Female; Humans; Intensive Care Units; Male; Middle Aged; Mycoses; Retrospective Studies

The purpose of this study was to determine the practice patterns of ophthalmologists in the management of fungal corneal ulcers.. In December 2007, a survey of 13 questions addressing the actual and preferred treatment of fungal ulcers was sent to the kera-net e-mail listserv facilitated by the Cornea Society.. Ninety-two respondents from North America, South America, Asia, Europe, and Australia participated by completing the electronic questionnaire. Natamycin was the most commonly used topical treatment for ulcers caused by filamentous fungi (96%) followed by amphotericin (75%) and voriconazole (63%). However, voriconazole was most often listed as the preferred topical treatment in an ideal world (79%) compared with 55% for natamycin. Approximately half of the respondents use combination topical therapy (56%) and the remainder monotherapy. The majority of respondents rescrape the epithelium at some time during the course of treatment, but the frequency of rescraping varied among the different topical treatments. The most common reasons cited for not using their preferred treatment were cost and a desire for further evidence to support preferred treatment.. There appears to be significant variation in the management of fungal corneal ulcers. Although natamycin was the most commonly used treatment for ulcers caused by filamentous fungi, voriconazole was the most preferred as the ideal treatment. These results highlight the need for more evidence regarding the efficacy of the newer topical antifungals.

Topics: Administration, Topical; Amphotericin B; Antifungal Agents; Corneal Ulcer; Debridement; Drug Costs; Drug Therapy, Combination; Humans; Mycoses; Natamycin; Ophthalmology; Patients; Practice Patterns, Physicians'; Pyrimidines; Surveys and Questionnaires; Treatment Outcome; Triazoles; Voriconazole

This report describes the molecular epidemiology, in vitro susceptibility, colonial and microscopic morphologies, and biochemical features of Trichosporon mycotoxinivorans, a newly recognized pathogen that appears to have a propensity for patients with cystic fibrosis. The index patient died with histologically documented Trichosporon pneumonia complicating cystic fibrosis. This is also the first report of disease caused by a Trichosporon species in a nontransplant patient with cystic fibrosis. As T. mycotoxinivorans has not previously been recognized as a respiratory pathogen, the significance of its recovery from sputum samples was not initially appreciated. Genetic analysis of archived clinical samples found three additional cases of T. mycotoxinivorans infection which had previously been identified as other members of the genus. An additional isolate of T. mycotoxinivorans was identified from a clinical sample on initial testing. Three of these four cases were also patients with cystic fibrosis. All isolates had MICs at 48 h of amphotericin B of > or = 1 microg/ml and of echinocandins of > or = 16 microg/ml, but they displayed various susceptibilities to the triazoles. In summary, Trichosporon mycotoxinivorans is a newly recognized human pathogen that is associated with cystic fibrosis.

Topics: Amphotericin B; Antifungal Agents; Cystic Fibrosis; Echinocandins; Fatal Outcome; Humans; Lung; Lung Diseases, Fungal; Microbial Sensitivity Tests; Molecular Epidemiology; Molecular Sequence Data; Mycoses; Radiography, Thoracic; Retrospective Studies; Triazoles; Trichosporon

The purpose of this study was to report the first case of fungal keratitis resulting from Thielavia sp.. We conducted a retrospective chart review.. A 10-year old girl presented 2 weeks after ocular plant injury with pain and corneal stromal infiltration with central ulceration and ill-defined margins. Cultures of corneal scrapings and biopsy sequence analysis of the ribosomal internal transcribed spacer region isolated Thielavia subthermophila Mouchacca. Clinically, the organism appeared to respond to topical amphotericin B and oral voriconazole. Best-corrected visual acuity at last follow-up visit counted 0.5.. A rare case of Thielavia sp. keratitis was successfully treated with topical amphotericin B and oral voriconazole. Newly developed molecular diagnostic tools contribute to the recognition of a widening spectrum of emerging fungal pathogens capable of causing serious ocular infections.

Topics: Amphotericin B; Antifungal Agents; Child; Corneal Ulcer; Drug Therapy, Combination; Eye Infections, Fungal; Female; Humans; Mycoses; Pyrimidines; Retrospective Studies; Sordariales; Triazoles; Voriconazole

Resistance to antifungal drugs, especially towards triazoles, is commonly referred to by clinicians, but data on its prevalence in developing countries is limited.. To determine the prevalence of triazole-resistance amongst pathogenic yeasts and moulds, we assessed the in vitro susceptibility of 250 isolates from hospitalized patients at five Mexican cities towards amphotericin B, fluconazole and voriconazole, by E-test.. All yeasts were susceptible to voriconazole, according to E-test interpretive criteria (MIC < or = 1 microg/mL), and all filamentous or dimorphic fungi also had voriconazole MIC < or = 1 microg/mL, except for one isolate each of Mucor sp. and Acremonium sp. Candida krusei and one isolate of C. glabrata were resistant to fluconazole, a drug that had MIC > or = 192 microg/mL for filamentous fungi. Although no breakpoints for amphotericin B are available, all three C. krusei, 2/25 C. glabrata, 3/22 C. parapsilosis and 1/108 C. albicans had MIC > or = 2 microg/mL.. In vitro, voriconazole is active against yeasts and moulds commonly causing severe mycoses in Mexico.

Topics: Amphotericin B; Antifungal Agents; Cities; Drug Resistance, Fungal; Fungi; Humans; Mexico; Microbial Sensitivity Tests; Mycoses; Triazoles; Urban Population

The prognosis for Fusarium keratitis is poor. Effective drugs to treat this infection are therefore needed.. A patient presented Fusarium solani keratitis. The infection regressed with topical amphotericin B and intravenous voriconazole. Topical steroids were introduced. There was reactivation and extension of the infection, invading the anterior chamber. Steroids were discontinued and the antifungal treatment was restarted but there was continued deterioration. Recovery was achieved without surgery, with topical voriconazole, topical liposomal amphotericin B, topical natamycin, intravenous liposomal amphotericin B, and intravenous voriconazole.. Combined orally and topically administered voriconazole is a promising therapy when the minimum inhibitory concentration is approximately 2 microg/ml. Liposomal amphotericin B seems to be the most effective drug for the different infection stages. Posaconazole is a useful alternative but further investigations must be pursued.

Topics: Amphotericin B; Antifungal Agents; Drug Resistance, Fungal; Eye Infections, Fungal; Fusarium; Humans; Keratitis; Liposomes; Male; Middle Aged; Mycoses; Remission Induction

This study aimed to report an outbreak of early-onset endophthalmitis caused by Fusarium species following cataract surgery.. The study was designed retrospectively to review microbiologic and medical records of eight cases of endophthalmitis caused by Fusarium species after cataract surgery performed in the same operating room and on the same date by different surgeons at Beyoğlu Eye Training and Research Hospital in Istanbul, Turkey. Seven patients had phacoemulsification and intraocular lens implantation surgery. Intracapsular cataract extraction was performed in one patient. The common feature of these surgeries was the use of intracameral injections of cefuroxime (1 mg in 0.1-ml balanced salt solution-BSS) solutions, which were preoperatively prepared from the same BSS bottle.. The duration between cataract surgery and the diagnosis of endophthalmitis was four days. Aqueous and vitreous specimens obtained from the patients grew fungus colonies that were identified according to their morphologic features and considered to be Fusarium solani. All patients underwent multiple vitrectomies with silicone oil injections. Patients were given local and systemic antifungal agents (amphotericin B and voriconazole). One patient with corneal involvement underwent evisceration despite a variety of treatments. One patient with unregulated diabetes was prephthisic without recurrence of infection. The final visual acuity of patients was between light perception and 20/100.. Fusarium should be considered in the differential diagnosis of early-onset endophthalmitis after cataract surgery. An aggressive treatment with local and systemic antifungal agents and multiple vitrectomies with silicone oil injection is helpful in the management of postoperative early-onset Fusarium endophthalmitis. In the prevention of such outbreaks, it is important to use solutions prepared differently for each patient.

Topics: Aged; Amphotericin B; Antifungal Agents; Combined Modality Therapy; Disease Outbreaks; Drug Therapy, Combination; Endophthalmitis; Eye Evisceration; Eye Infections, Fungal; Female; Fusarium; Humans; Lens Implantation, Intraocular; Male; Middle Aged; Mycoses; Phacoemulsification; Postoperative Complications; Pyrimidines; Retrospective Studies; Triazoles; Turkey; Visual Acuity; Vitrectomy; Voriconazole

(1) Amphotericin B is a standard antifungal drug with a narrow therapeutic margin. It has potentially severe adverse effects, especially renal and cardiac toxicity; (2) Three injectable forms of amphotericin B are currently available in France and elsewhere. They mainly differ in their dose regimens; (3) Cases of fatal overdose have occurred following confusion between the various injectable formulations; (4) Measures intended to prevent such errors include: specific training of healthcare staff; informing users that the different injectable forms of amphotericin B are not interchangeable; simultaneously mentioning the excipient and the international nonproprietary name (INN) and the brand name; remembering the maximum dose of the conventional formulation; noting the dose per kilogram per day, as well as the total daily dose; and if possible, involving the patient.

Topics: Amphotericin B; Antifungal Agents; Chemistry, Pharmaceutical; Humans; Injections; Inservice Training; Medication Errors; Mycoses; Risk Management

A 37-year-old woman, during her second remission of acute myeloid leukemia, presented with severe neck pain and cervico-brachial neuralgia. Investigation revealed a C5-C6 spondylodiscitis. A CT-guided anterior biopsy decompressed the mass, immediately alleviated the symptoms, and isolated a rare yeast: Blastoschizomyces capitatus. To our knowledge, only three cases of spondylodiscitis with this yeast have been described. Six months of voriconazole and liposomal amphotericin B treatment produced a complete resolution on CT and MRI imaging. However, the ongoing severe yeast infection prevented the planned bone marrow allograft.

Topics: Adult; Amphotericin B; Antifungal Agents; Cervical Vertebrae; Dipodascus; Discitis; Female; Humans; Leukemia, Myeloid, Acute; Mycoses; Neck; Pyrimidines; Tomography, X-Ray Computed; Triazoles; Ultrasonography; Voriconazole

This study evaluated the WIDERYST system, a commercially available computer-assisted image-processing device for the antifungal susceptibility testing of yeasts. A collection of 90 clinical isolates selected to represent ranges of susceptibilities in vitro as broad as possible was tested. An evaluation compared the results obtained by the new system with those achieved by both the Clinical and Laboratory Standards Institute (CLSI) microdilution reference procedure and the antifungal susceptibility standard of the European Committee for Antimicrobial Susceptibility Testing (EUCAST). Overall, the agreement and the correlation index between results obtained by the EUCAST method and the WIDERYST system were 89% and 0.84 (P < 0.01), respectively, and agreement and correlation index between data obtained by the CLSI procedure and the WIDERYST system were 90% and 0.86 (P < 0.01), respectively. The system was able to detect amphotericin B-resistant isolates. All Candida sp. isolates with resistance in vitro to azole agents were detected as well. The system misclassified some isolates belonging to the slowly growing genera Dipodascus and Pichia. A total of 2.7% very major errors were detected for fluconazole. The WIDERYST system is an alternative to reference procedures for antifungal susceptibility testing of clinical isolates of yeasts, particularly for Candida and Cryptococcus species.

