amphotericin-b and posaconazole

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

Acute respiratory distress syndrome is a common complication of severe viral pneumonia, such as influenza and COVID-19, that requires critical care including ventilatory support, use of corticosteroids and other adjunctive therapies to arrest the attendant massive airways inflammation. Although recommended for the treatment of viral pneumonia, steroid therapy appears to be a double-edged sword, predisposing patients to secondary bacterial and invasive fungal infections (IFIs) whereby impacting morbidity and mortality. Mucormycosis is a fungal emergency with a highly aggressive tendency for contiguous spread, associated with a poor prognosis if not promptly diagnosed and managed. Classically, uncontrolled diabetes mellitus (DM) and other immunosuppressive conditions including corticosteroid therapy are known risk factors for mucormycosis. Upon the background lung pathology, immune dysfunction and corticosteroid therapy, patients with severe viral pneumonia are likely to develop IFIs like aspergillosis and mucormycosis. Notably, the combination of steroid therapy and DM can augment immunosuppression and hyperglycaemia, increasing the risk of mucormycosis in a susceptible individual. Here, we report a case of sinonasal mucormycosis in a 44-year-old woman with hyperglycaemia secondary to poorly controlled diabetes following dexamethasone therapy on a background of influenza pneumonia and review 15 available literatures on reported cases of influenza and COVID-19 associated mucormycosis.

Topics: Adrenal Cortex Hormones; Adult; Amphotericin B; Antifungal Agents; COVID-19; Diabetes Complications; Female; Humans; Influenza, Human; Liposomes; Mucormycosis; Pneumonia, Viral; Triazoles

Blastomycosis is a serious fungal disease of humans and other mammals caused by environmentally acquired infection with geographically restricted, thermally dimorphic fungi belonging to the genus

Topics: Amphotericin B; Antifungal Agents; Blastomyces; Blastomycosis; Humans; Immunocompromised Host; Itraconazole; Triazoles; Voriconazole

Chronic pulmonary aspergillosis (CPA) is a chronic lung infection caused by. We discuss the approach to diagnosis and treatment of CCPA. We have searched the PubMed and EmBase databases (from inception till 31 October 2019) to identify studies describing the use of anti-fungal agents in CCPA.. Treatment for CCPA should be initiated with oral itraconazole for at least six months. In case of poor response or intolerance to itraconazole, voriconazole should be considered. Intravenous agents, including amphotericin B and echinocandins, may be used in those with either treatment failure or those who are intolerant to oral antifungal agents. Posaconazole and isavuconazole may be used as salvage therapy due to a better pharmacokinetic/pharmacodynamic profile of the former and reduced drug-drug interactions with the latter.

Topics: Amphotericin B; Antifungal Agents; Aspergillus fumigatus; Disease Management; Echinocandins; Humans; Itraconazole; Nitriles; Practice Guidelines as Topic; Pulmonary Aspergillosis; Pyridines; Triazoles; Voriconazole

The aim of this perspective is to give an overlook on the utility of pharmacokinetics/pharmacodynamics (PK/PD) in predicting the efficacy of antifungals in invasive candidiasis. Overall, from the available literature it appears that bridging data of PK/PD of antifungals from the laboratory to the clinic for the treatment of invasive candidiasis are feasible only partially. Fluconazole is the only antifungal agent having the pharmacodynamic threshold of efficacy identified in experimental animal models convincingly validated in the clinical setting of invasive candidiasis as well. Conversely, for voriconazole and posaconazole data on this topic are very limited. For the echinocandins, robust PK/PD identified in the laboratory represented the rationale for defining differential clinical breakpoints of echinocandins against different species of Candida by the regulatory agencies. However, translation of the findings in the clinical setting provided conflicting results. Data on PK/PD of amphotericin B and flucytosine in models of invasive candidiasis are quite limited, and clinical studies assessing the role of drug exposure on efficacy are currently lacking. The expectation is that prospective studies could test more and more frequently the validity of experimental PK/PD data of antifungals in the clinical setting of invasive candidiasis. The findings could represent a step forward in addressing adequate antifungal stewardship programmes.