Topics: Amphotericin B; Antifungal Agents; Azoles; Candida; Culture Media; Drug Resistance, Fungal; Fungi; Humans; Microbial Sensitivity Tests; Mycoses; Reproducibility of Results; Yeasts

The in vitro and in vivo antifungal activities of T-2307, a novel arylamidine, were evaluated and compared with those of fluconazole, voriconazole, micafungin, and amphotericin B. T-2307 exhibited broad-spectrum activity against clinically significant pathogens, including Candida species (MIC range, 0.00025 to 0.0078 microg/ml), Cryptococcus neoformans (MIC range, 0.0039 to 0.0625 microg/ml), and Aspergillus species (MIC range, 0.0156 to 4 microg/ml). Furthermore, T-2307 exhibited potent activity against fluconazole-resistant and fluconazole-susceptible-dose-dependent Candida albicans strains as well as against azole-susceptible strains. T-2307 exhibited fungicidal activity against some Candida and Aspergillus species and against Cryptococcus neoformans. In mouse models of disseminated candidiasis, cryptococcosis, and aspergillosis, the 50% effective doses of T-2307 were 0.00755, 0.117, and 0.391 mg.kg(-1).dose(-1), respectively. This agent was considerably more active than micafungin and amphotericin B against candidiasis and than amphotericin B against cryptococcosis, and its activity was comparable to the activities of micafungin and amphotericin B against aspergillosis. The results of preclinical in vitro and in vivo evaluations performed thus far indicate that T-2307 could represent a potent injectable agent for the treatment of candidiasis, cryptococcosis, and aspergillosis.

Topics: Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Benzamidines; Candida albicans; Candidiasis; Cryptococcosis; Cryptococcus neoformans; Male; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Mycoses; Specific Pathogen-Free Organisms; Treatment Outcome

A microdilution method was used to test 11 antifungal drugs against clinical isolates of Fusarium thapsinum and three different phylogenetic clades of Fusarium verticillioides that were characterized by sequencing a region of the beta-tubulin gene. Terbinafine was the most-active drug against both species, followed by posaconazole against F. verticillioides.

Topics: Animals; Antifungal Agents; Drug Resistance, Fungal; Fusarium; Humans; Microbial Sensitivity Tests; Molecular Sequence Data; Mycoses; Naphthalenes; Sequence Analysis, DNA; Terbinafine; Triazoles; Tubulin

Fusarium isolates from 75 Italian patients were identified by molecular methods, and their susceptibilities to antifungals were tested in vitro. Fusarium verticillioides was the species most frequently isolated from deep-seated infections, and F. solani was the species most frequently isolated from superficial infections. F. solani isolates showed high azole MICs, while F. verticillioides isolates showed low posaconazole MICs.

Topics: Antifungal Agents; Base Sequence; DNA Primers; DNA, Fungal; Drug Resistance, Fungal; Fusarium; Humans; Italy; Microbial Sensitivity Tests; Mycoses; Species Specificity

We compared the activities of antifungal agents against a wide range of yeasts and filamentous fungi. The methodology of the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for yeasts and spore-forming molds was applied; and a total of 349 clinical isolates of Candida spp., other yeast species, Aspergillus spp., and nondermatophyte non-Aspergillus spp. were investigated. The average geometric mean (GM) of the MICs of the various drugs for Candida spp. were as follows: amphotericin B (AMB), 0.55 microg/ml; liposomal amphotericin B (l-AMB); 0.35 microg/ml; itraconazole (ITC), 0.56 microg/ml; voriconazole (VRC), 0.45 microg/ml; posaconazole (POS), 0.44 microg/ml; and caspofungin (CPF), 0.45 microg/ml. The data indicated that the majority of Candida spp. were susceptible to the traditional and new antifungal drugs. For Aspergillus spp., the average GM MICs of AMB, l-AMB, ITC, VRC, POS, and CPF were 1.49 microg/ml, 1.44 microg/ml, 0.65 microg/ml, 0.34 microg/ml, 0.25 microg/ml, and 0.32 microg/ml, respectively. For the various zygomycetes, the average GM MICs of AMB, l-AMB, ITC, and POS were 1.36 microg/ml, 1.42 microg/ml, 4.37 microg/ml, and 1.65 microg/ml, respectively. Other yeastlike fungi and molds displayed various patterns of susceptibility. In general, the minimal fungicidal concentrations were 1 to 3 dilutions higher than the corresponding MICs. POS, AMB, and l-AMB showed activities against a broader range of fungi than ITC, VRC, and CPF did. Emerging pathogens such as Saccharomyces cerevisiae and Fusarium solani were not killed by any drug. In summary, the EUCAST data showed that the in vitro susceptibilities of yeasts and filamentous fungi are variable, that susceptibility occurs among and within various genera and species, and that susceptibility depends on the antifungal drug tested. AMB, l-AMB, and POS were active against the majority of pathogens, including species that cause rare and difficult-to-treat infections.

Topics: Amphotericin B; Antifungal Agents; Aspergillus; Candida; Drug Resistance, Fungal; Europe; Fungi; Guidelines as Topic; Humans; Microbial Sensitivity Tests; Mycoses; Opportunistic Infections; Triazoles; Yeasts

To report a case of fungal keratitis of the eye caused by Pichia anomala in a patient with systemic lupus erythematous and Stevens-Johnson syndrome.. This was a retrospective chart review.. A 50-year-old woman with systemic lupus erythematosus presented with ocular pain of 4-day duration. Culture of corneal scrapings was positive for P. anomala. Clinically, the organism appeared to respond to topical natamycin, amphotericine B, and oral itraconazole.. A rare case of P. anomala-associated keratitis was successfully treated with topical amphotericin B, natamycin, and systemic inidazole.

Topics: Amphotericin B; Antifungal Agents; Corneal Ulcer; Drug Therapy, Combination; Eye Infections, Fungal; Female; Humans; Imidazoles; Lupus Erythematosus, Systemic; Middle Aged; Mycoses; Natamycin; Pichia; Stevens-Johnson Syndrome

A case of chronic invasive rhinosinusitis in an apparently healthy man, caused by Fusarium verticillioides, is described. The identity of the isolate as F. verticillioides was established by demonstrating characteristic morphological features and by amplification of rDNA using species-specific primers. Surgical debridement of the infected nasal tissue and therapy with amphotericin B resulted in a favorable outcome. To the best of our knowledge, F. verticillioides has not been described previously to cause this condition.

Topics: Amphotericin B; Antifungal Agents; DNA, Fungal; DNA, Ribosomal; Fusarium; Humans; Male; Middle Aged; Mycoses; Polymerase Chain Reaction; Rhinitis; Sinusitis

Invasive fungal infections (IFI) are a major cause of morbidity and mortality in patients with haematological malignancies. Antifungal combination therapy is a promising treatment option. However, available data on feasibility, toxicity and efficacy of this therapy are limited. Therefore, this study was conducted to evaluate the feasibility, toxicity and outcome of different antifungal combination therapies. Patients with haematological malignancies receiving antifungal combination therapy for IFI were retrospectively analysed. Toxicity and response were documented at the end of therapy. Survival was evaluated at the end of therapy and after 12 weeks. Fifty-six patients were treated with different antifungal combinations in the period between 2001 and 2007. The majority of patients (63%) received a combination of liposomal amphotericin B and caspofungin as antifungal combination treatment. Toxicity of all applied combinations was tolerable. At the end of combination therapy, favourable response was 65%, whereas unfavourable outcome occurred in 35% of the cases. Mortality at the end of treatment was 11% and 34% 3 months after initiation of combination therapy. Antifungal combination therapy is feasible and efficient in haematological cancer patients and allogeneic stem cell transplant recipients with IFI. Prospective studies to evaluate the optimal combinations are needed.

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; Antineoplastic Agents; Caspofungin; Cohort Studies; Drug Therapy, Combination; Echinocandins; Female; Hematopoietic Stem Cell Transplantation; Humans; Leukemia; Lipopeptides; Male; Middle Aged; Mycoses; Myeloablative Agonists; Myelodysplastic Syndromes; Retrospective Studies; Survival Analysis; Transplantation, Homologous

Guidelines were introduced in 2000 at the Bristol Eye Hospital (BEH) for the management of fungal endophthalmitis. A 5-year retrospective audit re-evaluated the guidelines and monitored the management of this rare condition. Clinical effectiveness and management costs were considered in light of visual outcome.. Cases were identified through a 5-year retrospective review of theatre logbooks, Patient Administration System coded admissions with primary diagnosis of purulent endophthalmitis and pharmacy logbooks of patients receiving antifungal therapy. Data correlation and review of patient management were carried out in light of the findings.. Twenty-three cases were included, based on clinical disease and/or positive smears or cultures. Age range was 13-74 years, with a male : female ratio of 16 : 7 and right eye : left eye ratio of 14 : 9. Risk factors for fungal endophthalmitis included septicaemia caused by intravenous drug use (78%), presence of indwelling lines (9%), postocular surgery (9%) and post-trauma (4%). Guidelines were rigidly followed in 56% of cases, with improved visual acuity in 9/13 patients compared to 4/10 where management deviated from guidelines. Deviation from guidelines occurred with incomplete use of the recommended drug regimen for the disease severity or use of drugs that were alternative to the suggested guidelines. Treatment was initiated on clinical judgement in 91% of cases and laboratory diagnosis in 9%.. The BEH guidelines provided a useful reference when managing this uncommon condition. Voriconazole, a newer broad-spectrum agent with good ocular penetration (used in 9%), has been added to the revised guidelines. Monitoring rare conditions over prolonged time frames supports evidence-based medicine

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Drug Costs; Endophthalmitis; Eye Infections, Fungal; Female; Fluconazole; Flucytosine; Guideline Adherence; Health Care Costs; Humans; Male; Medical Audit; Middle Aged; Mycoses; Practice Guidelines as Topic; Pyrimidines; Retrospective Studies; Treatment Outcome; Triazoles; Visual Acuity; Voriconazole

The susceptibility of 1763 yeast isolates (from 22 species and seven genera) was tested using Clinical and Laboratory Standards Institute M27-A2 microdilution methodology. Candida spp. predominated (97.1%), mainly C. albicans (51.4%), C. glabrata (16.4%) and C. tropicalis (13.7%), followed by Trichosporon spp. (1.1%) and Cryptococcus neoformans (1.0%). Most isolates came from blood/catheters (72.0%) or the oesophagus/oropharynx (11.3%). The voriconazole, itraconazole, fluconazole and amphotericin B MIC90 values (minimum inhibitory concentration for 90% of the isolates) for all isolates were 1.0, 2.0, 64 and 1.0 microg/mL, respectively. Voriconazole MICs correlated with those for fluconazole (r = 0.91) and itraconazole (r = 0.90). Only 109 isolates (6.2%) had voriconazole MICs > or = 4.0 microg/mL; all were C. albicans, C. glabrata or C. tropicalis resistant to itraconazole (and most to fluconazole). Isolates from 22 patients with amphotericin MICs > or = 2.0 microg/mL (range 2.0-16.0 microg/mL) were also cross-resistant to one or more of the triazoles. Patients (n = 34) with voriconazole-resistant isolates showed a 56% response to voriconazole therapy, and those patients (n = 261) with susceptible isolates showed a 71% response. Twenty-three voriconazole-treated patients had baseline resistant isolates, in eight patients voriconazole resistance developed during therapy and in three patients a different resistant species arose during therapy. Thus, voriconazole MICs correlate with those of fluconazole and itraconazole and may predict clinical outcome.

Topics: Amphotericin B; Antifungal Agents; Candida; Candidiasis; Clinical Trials, Phase III as Topic; Fluconazole; Humans; Itraconazole; Microbial Sensitivity Tests; Mycoses; Pyrimidines; Triazoles; Voriconazole; Yeasts

Topics: Adult; Amphotericin B; Antifungal Agents; Combined Modality Therapy; Corneal Ulcer; Debridement; Drug Therapy, Combination; Exophiala; Eye Infections, Fungal; Female; Humans; Itraconazole; Keratomileusis, Laser In Situ; Microbial Sensitivity Tests; Mycoses; Myopia; Natamycin; Postoperative Complications; Surgical Flaps

Clinical studies have suggested that rates of infusion-related reactions (IRRs) may be higher with amphotericin B colloidal dispersion (ABCD) versus other forms of amphotericin B. However, these studies did not permit the use of pre-medications upfront, which are now commonly used. Objectives To describe the use of pre-medications and determine the rate of IRRs in the real-world setting.. PRoACT, a multicentre, worldwide observational registry, captured real-world data about pre-medication practices and IRRs in patients receiving ABCD. Eligible patients were those beginning treatment with ABCD; treatment was according to the site's standard treatment practice. Incidence of IRRs was collected during the first 10 days of ABCD therapy. Clinical response data were collected 12 weeks after treatment start.. One hundred and seventy patients from 21 worldwide sites were included (median age 37 years; 52% male). There were a total of 1230 ABCD infusions (mean dose 2.8 mg/kg/day); 90% of the infusions (1105/1230) had pre-medication. Common pre-medications included corticosteroids, antihistamines, paracetamol (acetaminophen) and metamizole. The overall IRR rate was 12% (147/1230) and was lower in infusions with pre-medication (11%) versus no pre-medication (22%), P < 0.001. Corticosteroids were associated with a decreased incidence of IRRs (P < 0.05), while paracetamol and antihistamines were not. The most common IRRs were chills (7%), fever (7%) and rigors (5%). Clearance of the fungal infection occurred in 52% of the participants.. These data suggest a lower rate of IRRs with ABCD than previously reported. Pre-medication is associated with decreased IRR incidence. Corticosteroids in particular appear to decrease IRRs while paracetamol and antihistamines, though commonly used, do not.

Topics: Acetaminophen; Adolescent; Adrenal Cortex Hormones; Adult; Aged; Aged, 80 and over; Amphotericin B; Anti-Inflammatory Agents; Antifungal Agents; Cholesterol Esters; Drug Combinations; Female; Histamine Antagonists; Humans; Infusions, Intravenous; Male; Middle Aged; Mycoses

Invasive fungal infections (IFIs) in patients undergoing lung transplantation (LT) are associated with significant mortality. Previous studies have shown the efficacy of aerosolized amphotericin B deoxycholate and oral fluconazole for antifungal prophylaxis. Evolving data show a potential advantage of prophylaxis with lipid-based formulations of amphotericin B in the prevention of IFIs. We reviewed the incidence of IFIs among patients receiving aerosolized amphotericin B lipid complex (ABLC) in LT.. We undertook a retrospective review of the results of our antifungal protocol in a cohort of 60 LT patients. We analyzed the efficiency, safety, and tolerability of 50 mg of aerosolized ABLC administered postoperatively for IFI prophylaxis once every 2 days for 2 weeks and then once per week for at least 13 weeks. In addition, these transplanted patients received fluconazole (200 mg/d) during the first 21 days posttransplant. The prophylaxis-related efficiency and safety were quantified for IFIs and adverse events (AEs) for 6 months after study drug initiation.. Prophylaxis was efficient in 59 (98.3%) patients. Only one patient developed a possible IFI, due to Aspergillus fumigatus. Four patients presented nausea and vomiting as an AE, although aerosolized amphotericin B was ongoing.. Nebulized ABLC was effective, safe, and well tolerated for the prophylaxis of aspergillosis in lung transplant patients during the early posttransplant period.

Topics: Administration, Inhalation; Administration, Oral; Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Aspergillosis; Child; Female; Fluconazole; Humans; Lung Transplantation; Male; Middle Aged; Mycoses; Nausea; Retrospective Studies; Risk Factors; Safety; Vomiting; Young Adult

To compare the differences in clinical therapeutic effect and safety between amphotericin B and its liposome form in treating invasive fungal infection (IFI) in hematological disorder with neutrocytopenia.. Of 111 patients with IFI, 82 were treated with amphotericin B and 29 with amphotericin B liposome. The mean cumulative dose of amphotericin B was 617 (60-1895) mg and the mean course was 18 (7-60) d, and those for amphotericin B liposome was 925 (140-3420) mg and 13 (7-50) d, respectively.. The total effective rates of amphotericin B and its liposome groups were 69% and 58%, respectively (P>0.05). The adverse effect rates of chill and fever in amphotericin B and its liposome groups were 21% and 10% (P>0.05), hypopotassemia 34% and 14% (P=0.03), hepatic impairment 22% and 17% (P>0.05), and renal impairment 9% and 3%, respectively (P>0.05).. The therapeutic effect for IFI of amphotericin B and its liposome was similar. The severe adverse reaction of amphotericin B liposome was slightly lower than that of amphotericin B.

Topics: Agranulocytosis; Amphotericin B; Antifungal Agents; Hematologic Diseases; Humans; Liposomes; Mycoses; Retrospective Studies; Treatment Outcome

A 4-year-old spayed female mixed breed dog was referred to the Michigan State University, Veterinary Teaching Hospital (MSU-VTH) with vomiting, lethargy and anorexia of 2 weeks duration. Abdominal radiographs and ultrasonography showed hepatosplenomegaly. Cytological evaluation of ultrasound-guided fine needle aspirates of the liver and spleen revealed fungal organisms and pyogranulomatous inflammation; fungal culture documented Paecilomyces variotii infection. The dog received antifungal therapy and supportive care. Multiple firm plaque-like skin lesions, predominantly involving the inguinal region, developed 18 days after initial presentation and were diagnosed histopathologically as calcinosis cutis. While generalized calcinosis cutis has been reported in three dogs with blastomycosis and one dog with leptospirosis, the association with disseminated Paecilomyces spp. infection is novel.

Topics: Amphotericin B; Animals; Antifungal Agents; Calcinosis; Dog Diseases; Dogs; Female; Mycoses; Paecilomyces; Skin Diseases

In this study the molecular identification and susceptibility profile of 21 clinical isolates, from a Brazilian hospital, belongs to six different species of Trichosporon were described. Trichosporon asahii was the predominant species and corresponded to 43% of isolates. Eighty three percent of the strains isolated from deep sites were identified as T. asahii, while only 17% belong to a non-T. asahii species (Trichosporon inkin). In general, the MICs were high and independent of the species of Trichosporon as well as the clinical origin of strain. Amphotericin B and fluconazole were less effective against Trichosporon spp. and high MIC values of voriconazole, posaconazole and ravuconazole were observed. Fifty-six percent (5/9) of T. asahii strains were isolated from deep sites, whereas 8% (1/12) of non-T. asahii species were isolated from those sites. A total of 89% of T. asahii isolates exhibited resistance to amphotericin B in vitro.

Topics: Amphotericin B; Antifungal Agents; Brazil; Cross Infection; Dermatomycoses; Drug Resistance, Fungal; Echinocandins; Female; Flucytosine; Fungemia; Hospitals, University; Humans; Mycological Typing Techniques; Mycoses; Onychomycosis; Opportunistic Infections; Organ Specificity; Triazoles; Trichosporon; Urine; Vaginitis

In recent years, superficial and deep mycoses caused by trichosporon were occasionally reported. In 2001, we reported the first case of disseminated trichosporonosis caused by Trichosporon asahii (T. asahii) in China. In this study, the pathogenicity of T. asahii was investigated in a murine model of disseminated trichosporonosis.. Seventy-five mice were randomly divided into 7 groups. Each group was inoculated with T. asahii, through intradermal, gastrointestinal tract or intravenous injection. The mice in the experimental groups were given an intraperitoneal injection of cyclophosphamide (CY) to induce granulocytopenia. Mice in the therapeutic group were given both liposomal amphotericin B and fluconazole. The main viscera of the mice were examined by means of tissue culture and pathologic sections.. In the two intravenous inoculation groups, T. asahii was isolated from at least one organ in 10 of the 12 granulocytopenic mice and 2 of the 14 immunocompetent mice. Two of the 7 mice in the granulocytopenia group presented with lesions in the inoculation position, but none of the 30 mice in the granulocytopenia and the control group which were inoculated intradermally or through the gastrointestinal tract had viscera infection. In the therapeutic group, the ratio of consequently dead mice, the number of involved viscera, and the incidence of systemic infection were significantly less than the untreated group. Acute purulent inflammation and granulomatous inflammation were the main pathological changes in the course of the infection. Arthrospores and filaments were found in the focus.. T. asahii is an opportunistic pathogen that causes cutaneous and visceral infections in immunologically impaired hosts. An immunocompetent host was to be infected by the invading T. asahii. Several organs, namely the liver, lungs, kidneys, spleen and heart, were predisposed. The therapy of combining liposomal amphotericin B with fluconazole can prevent the host from an infection and inhibit the diffusion of the infection.

Topics: Amphotericin B; Animals; Antifungal Agents; Cyclophosphamide; Disease Models, Animal; Fluconazole; Male; Mice; Mycoses; Random Allocation; Trichosporon

Invasive mold infections (IMI) are a leading cause of infectious mortality in allogeneic stem cell transplant (AlloSCT) recipients. Fluconazole, the current standard for fungal prophylaxis, is ineffective against molds. We initiated a pilot study to determine the safety and activity of prophylactic liposomal amphotericin B (AMB) in preventing IMI in pediatric and adolescent AlloSCT recipients during the first 100 days.. Fifty-one patients (57 AlloSCT) were given AMB (3 mg/kg/day) intravenously, day 0-100. Median age 6 years, 32 males, 19 females. Donors: 33 unrelated and 2 related cord blood, 13 related and 1 unrelated peripheral blood stem cell and 8 related bone marrow (BM); 30 received myeloablative and 27 reduced intensity conditioning. Graft-versus-host disease (GVHD) prophylaxis comprised tacrolimus and mycophenolate mofetil.. Median follow-up is 557 days. AMB was generally well tolerated. The probability of developing >/=grade II acute GVHD and extensive chronic GVHD was 45% and 7%, respectively. Estimated 1-year OS is 62.4% for all patients with 78.8% and 26.7% for average-risk and poor-risk, respectively. The incidence of IMI was 0%.. These results suggest prophylactic AMB is tolerable and may prevent IMI, especially Aspergillus, during the first 100 days post AlloSCT in pediatric and adolescent patients. A randomized study is needed to determine the efficacy of this approach.