Topics: Amphotericin B; Animals; Antifungal Agents; Antimicrobial Stewardship; Candida; Candida albicans; Candida glabrata; Candida parapsilosis; Candida tropicalis; Candidiasis, Invasive; Echinocandins; Fluconazole; Flucytosine; Humans; Species Specificity; Triazoles; Voriconazole

EUCAST has revised the definition of the susceptibility category I from 'Intermediate' to 'Susceptible, Increased exposure'. This implies that I can be used where the drug concentration at the site of infection is high, either because of dose escalation or through other means to ensure efficacy. Consequently, I is no longer used as a buffer zone to prevent technical factors from causing misclassifications and discrepancies in interpretations. Instead, an Area of Technical Uncertainty (ATU) has been introduced for MICs that cannot be categorized without additional information as a warning to the laboratory that decision on how to act has to be made. To implement these changes, the EUCAST-AFST (Subcommittee on Antifungal Susceptibility Testing) reviewed all, and revised some, clinical antifungal breakpoints.. The aim was to present an overview of the current antifungal breakpoints and supporting evidence behind the changes.. This document is based on the ten recently updated EUCAST rationale documents, clinical breakpoint and breakpoint ECOFF documents.. The following breakpoints (in mg/L) have been revised or established for Candida species: micafungin against C. albicans (ATU = 0.03); amphotericin B (S ≤/> R = 1/1), fluconazole (S ≤/> R = 2/4), itraconazole (S ≤/> R = 0.06/0.06), posaconazole (S ≤/> R = 0.06/0.06) and voriconazole (S ≤/> R = 0.06/0.25) against C. dubliniensis; fluconazole against C. glabrata (S ≤/> R = 0.001/16); and anidulafungin (S ≤/> R = 4/4) and micafungin (S ≤/> R = 2/2) against C. parapsilosis. For Aspergillus, new or revised breakpoints include itraconazole (ATU = 2) and isavuconazole against A. flavus (S ≤/> R = 1/2, ATU = 2); amphotericin B (S ≤/> R = 1/1), isavuconazole (S ≤ /> R = 1/2, ATU = 2), itraconazole (S ≤/> R = 1/1, ATU = 2), posaconazole (ATU = 0.25) and voriconazole (S ≤/> R = 1/1, ATU = 2) against A. fumigatus; itraconazole (S ≤/> R = 1/1, ATU = 2) and voriconazole (S ≤/> R = 1/1, ATU = 2) against A. nidulans; amphotericin B against A. niger (S ≤/> R = 1/1); and itraconazole (S ≤/> R = 1/1, ATU = 2) and posaconazole (ATU = 0.25) against A. terreus.. EUCAST-AFST has released ten new documents summarizing existing and new breakpoints and MIC ranges for control strains. A failure to adopt the breakpoint changes may lead to misclassifications and suboptimal or inappropriate therapy of patients with fungal infections.

Topics: Amphotericin B; Antifungal Agents; Aspergillus; Candida; Fluconazole; Itraconazole; Microbial Sensitivity Tests; Practice Guidelines as Topic; Triazoles; Voriconazole

Patients with diabetes are known as an important high-risk group for cerebral mucormycosis (CM).. We conducted a structured search using PubMed/MEDLINE to collect both case reports and case series case (ie including at least two patients) onto CM in diabetic patient published between 2000 and March 2020.. Forty-five reports of individual cases and eighteen case series articles were included. India accounted for the largest share of reports with 37.7% and 38.8% of individual cases and case series, respectively. Mortality ranged from 0% to 100% in the case series. The overall mortality in the individual cases was 46.3%, and 64.2% of deaths were reported in patients with ketoacidosis diabetes. Facial swelling (53.3%), headache (44.4%), loss of vision (35.5%) and ophthalmoplegia (35.5%) were the most frequently reported clinical symptoms. In all patients except 4 (91.1%), CM was treated surgically; however, in many cases (42%), despite the use of surgery, death occurred. Amphotericin B deoxycholate (AMB) and lipid-based AMB (LAMB) were used as the first lines of treatment for all patients; however, posaconazole, echinocandins, hyperbaric oxygen therapy (HBOT) and deferasirox were used in combination for a number of patients. Posaconazole has been shown to have positive therapeutic effect; however, posaconazole, LAMB and HBOT are not commonly used in low-income and health-challenged countries.. Cerebral mucormycosis is a rapidly progressive infection in diabetic patients and carries immense morbidity despite early diagnosis and treatment. Low-income countries have had the highest number of reports of the disease in recent years, indicating the need to control diabetes in these countries.