Topics: Adolescent; Adult; Amphotericin B; Antifungal Agents; Child; Child, Preschool; Female; Hematologic Diseases; Humans; Infant; Male; Mycoses; Postoperative Complications; Stem Cell Transplantation

To evaluate the efficacy of topical voriconazole in an experimental rabbit model of Fusarium keratitis.. Fungal keratitis was induced in the right eyes of 24 New Zealand rabbits. 8.6 x 10(3) CFU/0.1 ml F.solani spore suspension was injected midstromally into the central cornea. Group 1 received topical amphotericin B 0.15%, group 2 received topical itraconazole 1% and group 3 received topical voriconazole 1% hourly between 08:00 to 22:00 on days 1 and 2; 4 times daily on days 3-5. Control group received topical balanced salt solution at identical intervals. The eyes were examined clinically with a scoring system before treatment (day 0), on day 3 and on day 5. Cultures were taken from the lesion by scraping at the end of the treatment. Clinical scores and microbiologic results were analyzed statistically.. In the control group, keratitis progressed clinically and colony level was 2 x 10(3) CFU at day 5. In all treatment groups, progression of keratitis was inhibited clinically. Culture was sterile in the group receiving amphotericin B. Colony level was 0.3 x 10(2) CFU in the itraconazole group and 2 x 10(2) CFU in the voriconazole group at day 5.. Progression of keratitis was inhibited clinically in all treatment groups. Colony level decreased significantly in all treatment groups. As a result, itraconazole 1% and voriconazole 1% were found to be effective in Fusarium keratitis clinically and microbiologically, although their activity was not as effective as amphotericin B 0.15%.

Topics: Administration, Topical; Amphotericin B; Animals; Antifungal Agents; Colony Count, Microbial; Corneal Ulcer; Disease Models, Animal; Eye Infections, Fungal; Fusarium; Itraconazole; Mycoses; Pyrimidines; Rabbits; Treatment Outcome; Triazoles; Voriconazole

To evaluate antifungal chemotherapy in patients with fungal keratitis guided by in vivo confocal microscopy.. A total of 121 patients (121 eyes) with fungal keratitis were enrolled in this study. Confocal microscopy was performed in real time after topical and/or oral antifungal chemotherapy. Hyphal density and morphology, composition of inflammatory cells, and appearance of corneal stromal cells at the central and peripheral corneal lesions were recorded. Antifungal therapy discontinued at 1 week after hyphae and inflammatory cells could not be detected, and affected corneal stromal cells became visible.. Successful outcomes were achieved in 110 patients (90.9%). By confocal microscopy, we observed the gradual decrease of hyphae-positive sites and hyphal density during the chemotherapy. The inflammatory cells reduced in number and heterogeneity, while corneal stromal cells recovered. The antifungal drugs were tapered according to the changes in hyphae, inflammatory cells, and corneal stromal cells. There was no fungal recurrence during the 2-month follow-up period. The other 11 patients (9.1%) had deteriorated infection within 1 week of antifungal therapy, and therefore were subjected to corneal transplantation.. In vivo confocal microscopy appears to be an effective approach to guide antifungal chemotherapy. It allows comprehensive evaluation of hyphae, inflammatory cells, and corneal stromal cells in real time, and provides valuable and objective information required in selecting and adjusting therapeutic regimens for the treatment of fungal keratitis.

Topics: Administration, Oral; Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Child; Corneal Stroma; Corneal Ulcer; Drug Therapy, Combination; Eye Infections, Fungal; Female; Fluconazole; Fungi; Humans; Itraconazole; Male; Microscopy, Confocal; Middle Aged; Mycoses; Natamycin; Ophthalmic Solutions

A 37-year-old female patient was diagnosed with ulcerative colitis 8 months ago and medical treatment with oral azathioprine, low-dose corticosteroids and 5-ASA was started. Following 3 months without any symptoms, the patient had total colectomy and ileostomy. After this period, liposomal amphotericin B (3 mg kg(-1) day(-1)) was given with the diagnosis of probable fungal infection. Palpable purpuric skin lesions on the anterior surface of both legs appeared on the 55th day of amphotericin B treatment. Histological examination of a skin biopsy was consistent with leucocytoclastic vasculitis. We present a case of cutaneous leucocytoclastic vasculitis in which amphotericin B might presumably be the aetiological factor.

Topics: Adult; Amphotericin B; Biopsy; Female; Humans; Mycoses; Skin Diseases; Vasculitis

We report 4 patients who developed hyperphosphatemia while receiving liposomal amphotericin B to treat an invasive fungal infection. Resolution of the hyperphosphatemia occurred after transition to amphotericin B lipid complex. This phenomenon may occur more commonly in patients with mild to moderate renal insufficiency.

Topics: Adolescent; Amphotericin B; Child; Drug Combinations; Female; Humans; Hyperphosphatemia; Male; Mycoses; Phosphatidylcholines; Phosphatidylglycerols; Renal Insufficiency

We report a case of disseminated infection due to Bipolaris spicifera in an immunocompetent male. Histopathological studies of lymph node, lung, and liver biopsy specimens showed a dark pigmented, granular fungal structure inside the granuloma. The disease was accompanied by the unusual feature of positive lupus anticoagulant in serum and low-density areas expanding along the portal vein in the liver. The disease responded to combination therapy with intravenous amphotericin B and voriconazole, but recurred during oral itraconazole. The fungal isolate from the lymph node was identified as Bipolaris spicifera on the basis of morphology and molecular biological data.

Topics: Adult; Amphotericin B; Ascomycota; DNA, Fungal; DNA, Ribosomal; Humans; Immunocompetence; Itraconazole; Lymph Nodes; Male; Mycoses; Pyrimidines; Sequence Analysis, DNA; Triazoles; Voriconazole

Fungal peritonitis is a rare but serious complication in children on peritoneal dialysis. Clinical presentation of fungal peritonitis is similar to bacterial peritonitis and Candida spp. are the most common agent. Fungal peritonitis has been usually associated with high morbidity, mortality and its treatment is difficult. In this report, we present an infant with Acremonium spp. peritonitis. A 7-month-old boy with Down syndrome, congenital heart disease, pulmonary hypertension and congestive heart failure required peritoneal dialysis for his persistent pulmonary oedema and symptomatic hyponatremia. Acremonium spp. peritonitis developed while he was on extended spectrum antibiotics and fluconazole. The patient was successfully treated with peritoneal dialysis catheter removal and liposomal amphotericin B. The case was presented to draw attention to a rare cause of peritonitis -Acremonium spp. - in a paediatric patient.

Topics: Acremonium; Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Down Syndrome; Fluconazole; Heart Defects, Congenital; Humans; Infant; Male; Mycoses; Peritoneal Dialysis; Peritonitis

Topics: Amphotericin B; Antifungal Agents; Humans; Liposomes; Mycoses

Topics: Amphotericin B; Antifungal Agents; Cost-Benefit Analysis; Drug Costs; Humans; Liver Transplantation; Mycoses; Premedication; Research Design; Risk Assessment; Treatment Outcome

We evaluated the efficacy of voriconazole, amphotericin B and micafungin alone and combined in a murine model of disseminated infection by Fusarium solani.. Immunosuppressed mice were treated with voriconazole at 60 mg/kg/day, amphotericin B at 3 mg/kg/day, micafungin at 10 mg/kg/day or combinations of these antifungal drugs. For survival studies, treatment began 1 day after infection and continued for 10 days. For tissue burden studies, animals were sacrificed on day 6 of the treatment and the fungal load in the kidneys and spleens was measured. The experiments were carried out using two different clinical strains of F. solani.. Only the combination of voriconazole plus amphotericin B prolonged the survival of the mice versus the controls for the two strains tested. However, this combination only reduced tissue burden in the kidney and spleen of mice infected by one strain. The other treatments were clearly less effective.. Voriconazole plus amphotericin B may have a role in the treatment of fusariosis.

Topics: Amphotericin B; Animals; Antifungal Agents; Colony Count, Microbial; Drug Therapy, Combination; Echinocandins; Fusarium; Immunocompromised Host; Kidney; Lipopeptides; Lipoproteins; Male; Micafungin; Mice; Mycoses; Pyrimidines; Spleen; Survival Analysis; Triazoles; Voriconazole

A series of bis(pyridinium)alkanes have been prepared and their antifungal activity, haemolytic activity and ability to inhibit fungal phospholipase B1 have been investigated, together with those of the commercially available antiseptics octenidine and dequalinium. Removal of the amino substituents from the pyridinium rings resulted in a significant decrease in antifungal activity. However, shortening or removing the alkyl chains attached to the amino groups had little effect on antifungal activity and significantly reduced haemolytic activity. Only octenidine was a strong inhibitor of fungal phospholipase B1.

Topics: Alkanes; Amphotericin B; Anti-Infective Agents, Local; Antifungal Agents; Candida albicans; Cryptococcus neoformans; Dequalinium; Enzyme Inhibitors; Fungi; Hemolytic Agents; Humans; Imines; In Vitro Techniques; Indicators and Reagents; Magnetic Resonance Spectroscopy; Microbial Sensitivity Tests; Mycoses; Phospholipases; Pyridines; Pyridinium Compounds; Structure-Activity Relationship

In a murine model of blastoschizomycosis, amphotericin B combined with micafungin, flucytosine or voriconazole did not improve the efficacy of fluconazole. However, such combinations can constitute therapeutic options for those cases where fluconazole fails.

Topics: Amphotericin B; Animals; Antifungal Agents; Colony Count, Microbial; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Echinocandins; Flucytosine; Geotrichosis; Geotrichum; Humans; Immunocompromised Host; Lipopeptides; Lipoproteins; Male; Micafungin; Mice; Mice, Inbred Strains; Microbial Sensitivity Tests; Mycoses; Peptides, Cyclic; Pyrimidines; Survival Analysis; Triazoles; Trichosporon; Voriconazole

A survey of medicinal plants used to treat common mycoses was done in the Curituba district, Sergipe State, Brazil. One hundred inhabitants were interviewed by health agents and traditional healers. Four different plants were the most cited (more than 50% of the citations): Ziziphus joazeiro, Caesalpinia pyramidalis, Bumelia sartorum and Hymenea courbaril. The aqueous extracts obtained following traditional methods and using different parts of these plants, were submitted to drop agar diffusion tests for primary antimicrobial screening. Only the water infusion extract of Ziziphus joazeiro and Caesalpinea pyramidalis presented a significant antifungal activity against Trichophyton rubrum, Candida guilliermondii, Candida albicans, Cryptococcus neoformans and Fonsecaea pedrosoi, when compared to the antifungal agent amphotericin B. The minimal inhibitory concentration (MIC) of the bioactive extracts was evaluated by the microdilution method. Best activity with a MIC of 6.5 microg/ml for both extracts was observed against Trichophyton rubrum and Candida guilliermondii. Ziziphus joazeiro and Caesalpinea pyramidalis extracts presented also low acute toxicity in murine models. The present study validates the folk use of these plant extracts and indicates that they can be effective potential candidates for the development of new strategies to treat fungal infections.

Topics: Amphotericin B; Antifungal Agents; Brazil; Data Collection; Ethnobotany; Health Personnel; Interviews as Topic; Medicine, Traditional; Microbial Sensitivity Tests; Mycoses; Plant Extracts; Plants, Medicinal; Reproducibility of Results; Water

In spite of the development of new antifungal drugs, amphotericin B deoxycholate (d-AMB) remains the gold standard in the treatment of severe fungal infections in immunosuppressed hosts. However, d-AMB is a toxic drug, the most important dose-limiting toxicities being nephrotoxicity and infusion-related allergic reactions. Lipid and liposomal formulations of d-AMB have relatively lower toxicity and are considered alternative choices. However, the routine use of these formulations is limited by their higher cost. Using retrospective analysis, we explored the incidence of nephrotoxicity and allergic reactions requiring the cessation of conventional d-AMB in 113 cases treated with the drug. In contrast to knowledge in the relevant literature, we did not detect significant toxicity, which would have required discontinuation of the d-AMB treatment. Mean serum creatinine levels were 0.72 +/- 0.25 and 0.84 +/- 0.31 mg dl(-1) before and after therapy, respectively. Although the difference between creatinine levels before and after d-AMB is statistically significant, the creatinine level increased twofold in only eight cases. Mean serum potassium levels were 3.8 +/- 0.54 and 3.6 +/- 0.7 mmol l(-1) before and after d-AMB respectively. Potassium levels below 3 mmol l(-1) were found in 7 and 17 cases before and after d-AMB respectively. Potassium levels were statistically lower in cases with fungal mucositis. Severe infusion-related allergic reactions were observed in three cases. Antihistamine and corticosteroid were added to the treatment in these cases. With these findings, we can conclude that d-AMB is a tolerable, low cost drug which can be safely used provided there is suitable premedication and monitoring of blood urea nitrogen, serum potassium and magnesium levels.

Topics: Adolescent; Adult; Amphotericin B; Creatinine; Deoxycholic Acid; Drug Combinations; Drug Hypersensitivity; Female; Humans; Kidney; Magnesium; Male; Middle Aged; Mycoses; Neutropenia; Potassium; Retrospective Studies; Urea

To evaluate the efficacy of intracameral amphotericin B injection in the adjunctive management of keratomycosis with probable intraocular extension not responding to conventional antifungal therapy.. Fourteen eyes of 12 patients with fungal keratitis that did not respond to initial treatment with topical and intravenous fluconazole and oral itraconazole were treated with up to 5 intracameral injections of 5 microg of amphotericin B. Six eyes received one injection, and 8 required subsequent injections.. Twelve eyes responded to amphotericin B therapy, including 5 that healed with a central corneal scar and 8 that healed with a peripheral opacity. Two eyes progressed to evisceration. Four eyes developed anterior subcapsular cataract after intracameral amphotericin B.. Intracameral amphotericin B may be an effective adjunctive treatment of fungal keratitis unresponsive to conventional antifungal therapy, although cataract may occur.

Topics: Adult; Aged; Amphotericin B; Anterior Chamber; Antifungal Agents; Aspergillus; Candida albicans; Corneal Ulcer; Endophthalmitis; Eye Infections, Fungal; Female; Fusarium; Humans; Injections; Male; Middle Aged; Mycoses; Recurrence; Retreatment; Treatment Outcome

Nebulized amphotericin B deoxycholate (AmBd) has been used to prevent invasive pulmonary aspergillosis after lung transplantation.. In this retrospective study we compared the safety and tolerability of nebulized AmBd and nebulized liposomal amphotericin B (L-AmB) in 38 consecutive lung transplant recipients. Progress notes, medication administration records, microbiology, and pulmonary function reports were reviewed. Histologic sections from lung tissue were examined. Plasma amphotericin B levels were measured.. A total of 1206 doses of AmBd and 1149 doses of L-AmB were administered. Eighteen patients received AmBd only, 11 received L-AmB only, and 9 received the medications sequentially. The total number of complaints vs. the number of doses administered was 1.0% for AmBd-treated patients and 1.2% for L-AmB-treated patients. No differences were observed between the treatment groups on lung biopsy specimens. Plasma amphotericin B levels were <0.2-0.9 microg/mL in AmBd-treated patients and <0.2 microg/mL in L-AmB-treated patients.. In lung transplant recipients, both inhaled AmBd and L-AmB were safe and well tolerated over a large number of medication exposures.

Topics: Aerosols; Amphotericin B; Antifungal Agents; Chemistry, Pharmaceutical; Deoxycholic Acid; Drug Combinations; Drug Resistance, Fungal; Female; Humans; Lung Transplantation; Male; Middle Aged; Mycoses; Retrospective Studies

Fusarium spp. is being isolated with increasing frequency as a pathogen in oncohematologic patients. Caspofungin and amphotericin B have been reported to have synergistic activity against Fusarium spp.. We herein report a case of disseminated fusariosis diagnosed by chest CT scan and positive blood cultures to Fusarium spp. Because the patient's clinical condition deteriorated, CRP levels increased, and blood cultures continued to yield Fusarium spp. despite liposomal amphotericin B monotherapy up to 5 mg/kg daily, treatment with caspofungin was added. Within 2 weeks of onset of combined antifungal therapy, the chest CT scan demonstrated a progressive resolution of the pulmonary lesions. Upon discontinuation of intravenous antifungals, the patient received suppressive therapy with oral voriconazole. Three months later, a chest CT scan showed no abnormalities. Twenty-five months after discontinuation of all antifungal therapy, the patient remains in complete remission of her neoplastic disease with no signs of clinical activity of the Fusarium infection.. This is the first description of successful treatment of disseminated fusariosis in a pediatric patient with acute lymphoblastic leukemia with caspofungin and amphotericin B followed by oral suppressive therapy with voriconazole.

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Child; Drug Therapy, Combination; Echinocandins; Female; Fusarium; Humans; Lipopeptides; Mycoses; Peptides, Cyclic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrimidines; Treatment Outcome; Triazoles; Voriconazole

Topics: Amphotericin B; Antifungal Agents; Deoxycholic Acid; Drug Administration Schedule; Drug Combinations; Hematologic Diseases; Humans; Infusions, Intravenous; Kidney; Middle Aged; Mycoses; Treatment Outcome

We describe 2 patients with hematologic malignancy who developed endophthalmitis due to Trichosporon beigelii during the course of treatment with multiagent chemotherapy. Blood cultures revealed T beigelii for both patients. Although one of the patients was treated with fluconazole (FLCZ) and 5-fluorocytosine, the trichosporonous endophthalmitis was resistant to both drugs. This patient subsequently received amphotericin B (AMPH-B) therapy, and the eyes were treated with vitrectomy. The second patient also received AMPH-B for FLCZ-resistant trichosporonous chorioretinitis. In both patients, systemic treatment with AMPH-B successfully resolved the trichosporonous endophthalmitis that was resistant to multiple antifungal drugs. Endophthalmitis due to trichosporonosis is difficult to treat. The administration of AMPH-B is likely to be more effective in treating endophthalmitis due to trichosporonosis when the disease is at an early stage.

Topics: Acute Disease; Adult; Amphotericin B; Antifungal Agents; Drug Resistance, Fungal; Endophthalmitis; Female; Fluconazole; Flucytosine; Humans; Leukemia, Myeloid; Male; Middle Aged; Mycoses; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Trichosporon

To evaluate the efficacy of caspofungin in an experimental rabbit model of Fusarium keratitis and to compare it with amphotericin B.. Eighteen New Zealand white rabbits were randomly divided into 2 treatment groups and 1 control group. One cornea of each rabbit was inoculated with Fusarium solani spores. The first group received topical amphotericin B 0.15%, the second group received topical caspofungin 1%, and the control group received topical balanced salt solution hourly for 2 days and then 4 times daily for 3 additional days. Treatment effects were evaluated by clinical assessment at days 3 and 5 and by fungal culture after 5 days of treatment.. In the treatment groups, progression of keratitis was inhibited, and cultures were sterile at the end of the study. In the control group, keratitis progressed, and cultures were positive for F. solani.. Topical caspofungin is effective in Fusarium keratitis, and clinical efficacy studies seem justified.

Topics: Administration, Topical; Amphotericin B; Animals; Antifungal Agents; Caspofungin; Corneal Ulcer; Disease Models, Animal; Echinocandins; Eye Infections, Fungal; Fusarium; Lipopeptides; Mycoses; Peptides, Cyclic; Rabbits; Treatment Outcome

Amphotericin B-induced nephrotoxicity is frequent, severe and associated with an increased risk of death. Patients with underlying renal disease are considered to be at high risk for amphotericin B nephrotoxicity. Amphotericin B is a molecule that is highly protein bound over a wide range of protein and drug concentrations, including those seen in patients with >or= 3 + proteinuria. We hypothesized that amphotericin B treatment in patients with proteinuria will be associated with less hypokalaemia than patients with non-proteinuric renal disease.. Thirty-six subjects who received amphotericin B deoxycholate were studied retrospectively. Twenty-five patients with proteinuria < 3 g/L and 11 with proteinuria >or= 3 g/L were compared.. Hypokalaemia (K+ < 3.5 mmol/L) developed in 47.2% (17/36) of our cohort of patients. There was a 64% (16/25) incidence of hypokalaemia in the group with < 3 g/L of proteinuria in contrast to an incidence of 9.1% (1/11) in the other group.. In our study, heavy proteinuria appears to protect the tubular luminal membrane by decreasing the luminal concentration of free drug available to bind with the membrane. Our findings redefine the patient population deemed to be at risk of developing amphotericin B nephrotoxicity. This ensures the benefit of this important antifungal treatment option to patients with heavy proteinuria who might otherwise not be administered this drug due to the presence of pre-existing kidney disease.