Topics: Amphotericin B; Antifungal Agents; Brain Diseases; Deoxycholic Acid; Diabetes Complications; Diabetes Mellitus; Drug Combinations; Humans; Mucormycosis; Risk Factors; Triazoles

Saksenaea species (spp.) are uncommon causes of mucormycosis but are emerging pathogens mostly associated with trauma and soil contamination often in immunocompetent hosts. Due to lack of sporulation in the laboratory, diagnosis and susceptibility testing is difficult so optimal treatment regimens are unknown.. A 67 year-old man from the Northern Territory in Australia, with a history of eosinophilic granulomatosis with polyangiitis, developed disseminated Saksenaea infection after initially presenting with symptoms consistent with bacterial pyelonephritis. Despite a delay in diagnosis; with aggressive surgical management and dual therapy with amphotericin B and posaconazole, he survived.. We describe an unusual case of disseminated infection with a favourable outcome to date.

Topics: Aged; Amphotericin B; Antifungal Agents; Granulomatosis with Polyangiitis; Humans; Immunocompromised Host; Male; Mucormycosis; Northern Territory; Triazoles

This mini-review focuses on leishmanicidal drugs that were sourced from small molecules previously approved for other diseases. The mechanisms of action of these molecules are herein explored, to probe the origins of their inter-species growth inhibitory activities. It is shown how the transversal action of the azoles - fluconazole, posaconazole and itraconazole - in both fungi and Leishmania is due to the occurrence of the same target, lanosterol 14-α-demethylase, in these two groups of species. In turn, the drugs miltefosine and amphotericin B are presented as truly multi-target agents, acting on small molecules, proteins, genes and even organelles. Steps towards future leishmanicidal drug candidates based on the multi-target strategy and on drug repurposing are also briefly presented.

Topics: Amphotericin B; Antifungal Agents; Drug Repositioning; Drug Resistance, Fungal; Fluconazole; Humans; Itraconazole; Leishmaniasis; Molecular Targeted Therapy; Phosphorylcholine; Sterol 14-Demethylase; Triazoles; Voriconazole

Saksenaea vasiformis is one of the numerous fungi of the Order Mucorales. Rapid progression and invasion of neighboring tissues are the most characteristic features of S. vasiformis mucormycosis.. The objective of this review is the management of this type of infections.. Case report and literature review.. A 62-year old woman, without a history of immunocompromisation, developed a localized cutaneous infection at her right thigh. No trauma, skin laceration or insect bite was reported at the side of infection. The initial treatment was surgical debridements and intravenous administration of amphotericin B/posaconazole. In order to avoid the further rapid progression of the infection and save her life, it was decided to proceed to amputation of the patient's right leg. This is the first case of S. vasiformis cutaneous infection in an immunocompetent patient, in Greece.. Early diagnosis of S. vasiformis mucormycosis is of paramount importance. Clinical suspicion, based on the rapid progression of the infection and on the medical history of the patient, is sufficient to start antifungal treatment. Broad, aggressive, and repeated surgical debridement of the infection site together with systemic antifungal agents administration is the key point for successful treatment.

Topics: Administration, Intravenous; Amphotericin B; Amputation, Surgical; Antifungal Agents; Debridement; Dermatomycoses; Female; Greece; Humans; Middle Aged; Mucorales; Mucormycosis; Thigh; Triazoles

With the advent of newer antifungals, optimum treatment of mucormycosis remains to be fully elucidated. This study systematically evaluated the contemporary management and outcomes of mucormycosis. Mucormycosis cases in patients aged ≥18 years published between January 2000 and January 2017 were identified through Ovid MEDLINE and Embase. Of the 3619 articles identified, 600 (851 individual patient cases) were included in the review. Of the 851 patient cases, antifungal treatment details were available for 785. Intravenous (i.v.) amphotericin B formulations remained the most commonly prescribed first-line antifungals (760/785; 96.8%): 88.2% (670/760) were initiated as monotherapy and 11.8% (90/760) as combination antifungal therapy. Posaconazole oral suspension monotherapy was prescribed as an initial antifungal in 11 cases. It was also administered as maintenance or salvage therapy in 39 and 25 cases, respectively. Itraconazole capsule monotherapy (n = 10) was prescribed primarily for cutaneous disease in patients not receiving any immunosuppressive therapy. All-cause 90-day mortality was 41.0% (349/851). Initial treatment with combination antifungals did not reduce 90-day mortality compared with i.v. conventional amphotericin B or i.v. liposomal amphotericin B monotherapy [35/90 (38.9%) vs. 146/369 (39.6%) vs. 91/258 (35.3%), respectively; P = 0.541]. Concomitant surgical and antifungal therapy was associated with significantly lower 90-day mortality compared with treatment with antifungals alone (OR = 0.23, 95% CI 0.13-0.41; P < 0.001). The findings suggest that first-line antifungals with good efficacy remain an urgent unmet need. Whilst surgery is fundamental to improving survival, the clinical utility of combination antifungal therapy or posaconazole monotherapy requires further investigation.

Topics: Administration, Intravenous; Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Combined Modality Therapy; Disease Management; Drug Therapy, Combination; Female; Humans; Itraconazole; Male; Middle Aged; Mucormycosis; Surgical Procedures, Operative; Survival Analysis; Treatment Outcome; Triazoles; Young Adult

Candidiasis is one of the most common opportunistic oral infections that presents different acute and chronic clinical presentations with diverse diagnostic and therapeutic approaches. The present study carries out a bibliographic review on the therapeutic tools available against oral candidiasis and their usefulness in each clinical situation.. Recent studies on treatment of oral candidiasis were retrieved from PubMed and Cochrane Library.. Nystatin and miconazole are the most commonly used topical antifungal drugs. Both antifungal drugs are very effective but need a long time of use to eradicate the infection. The pharmacological presentations of miconazole are more comfortable for patients but this drug may interact with other drugs and this fact should be assessed before use. Other topical alternatives for oral candidiasis, such as amphotericin B or clotrimazole, are not available in many countries. Oral fluconazole is effective in treating oral candidiasis that does not respond to topical treatment. Other systemic treatment alternatives, oral or intravenous, less used are itraconazole, voriconazole or posaconazole. Available novelties include echinocandins (anidulafungin, caspofungin) and isavuconazole. Echinocandins can only be used intravenously. Isavuconazole is available for oral and intravenous use. Other hopeful alternatives are new drugs, such as ibrexafungerp, or the use of antibodies, cytokines and antimicrobial peptides.. Nystatin, miconazole, and fluconazole are very effective for treating oral candidiasis. There are systemic alternatives for treating recalcitrant infections, such as the new triazoles, echinocandins, or lipidic presentations of amphotericin B.

Topics: Administration, Intravenous; Administration, Oral; Administration, Topical; Amphotericin B; Anidulafungin; Antifungal Agents; Azoles; Candidiasis, Oral; Caspofungin; Clotrimazole; Databases, Factual; Drug Interactions; Echinocandins; Fluconazole; Humans; Miconazole; Nitriles; Nystatin; Pyridines; Triazoles

Fusarium spp. are an uncommon cause of fungaemia in immunocompromised and neutropenic patients that may hematogenously disseminate to the eyes. Herein, we describe a patient with acute lymphoblastic leukaemia and a prior history of extensive corticosteroid exposure who developed disseminated Fusarium solani infection following chemotherapy despite posaconazole prophylaxis. She was successfully treated with combination liposomal amphotericin B and voriconazole, intraocular injections of voriconazole, topical amphotericin B and bilateral vitrectomy. We also review published literature describing the management of endogenous Fusarium endophthalmitis in immunocompromised hosts.