Topics: Adult; Amphotericin B; Antifungal Agents; Female; Humans; Hypokalemia; Kidney Diseases; Male; Middle Aged; Mycoses; Proteinuria; Retrospective Studies; Risk

In August 2002, the antifungal prophylaxis algorithm for neutropenic hematology/oncology (NHO) patients at the Medical Center was changed from conventional amphotericin (AMB) to an azole (AZ) based regimen (fluconazole [FLU] in low-risk and voriconazole [VOR] in high-risk patients). The aim of our study was to compare outcomes associated with the two regimens, including breakthrough fungal infection, adverse drug events, and costs.. Adult, non-febrile, NHO patients who received prophylactic AMB from 01 August 2001-30 July 2002 or AZ from 01 August 2002-30 July 2003 were retrospectively evaluated.. A total of 370 patients (AMB: n = 181; AZ: n = 216) associated with 580 hospitalizations (AMB: n = 259; AZ: n = 321) were included. The incidence of probable/definite breakthrough Aspergillus infections was similar among regimens (AMB: 1.9% vs AZ: 0.6%; p=0.19). A greater incidence of mild/moderate (24.7% vs. 5.3%; p < 0.0001) and severe renal dysfunction (13.5% vs. 4.4%; p < 0.0012) was observed with AMB. In contrast, patients treated with VOR were found to have an increased rate of severe hepatic toxicity (32.5%) compared with patients treated with either AMB (22.6%) or FLU (21.4%) (p = 0.05). While the AZ period was associated with a >$9,000 increase in mean total costs/hospitalization, the mean acquisition cost associated with AZ was only $947/hospitalization more than AMB.. While an AZ-based regimen is associated with increased cost, the reduced rate of nephrotoxicity and availability of oral dosage forms, suggests that azoles be used preferentially over AMB. However, an increased rate of severe hepatic toxicity may be associated with VOR.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Antibiotic Prophylaxis; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Drug Therapy, Combination; Female; Fluconazole; Humans; Male; Middle Aged; Mycoses; Neutropenia; Pyrimidines; Retrospective Studies; Triazoles; Voriconazole

Topics: Adult; Amphotericin B; Antifungal Agents; Child; Combined Modality Therapy; Corneal Ulcer; Disease Outbreaks; Drug Therapy, Combination; Eye Infections, Fungal; Female; Fusarium; Humans; Keratoplasty, Penetrating; Microbial Sensitivity Tests; Mycoses; Natamycin; Pyrimidines; Triazoles; Voriconazole

While dematiaceous (dark-walled) fungi are ubiquitous in the environment, their involvement in invasive human infections has rarely been reported. However, these organisms have been identified as potential emerging pathogens, particularly among immunocompromised hosts. We describe a diabetic patient with Lecythophora mutabilis prosthetic valve endocarditis who was treated surgically, as well as with amphotericin B lipid complex and voriconazole, which were subsequently followed by prolonged voriconazole suppressive therapy. To the best of our knowledge, our patient is the first reported survivor of L. mutabilis prosthetic valve endocarditis.

Topics: Amphotericin B; Antifungal Agents; Aortic Valve; Ascomycota; Diabetes Complications; Drug Combinations; Endocarditis; Heart Valve Prosthesis; Humans; Male; Middle Aged; Molecular Sequence Data; Mycoses; Phosphatidylcholines; Phosphatidylglycerols; Prosthesis-Related Infections; Pyrimidines; Sequence Analysis, DNA; Treatment Outcome; Triazoles; Voriconazole

A neutropenic patient with acute myeloid leukaemia experienced a breakthrough infection of Trichosporon asahii during posaconazole treatment. After treatment was changed to a combination therapy with voriconazole and liposomal amphotericin B, the infection resolved. Posaconazole works effectively as an antifungal prophylaxis and salvage therapy in rare invasive fungal infections. This case however illustrates that breakthrough infections with T. asahii may occur during posaconazole treatment.

Topics: Aged; Amphotericin B; Antifungal Agents; Cross Infection; Drug Therapy, Combination; Humans; Leukemia, Myeloid, Acute; Male; Mycoses; Pyrimidines; Triazoles; Trichosporon; Voriconazole

Topics: Adult; Amphotericin B; Antifungal Agents; England; Humans; Male; Medication Errors; Mycoses; Neoplasms

The effect of the incorporation of amphotericin B into bone cement was examined; as literature suggests, this may be a feasible method for the treatment of periprosthetic fungal infections. Addition of antifungal increased the compressive strength of the bone cement--a statistically significant amount from 107 +/- 2.3 to 121 +/- 1.5 MPa. Elution of tobramycin and amphotericin B was quantified using ultraviolet-visible spectroscopy. Spectroscopy showed that 18% of the antibiotic was released during the first week, with most released in the first 24 hours. The elution of antifungal, however, was unable to be detected after 1 week, with less than 0.03% released. Amphotericin B does not weaken bone cement. Its inability to be delivered at a clinically significant dose gives no clear indication for its incorporation into cement.

Topics: Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Bone Cements; Humans; Mycoses; Prosthesis-Related Infections; Spectrum Analysis; Tobramycin

Disseminated phaeohyphomycosis is an uncommon infection affecting immunocompetent and immunocompromised individuals in which response to older antifungal agents has been variable. We compared the effect of six days of therapy with caspofungin, posaconazole, and amphotericin B in parallel studies of survival and fungal burden in an immunocompromised mouse model of Exophiala infection. Mice immunocompromised with cyclophosphamide were treated for 6 days starting one day after initiation of infection. Treatment regimens included amphotericin B, caspofungin, and posaconazole. In the survival studies, experimental animals were observed for 14 days. In the fungal burden tests the experimental animals were sacrificed 7 days after infection and brain and kidney burden determined. Treatment with any agent decreased mortality (P < 0.05), with 40%, 30%, and 80% observed survival of the animals treated with amphotericin B, caspofungin, and posaconazole, respectively. Amphotericin B and posaconazole treatment resulted in a decrease in fungal burden compared to untreated controls (P < 0.05). No reduction in fungal burden was noted in the caspofungin group. All three antifungals evaluated improved survival of immunocompromised mice in this otherwise fatal disseminated phaeohyphomycosis. Amphotericin B and posaconazole reduced fungal burden. Posaconazole and caspofungin appear to have potential for use in treatment of this rare infection.

Topics: Amphotericin B; Animals; Antifungal Agents; Brain; Caspofungin; Disease Models, Animal; Echinocandins; Exophiala; Female; Immunocompromised Host; Kidney; Lipopeptides; Mice; Mice, Inbred ICR; Mycoses; Survival Analysis; Triazoles

To report a case of a dendritic epithelial defect with interface inflammation associated with Alternaria sp. after laser in situ keratomileusis (LASIK) surgery.. A case report of a 46-year-old woman who presented with a dendritic epithelial defect and interface inflammation after LASIK surgery.. After an apparent post-LASIK herpes simplex keratitis with related interface inflammation failed to respond to medical therapy, cornea culture results were positive for Alternaria fungal sp. 2 weeks and 6 days after presentation. Viral cultures and polymerase chain reaction were negative for herpes simplex virus. Six months after penetrating keratoplasty (and 1 year after LASIK), the patient underwent a cataract extraction OD. Best-corrected visual acuity 18 months after the original LASIK procedure was 20/25 OD.. Alternaria keratitis may present with a dendritic epithelial defect with interface inflammation mimicking herpes simplex virus.

Topics: Alternaria; Amphotericin B; Antifungal Agents; Combined Modality Therapy; Corneal Ulcer; Debridement; Drug Combinations; Drug Therapy, Combination; Epithelium, Corneal; Eye Infections, Fungal; Female; Humans; Itraconazole; Keratomileusis, Laser In Situ; Keratoplasty, Penetrating; Middle Aged; Mycoses; Ofloxacin; Polymyxin B; Postoperative Complications; Trimethoprim

Activity and efficacy of liposomal amphotericin B have been established for the treatment of severe fungal infections. Nephrotoxic side effects, especially during prolonged administration, are regarded as a major disadvantage. In this study we examined the response rates and side effects, particularly nephrotoxicity, of treatment with liposomal amphotericin B in a large cohort of patients.. 406 patients treated with liposomal amphotericin B between January 1999 and August 2003 in participating German hospitals were included. Documentation included demographic and clinical data, reason for the treatment with liposomal amphotericin B, length of treatment, response to antifungal treatment and side effects.. 42.4% of the 406 patients were females. Their ages ranged from 1 day to 77 years. 83 % of the patients had malignancies and 65.5 % had fever of unknown origin (FUO). Mean duration of treatment with liposomal amphotericin B was 20 +/- 20 days, at an average dose of 2.3 mg/kg/d. 209 patients (51.5 %) showed complete response (CR),105 patients (25.9 %) partial response (PR) and 51 (12.6 %) patients died during the observation. 80.0 % of patients with FUO showed complete or partial response of symptoms. Mean serum creatinine increased from 0.9 mg/kg before start of therapy with liposomal amphotericin B to 1.1 mg/kg during treatment. Side effects (common toxicity criteria > grade 1) occurred in 94 patients (23/2 %). Among these hypokalemia (6.2 %) and liver damage (5,2 %) were the most common. Nephrotoxicity was documented in 17 patients (4.2 %).. Liposomal amphotericin B is a safe and efficacious antifungal drug in the treatment of severe invasive fungal infections and fever of unknown origin. Nephrotoxicity is usually not a limiting factor when using liposomal amphotericin B, if it is administered in approved dosage.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Child; Child, Preschool; Cohort Studies; Female; Fever of Unknown Origin; Humans; Infant; Infant, Newborn; Kidney; Liposomes; Male; Middle Aged; Mycoses; Neoplasms; Prospective Studies; Treatment Outcome

Composite tissue allograft recipients require intensive immunosuppression and are therefore at risk of infections. Filamentous fungal infections are among the complications most difficult to manage in organ transplant recipients.. Case report and literature review.. Two years after bilateral forearm transplantation, a 35-year-old patient presented with a tumor-like lesion on his thigh after a penetrating injury caused by a sliver acquired during hiking. The lesion was excised completely, and microscopic examination revealed a filamentous fungal infection. Alternaria alternata was identified as the causative agent. Induction therapy with liposomal amphotericin B for one week followed by oral itraconazole maintenance therapy for eight weeks was successful, with no signs of recurrence or side effects at 18 months' follow-up.. This is the first reported case of invasive A. alternata infection in a composite tissue allograft recipient. The infection was managed successfully with local excision and systemic antifungal treatment.