Topics: Amphotericin B; Antifungal Agents; Drug-Related Side Effects and Adverse Reactions; Endophthalmitis; Female; Fungemia; Fusariosis; Fusarium; Humans; Immunocompromised Host; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrimidines; Treatment Outcome; Triazoles; Voriconazole

Mucormycosis is an uncommonly encountered fungal infection in solid organ transplantation. The infection is severe and often results in a fatal outcome. The most common presentations are rhino-sino-orbital and pulmonary disease. We describe a rare case of gastric mucormycosis in a patient with a combined liver-kidney transplant affected by glycogen storage disease type Ia. A 42-year-old female patient presented with gastric pain and melena 26 days after transplantation. Evaluation with upper endoscopy showed two bleeding gastric ulcers. Histological examination of gastric specimens revealed fungal hyphae with evidence of Mucormycetes at subsequent molecular analysis. Immunosuppressive therapy was reduced and antifungal therapy consisting of liposomal amphotericin B and posaconazole was promptly introduced. Gastrointestinal side effects of posaconazole and acute T-cell rejection of renal graft complicated management of the case. A prolonged course of daily injections of amphotericin B together with a slight increase of immunosuppression favored successful treatment of mucormycosis as well as of graft rejection. At 2-year follow-up, the woman was found to have maintained normal renal and liver function. We conclude that judicious personalization of antimicrobial and antirejection therapy should be considered to resolve every life-threatening case of mucormycosis in solid organ transplantation.

Topics: Adult; Amphotericin B; Antifungal Agents; Female; Humans; Immunocompromised Host; Kidney Transplantation; Liver Transplantation; Mucormycosis; Stomach Diseases; Triazoles

Invasive fungal diseases (IFDs) are a major cause of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplant (HSCT). Improvement in the management of IFDs have been achieved with the availability of new effective and safe antifungal drugs, however, many of these newer treatments have some limitations in their variable toxicity and unique predisposition for pharmacokinetic drug-drug interactions. Areas covered: This article is an update of a previous review published in this journal evaluating the safety profile of the antifungal drugs. Interesting new features include the availability of the new drug isavuconazole and the new tablet and intravenous formulations of posaconazole. Different dosages and new ways of administration of liposomal Amphotericin B (L-AmB) and echinocandins may be considered in the HSCT practice. Expert opinion: Nephrotoxicity continues to be a clinically relevant and frequent side effect of L-AmB which may cause a reduced clearance of other renally eliminated drugs frequently used in HSCT patients. Echinocandins are favorable therapeutic options in view of their low toxicity and uncommon drug-drug interactions. Important limitations of triazoles are represented by hepatic toxicity and certain side effects particularly after prolonged treatments. The new triazole isavuconazole and the new tablet formulation of posaconazole will be probably increasingly used in the HSCT setting not only due to their efficacy but in particular for their interesting toxicity profile and pharmacokinetic characteristics. The knowledge of these pharmacological findings is crucial in the daily care of allogeneic HSCT patients.

Topics: Amphotericin B; Antifungal Agents; Dose-Response Relationship, Drug; Drug Interactions; Hematopoietic Stem Cell Transplantation; Humans; Invasive Fungal Infections; Nitriles; Pyridines; Triazoles

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

Fusarium spp. causes infections mostly in patients with prolonged neutropenia. We describe the case of a disseminated Fusarium solani infection in a patient with acute myeloid leukemia which never reached complete remission during its clinical course. The patient had profound neutropenia and developed skin nodules and pneumonia in spite of posaconazole prophylaxis. F. solani was isolated from blood and skin biopsy, being identified from its morphology and by molecular methods. By broth dilution method, the strain was resistant to azoles, including voriconazole and posaconazole, and to echinocandins. MIC to amphotericin B was 4 mg/L. The patient initially seemed to benefit from therapy with voriconazole and amphotericin B, but, neutropenia perduring, his clinical condition deteriorated with fatal outcome. All efforts should be made to determine the correct diagnosis as soon as possible in a neutropenic patient and to treat this infection in a timely way, assuming pathogen susceptibility while tests of antimicrobial susceptibility are pending. A review of the most recent literature on invasive fungal infections is reported.