Topics: Adult; Alternaria; Amphotericin B; Antifungal Agents; Arm; Drug Therapy, Combination; Forearm; Humans; Itraconazole; Male; Mycoses; Transplantation; Wound Infection; Wounds, Penetrating

To evaluate the safety, efficacy and economics of amphotericin B for the treatment of deep fungal infection.. Retrospectively analyze the data from 113 cases with invasive fungal infection, who were treated with amphotericin B.. The total efficacy of amphotericin B is above 76%. The incidence of hypokalemia, creatinine (Cr) and blood urea nitrogen (BUN) elevation were 33.6%, 29.0% and 27.4%, respectively. The instant side effect such as fever and etc. was seen in 15.0%. No dead cases and irreversible renal function impairment could be attributed to amphotericin B. The incidence of allergic reaction and other instant reaction declined after amphotericin B manufacture techniques improved. For standard recommended duration from major guidelines, such as infective endocarditis, osteomyelitis and meningitis, the management with amphotericin B should last at least 12 weeks. The cost for treatment with different agents, such as amphotericin B, fluconazole, itraconazole, liposomal amphotericin B (LamB), voriconazole and caspofungin acetate were RMB 4600, 38,000, 99,100, 190,000, 250,000 and 270,000 yuan, respectively.. Amphotericin B is still the most effective agent for anti-fungal treatment. The incidence of allergic reaction and other instant reaction declined after amphotericin B manufacture techniques improved. Most patients can finish the treatment and be cured. Among all the anti-fungal agents, amphotericin B is still the most cost-effective medicine, especially for the patients who need long time treatment.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Child; Female; Humans; Male; Middle Aged; Mycoses; Retrospective Studies

Abnormal liver function test (LFT) results are common in patients with hematologic abnormalities, making the assessment of drug-related hepatotoxicity difficult. Studies based on elevated LFT levels have found that use of liposomal amphotericin B (L-AMB) was associated with increased hepatotoxicity compared with amphotericin B (AMB)/deoxycholate or amphotericin B lipid complex (ABLC). Because LFT abnormalities are multifactorial in severely immunocompromised patients, uncertainty remains regarding the clinical significance of these laboratory findings.. The aim of this study was to present the hepatic histopathologic findings on autopsy in patients who had hematologic malignancies and fungal infections and had received L-AMB or ABLC.. This study was conducted at The University of Texas M.D. Anderson Cancer Center, Houston, Texas. Records from 1995 to 2004 of patients who had received L-AMB or ABLC for > or =7 days, within 30 days before death, were reviewed by 1 investigator. Hepatic autopsy slides were independently reviewed by another investigator (pathologist) in a blinded fashion. Histopathologic evidence of amphotericin-related hepatotoxicity was predetermined based on histopathologic abnormalities reported in animal studies (eg, macrophage vacuolation, multifocal hepatocellular necrosis). Based on data from animal studies and in view of the lack of studies in humans, multifocal necrosis, fatty infiltration, macrophage vacuolation, and/or "foamy macrophage" accumulation were all considered histopathologic abnormalities associated with the use of lipid formulations of AMB.. Data from 64 patients were included (32 patients per group). The demographic characteristics were comparable between the ABLC and L-AMB groups (median ages, 47.5 and 53.0 years, respectively; male, 44% and 53%; white, 75% and 78%; median weight, 67 and 78 kg; active underlying malignancy, 84% and 78%). There were no significant between-group differences in cumulative dose (6 and 7 g), median daily dose (both, 5 mg/kg), or median duration of treatment (19.5 and 19.0 days). Abnormal results (>5 x from baseline) on LFT were found in 12 (38%) and 10 (31%) patients who received ABLC and L-AMB, respectively, but these findings were thought to be associated with concomitant use of triazoles (4/12 [33%] and 1/10 [10%] patients, respectively), hepatotoxic antibiotics (8/12 [67%] and 5/10 [50%]), and/or other hepatotoxic medications (2/12 [17%] and 1/10 [10%]). Nonspecific abnormalities were observed on histopathology in 94% of patients. There was no evidence of histopathologic abnormalities reported in animal toxicity studies of lipid AMB, such as macrophage vacuolation or multifocal hepatocellular necrosis.. Although abnormal results on LFT and/or histopathologic changes in liver were found in 92% of these debilitated patients with hematologic malignancy, direct histopathologic evidence of toxicity associated with lipid formulations of AMB was not established in our study.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Autopsy; Chemical and Drug Induced Liver Injury; Drug Carriers; Drug Combinations; Female; Hematologic Neoplasms; Humans; Liposomes; Liver; Male; Middle Aged; Mycoses; Phosphatidylcholines; Phosphatidylglycerols; Retrospective Studies

To report the clinical features and management outcomes of a cluster of Fusarium keratitis in patients that used the Bausch & Lomb ReNu MostureLoc contact lens solution.. Retrospective case series.. In a 1-year period starting from June 2005, we treated 12 patients with unilateral Fusarium keratitis in our tertiary care center. All patients were contact lens users that used ReNu MostureLoc contact lens solution and had no other specific predisposing conditions. Microbiological examination yielded growth of Fusarium spp. in 7 patients from corneal scrapings at presentation and from 3 patients in subsequent corneal specimens. For 2 other patients, fungi were not detected from corneal scrapings, but Fusarium spp. were isolated from their contact lenses. The infections were treated with topical natamycin and amphotericin B eye drops and with systemic itraconazole in 8 patients. The infection resolved with medical treatment in 8 eyes, a conjunctival flap in 1 eye, and a therapeutic corneal graft in 1 eye. Two eyes required tectonic corneal grafts for perforation. Two of the 3 corneal grafts failed because of graft rejection. Final visual acuities ranged from count fingers to 1.0.. This cluster of Fusarium keratitis seems to be related to the use of the ReNu MoistureLoc contact lens solution. The cure rate with medical therapy was 66%. However, corneal scarring limited visual recovery. This episode highlights the need for clinical vigilance when dealing with corneal infiltrates in contact lens users.

Topics: Adolescent; Adult; Amphotericin B; Antifungal Agents; Contact Lens Solutions; Contact Lenses; Corneal Ulcer; Drug Therapy, Combination; Eye Infections, Fungal; Female; Fusarium; Hong Kong; Humans; Itraconazole; Male; Middle Aged; Mycoses; Natamycin; Retrospective Studies

We sought to determine whether the prophylactic use of amphotericin B products (conventional amphotericin B and liposomal amphotericin B) reduces the incidence of fungal infections in high-risk liver transplant recipients, and if so, whether this lowers the cost of care. The study sample comprised 232 adult orthotopic liver transplants performed from 1994 to 2005 at a single center for patients classified as being at high risk for fungal infections. High-risk patients who received transplants with a prophylaxis regimen of amphotericin B (n=58 transplants) were compared with high-risk patients who received no prophylaxis (n=174 transplants). Fungal infections occurred in 3 transplants (5.17%) of those who received amphotericin B and 28 transplants (16.09%) in those without prophylaxis (P=0.0432). Regression models were used to analyze fungal infection and costs for the 232 high-risk transplants. Failure to offer prophylaxis conferred a 4-fold greater risk of fungal infection (P=0.046) compared with those who received amphotericin B. A fungal infection in a high-risk recipient increased mean costs by 46.48%. The indirect effect of prophylaxis (operating through infection reduction) is estimated to reduce overall costs in high-risk patients by 8.73%.

Topics: Adult; Amphotericin B; Antifungal Agents; Cost-Benefit Analysis; Drug Costs; Female; Humans; Liver Transplantation; Logistic Models; Male; Middle Aged; Models, Economic; Mycoses; Odds Ratio; Retrospective Studies; Risk Assessment; Treatment Outcome

We evaluated the in vitro activity of voriconazole, amphotericin B, and itraconazole against 192 clinical mould isolates recovered in twenty Italian microbiology laboratories. The vast majority of isolates belonged to the genus Aspergillus (94.2%) with A. fumigatus (58.3%) being the most frequently isolated species. Antifungal susceptibility testing was performed using the broth microdilution method defined by the CLSI M38-A standard, and results were compared to those obtained with Sensititre panels. Aspergillus flavus ATCC 204304 was employed as reference strain and results were within all expected ranges. Voriconazole's activity against the 192 mould isolates was comparable to that of amphotericin B and itraconazole: voriconazole MIC90 (CLSI 1 microg/ml, Sensititre 1 microg/ml), itraconazole MIC90 (CLSI 0.5 microg/ml, Sensititre 0.5 microg/ml), amphotericin B MIC90 (CLSI 1 microg/ml, Sensititre 1 microg/ml). In conclusion, these in vitro data highlight voriconazole's broad spectrum activity against filamentous fungi and support its use as a first line agent for the treatment of fungal diseases.

Topics: Amphotericin B; Antifungal Agents; Drug Resistance, Fungal; Fungi; Humans; In Vitro Techniques; Itraconazole; Microbial Sensitivity Tests; Mycoses; Pyrimidines; Triazoles; Voriconazole

Invasive fungal rhinosinusitis, a rare infection, is a life threatening disease. Delay in diagnosis may consequently lead to high morbidity and mortality.. Encourage early detection and proper management of invasive fungal rhinosinusitis.. Medical records, radiological, and pathological reports of five patients who were diagnosed as invasive fungal rhinosinusitis were reviewed retrospectively.. Four in five cases of invasive fungal rhinosinusitis, confirmed by pathological study, had successful treatment. One patient had intracerebral hemorrhage that may be associated with the disease spreading. Disease extension was evaluated by CT paranasal sinus in all cases, but it usually did not have classic bony erosion.. Curing infection, correcting underlying conditions, and working up fungal infection should be carried out as early as possible, because morbidity and mortality depend on disease extension and host status.

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; Female; Humans; Itraconazole; Male; Middle Aged; Mycoses; Retrospective Studies; Rhinitis; Sinusitis; Thailand; Time Factors

The objective of this study was to determine if total plasma and lipoprotein cholesterol (C) and triglyceride (TG) concentrations could predict the degree of nephrotoxicity caused by the antifungal agent amphotericin B (AmpB); and to use the average amount of potassium supplementation received daily as a indicator of nephrotoxicity in pediatric oncology patients.. Plasma samples from 18 patients (ages < 17 years) who were receiving AmpB due to suspected or confirmed fungal infection at British Columbia Children's Hospital were analyzed for lipid concentrations. The high density lipoprotein (HDL) fractions were separated by precipitation; total (TOT) plasma and fraction C and TG concentrations were measured by enzymatic colorimetric assays; and low density lipoprotein (LDL) C levels were determined by Friedewald's formula. Changes in serum creatinine levels from baseline and amounts of potassium supplementation were used as indicators of nephrotoxicity; both were obtained from patients' medical charts. Pearson correlation coefficients (r) were determined and considered significant if P < 0.05.. The total cumulative AmpB dose, adjusted for weight, does not seem to predict AmpB-induced nephrotoxicity. Positive but relatively weak correlations were found between total potassium supplementation and LDL C (r = 0.489, P < 0.02); and TOT C (r = 0.551, P < 0.01). In addition, a positive but relatively weak correlation between the average amount of potassium supplementation per day above baseline and HDL C (r = 0.407; P < 0.02) was observed.. Differences in total plasma and LDL cholesterol concentrations may be used as predictors of AmpB-induced nephrotoxicity in pediatric oncology patients.

Topics: Adolescent; Amphotericin B; Child; Child, Preschool; Cholesterol; Creatinine; Female; Humans; Infant; Kidney Diseases; Kidney Function Tests; Male; Mycoses; Neoplasms; Prognosis; Triglycerides

Amphotericin B (AmB) is widely used for treating severe systemic fungal infections. However, long-term AmB treatment is invariably associated with adverse effects such as anemia. The erythropoietin (EPO) suppression by AmB has been proposed to contribute to the development of anemia. However, the mechanism whereby EPO is suppressed remains obscure. In this study, we investigated the possibility that AmB inhibits the transcription of the EPO gene by inactivating HIF-1, which is a known key transcription factor and regulator of EPO expression. EPO mRNA levels were markedly attenuated by AmB treatment both in rat kidneys and in Hep3B cells. AmB inactivated the transcriptional activity of HIF-1alpha, but did not affect the expression or localization of HIF-1 subunits. Moreover, AmB was found to specifically repress the C-terminal transactivation domain (CAD) of HIF-1alpha, and this repression by AmB required Asn803, a target site of the factor-inhibiting HIF-1 (FIH); moreover, this repressive effect was reversed by FIH inhibitors. Furthermore, AmB stimulated CAD-FIH interaction and inhibited the p300 recruitment by CAD. We propose that this mechanism underlies the unexplained anemia associated with AmB therapy.

Topics: Amphotericin B; Anemia; Animals; Antifungal Agents; Cell Line; Down-Regulation; E1A-Associated p300 Protein; Erythropoietin; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney; Male; Mycoses; Protein Structure, Tertiary; Rats; Rats, Sprague-Dawley; Repressor Proteins; Transcription, Genetic

Topics: Adult; Amphotericin B; Antifungal Agents; Fusarium; Humans; Male; Mycoses; Neutrophils; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Time Factors; Tomography, X-Ray Computed; Treatment Outcome

Combination of caspofungin and another anti-fungal agent raise expectation of improved efficacy in severe fungal infections including failures to first line therapy.. We assessed the efficacy and safety of a combination therapy including caspofungin in 17 immunosuppressed or postoperative patients progressive despite standard anti-fungal therapy.. The infections included aspergillosis (6), invasive candidiasis (9), mucormycosis (1) and Scedosporium pneumonia (1). Infections had failed one to four prior lines of treatment. The anti-fungal agent combined to caspofungin was either an amphotericin B formulation or an azole. There were 12 favourable responses (71%) and five failures. The survival rate at 3 months was 47%. Eleven patients died within 2-533 days. The causes of death included the initial fungal infection (4), relapse of the infection after switching to oral monotherapy (2), breakthrough aspergillosis (1), and the underlying condition (4). Clinical and renal tolerance were good. Significant hepatic abnormalities were recorded in eight (50%) of the 16 patients evaluable for biological tolerance.. Caspofungin combined with an azole or with amphotericin B may be of interest in the treatment of serious fungal infections after failure of conventional therapy. Close monitoring of hepatic function is required. These approach should be evaluated in prospective trials.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Caspofungin; Child, Preschool; Drug Therapy, Combination; Echinocandins; Fluconazole; Humans; Lipopeptides; Middle Aged; Mycoses; Peptides, Cyclic; Risk Factors

Topics: Aged; Amphotericin B; Antifungal Agents; Ascomycota; Cataract Extraction; Chronic Disease; Combined Modality Therapy; Device Removal; Drug Therapy, Combination; Endophthalmitis; Eye Infections, Fungal; Female; Humans; Itraconazole; Lenses, Intraocular; Mycoses; Postoperative Complications; Vitrectomy

A 30-year-old man with acute myeloid leukemia who was pancytopenic after undergoing intensive chemotherapy developed pyrexia and severe pain of both lower legs. We immediately started empiric therapy with cefepime, vancomycin, and fluconazole for febrile neutropenia. However, symptoms progressed. After 4 days, Trichosporon was isolated from venous blood cultures. MRI showed hyperintense lesions within both gastrocnemius muscles and demonstrated reactive vasodilatation and interstitial tissue edema, thought to be induced by hyperpermeability of vessel membranes due to the local fungal infection. Amphotericin B was very effective against this organism. Trichosporosis is a rare infectious disease generally occurring in immunocompromized hosts. To the best of our knowledge, this is first reported case of bilateral Trichosporon infection of lower leg muscles. Severe leg pain was one of the most important signs of fungal infection in this patient with hematologic malignancy.

Topics: Adult; Amphotericin B; Humans; Magnetic Resonance Imaging; Male; Muscle, Skeletal; Muscular Diseases; Mycoses; Trichosporon

Invasive fungal infections are fatal complications for patients on chemotherapy, and antifungal prophylactic treatment has been commonly recommended. Because its clinical and economic impact is not well known, we evaluated cost-effectiveness of anti-fungal treatment for patients who were neutropoenic as a result of chemotherapy. We constructed a hypothetical cohort of 40-year-old patients with acute myelogenic leukemia to evaluate years of life survived (YLS), costs (US$), and incremental cost-effectiveness ratio (US$/YLS). The following treatment strategies for fungal infections were compared: (1) prophylactic fluconazole strategy: oral fluconazole administration concurrently with chemotherapy; (2) empirical amphotericin B strategy: empirical intravenous amphotericin B administration at the point where fever is detected; and (3) no prophylaxis strategy: intravenous micafangin administration at the point where fungal infections is diagnosed. Baseline analyses showed that prophylactic fluconazole strategy involved higher costs but also longer YLSs (25,900 US$ and 24.08 YLS). The incremental cost-effectiveness ratio of prophylactic fluconazole strategy was 625 US$/YLS compared to no prophylaxis strategy, and 652 US$/YLS compared to empirical amphotericin B strategy. Baseline result was found to be robust through sensitivity analyses. Our study showed that concurrent administration of oral fluconazole during induction chemotherapy appears to ensure clinical benefits together with acceptable cost-effectiveness.

Topics: Adult; Amphotericin B; Antifungal Agents; Antineoplastic Agents; Cohort Studies; Cost-Benefit Analysis; Echinocandins; Fluconazole; Humans; Leukemia, Myeloid, Acute; Lipopeptides; Lipoproteins; Micafungin; Mycoses; Opportunistic Infections; Peptides, Cyclic

Amphotericin B deoxycholate (AmBd) has been a standard therapy for IFI but is associated with high adverse event and mortality rates. A retrospective review was undertaken to describe adverse events and clinical outcomes in adult patients with IFI treated with only AmBd as initial therapy.

Topics: Amphotericin B; Antifungal Agents; Deoxycholic Acid; Drug Combinations; Female; Hospitalization; Humans; Kidney Diseases; Male; Medical Records; Middle Aged; Mycoses; Retrospective Studies

A total of 60 clinical fungal isolates from patients without prior amphotericin B treatment and three control strains were evaluated for their intrinsic susceptibility to amphotericin B (AmB) using microdilution, Etest and disc diffusion assays, on three media each, Roswell Park Memorial Institute (RPMI) 1640, Antibiotic Medium 3 (AM3) and High Resolution Medium. The fungal strains included isolates of Aspergillus fumigatus (n = 10), Aspergillus terreus (n = 12), Aspergillus nidulans (n = 9), Candida albicans (n = 6) and Candida lusitaniae (n = 23). The A. terreus strains were significantly less susceptible to AmB than the A. fumigatus strains in all nine experimental settings (P-values ranging from 0.009 to <0.00001). The A. nidulans strains were equally susceptible to AmB as the A. fumigatus strains in seven of nine experimental settings and less susceptible in two (microdilution performed on RPMI and AM3, P = 0.01 and 0.007). The C. lusitaniae strains were equally susceptible to AmB as the C. albicans strains in seven of nine experimental settings and more susceptible in two (microdilution and Etest, both performed on AM3, P = 0.01 and 0.0002). Thus, we confirmed that A. terreus is intrinsically less susceptible to AmB than A. fumigatus. In contrast, nine German clinical isolates of Aspergillus nidulans were found equally susceptible to AmB as 10 isolates of A. fumigatus. Furthermore, we found 23 German clinical isolates of C. lusitaniae from patients without prior treatment with AmB equally susceptible to AmB as C. albicans.

Topics: Amphotericin B; Antifungal Agents; Aspergillus; Aspergillus fumigatus; Aspergillus nidulans; Candida; Candida albicans; Culture Media; Humans; Microbial Sensitivity Tests; Mycoses

Micafungin is a newly approved antifungal agent in the echinocandin class that is active against Candida species and Aspergillus species. However, this agent has limited activity against a number of fungi, including Trichosporon species. We describe 4 patients who developed disseminated trichosporonosis during the use of micafungin. No cases of trichosporonosis had been seen in the 2 years prior to January 2003, when micafungin became available in our hospital.. We reviewed microbiological records of patients at Kameda General Hospital (Kamogawa City, Chiba, Japan) from 1 January 2002 to 31 July 2005, and identified 4 patients whose blood culture results were positive for Trichosporon species.. Since January 2003, four patients--3 with acute myelocytic leukemia and 1 with myelodysplastic syndrome--developed disseminated trichosporonosis while receiving treatment with micafungin with or without amphotericin B. The initial 2 isolates were identified as Trichosporon beigelii, and the later 2 isolates were identified as Trichosporon asahii. All 4 patients received micafungin, and 2 also received amphotericin B concomitantly. Minimal inhibitory concentrations of micafungin were >16 microg/mL for the 2 isolates available for susceptibility testing. One patient with hematologic recovery (neutrophils >500 cells/mm3) showed elimination of the fungus after receiving treatment with voriconazole. However, the 3 other patients without hematologic or immunological recovery died of disseminated infection.. The rarity of trichosporonosis in our hospital and its emergence after the introduction of micafungin therapy support the idea that micafungin may exert a significant, selective pressure toward resistant fungi, such as Trichosporon species. Therefore, care should be taken regarding the possibility of trichosporonosis in patients receiving micafungin with or without amphotericin B.

Topics: Amphotericin B; Antifungal Agents; Drug Resistance, Fungal; Drug Therapy, Combination; Echinocandins; Hematologic Neoplasms; Humans; Japan; Lipopeptides; Lipoproteins; Male; Micafungin; Microbial Sensitivity Tests; Middle Aged; Mycoses; Peptides, Cyclic; Selection, Genetic; Trichosporon

We have compared the activities of posaconazole and other currently available antifungal agents against a collection of 3,378 clinical isolates of yeasts and filamentous fungi. A total of 1,997 clinical isolates of Candida spp., 359 of other yeast species, 697 strains of Aspergillus spp., and 325 nondermatophyte non-Aspergillus spp. were included. The average geometric means of the MICs of agents that were tested against Candida spp. were 0.23 microg/ml for amphotericin B, 0.29 microg/ml for flucytosine, 0.97 microg/ml for fluconazole, 0.07 microg/ml for itraconazole, 0.04 microg/ml for voriconazole, 0.15 microg/ml for caspofungin, and 0.03 microg/ml for posaconazole. Voriconazole and posaconazole were active in vitro against the majority of isolates, with resistance to fluconazole and itraconazole, and against Cryptococcus neoformans and other Basidiomycota yeasts. Posaconazole was the most active of antifungal agents tested against Aspergillus spp., with an average geometric mean of 0.10 microg/ml. It was active against Paecilomyces spp., Penicillium spp., Scedosporium apiospermum, and some black fungi, such as Alternaria spp. Multiresistant filamentous fungi, such as Scedosporium prolificans, Scopulariopsis brevicaulis, and Fusarium solani, were also resistant to voriconazole, caspofungin, and posaconazole. Amphotericin B and posaconazole were found to be active against most of the Mucorales strains tested. Posaconazole and currently available antifungal agents exhibit a potent activity in vitro against the majority of pathogenic fungal species.

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Echinocandins; Fluconazole; Flucytosine; Fungi; Humans; Itraconazole; Lipopeptides; Microbial Sensitivity Tests; Mycoses; Peptides, Cyclic; Pyrimidines; Spain; Triazoles; Voriconazole; Yeasts