Topics: Adult; Amphotericin B; Antifungal Agents; Blood; Fatal Outcome; Fusariosis; Fusarium; Humans; Leukemia, Myeloid, Acute; Lung; Male; Microbial Sensitivity Tests; Microbiological Techniques; Radiography, Thoracic; Skin; Tomography, X-Ray Computed; Triazoles

Mucormycosis is an opportunistic mold infection whose management is difficult, as there is a paucity of evidence-based data. We summarize the latest advances in diagnosis and management of mucormycosis in transplant recipients.. There is promise for improvement in nonculture-based diagnostics with new biomarkers of Mucorales DNA that can be used for early diagnosis, and monitoring of response. Antifungal treatment consists of high-dose lipid formulations of amphotericin B or isavuconazole as the first-line therapy and posaconazole as salvage therapy. The new, pharmacokinetically more reliable formulations of posaconazole (intravenous, extended-release tablets) are welcomed improvements. Yet, the role of combination therapy is still uncertain. Surgery had a significant role in selected cases, such as in patients with rhinosinusitis form of mucormycosis, which nowadays can be performed with minimal invasive technique.. Mucormycosis remain a life-threatening opportunistic mold infection among transplant patients. Early diagnosis, prompt treatment with effective antifungals in combination with surgery if feasible is essential. Immune adjunct therapy and improvement of early diagnostics are important areas for future research. There are good prospects of progress in diagnostics and management of mucormycosis in transplant patients.

Topics: Amphotericin B; Antifungal Agents; DNA, Fungal; Humans; Mucorales; Mucormycosis; Nitriles; Opportunistic Infections; Pyridines; Salvage Therapy; Transplant Recipients; Triazoles

To review the current literature for the pathogenesis of mucormycosis, discuss diagnostic strategies, and evaluate the efficacy of polyenes, triazoles, and echinocandins as pharmacological treatment options.. An electronic literature search was conducted in PubMed using the MESH terms Rhizopus, zygomycetes, zygomycosis, Mucorales and mucormycosis, with search terms amphotericin B, micafungin, anidulafungin, caspofungin, extended infusion amphotericin B, liposomal amphotericin B, combination therapy, triazole, posaconazole, isavuconazole, diagnosis, and clinical manifestations.. Studies written in the English language from January 1960 to March 2016 were considered for this review article. All search results were reviewed, and the relevance of each article was determined by the authors independently.. Mucormycosis is a rare invasive fungal infection with an exceedingly high mortality and few therapeutic options. It has a distinct predilection for invasion of endothelial cells in the vascular system, which is likely important in dissemination of disease from a primary focus of infection. Six distinct clinical syndromes can occur in susceptible hosts, including rhino-orbital-cerebral, pulmonary, gastrointestinal, cutaneous, widely disseminated, and miscellaneous infection.. Diagnosis of mucormycosis is typically difficult to make based on imaging studies, sputum culture, bronchoalveolar lavage culture, or needle aspirate. Surgical debridement prior to dissemination of infection improves clinical outcomes. Surgery combined with early, high-dose systemic antifungal therapy yields greater than a 1.5-fold increase in survival rates. The Mucorales are inherently resistant to most widely used antifungal agents. Amphotericin B is appropriate for empirical therapy, whereas posaconazole and isavuconazole are best reserved for de-escalation, refractory cases, or patients intolerant to amphotericin B.

Topics: Amphotericin B; Anidulafungin; Antifungal Agents; Caspofungin; Debridement; Drug Resistance, Fungal; Echinocandins; Humans; Lipopeptides; Male; Micafungin; Middle Aged; Mucorales; Mucormycosis; Nitriles; Pyridines; Triazoles; Virulence

Cunninghamella bertholletiae as a rare cause of mucormycosis has been described almost exclusively in immunosuppressed patients such as hematopoietic stem cell transplant (HSCT) recipients. The infection is associated with high rates of mortality despite aggressive treatment. We describe a 40-year-old male with HLA-haploidentical HSCT developed fungal pneumonitis caused by C. bertholletiae complicated by graft failure and prolonged neutropenia. The patient died 102 days after HSCT despite early use of posaconazole and amphotericin B, which are believed to be the two most effective antifungal antibiotics against C. bertholletiae. The case highlights extreme unfavorable outcome in C. bertholletiae infection and neutropenia as a major risk factor.

Topics: Adult; Amphotericin B; Antifungal Agents; Cunninghamella; Fatal Outcome; Graft Rejection; Hematopoietic Stem Cell Transplantation; Humans; Male; Microbiological Techniques; Microscopy; Mucormycosis; Thorax; Tomography, X-Ray Computed; Transplant Recipients; Triazoles

BACKGROUND The clinical presentation of mucormycosis can vary widely based on various host factors. Among malignancy- and bone marrow transplant-associated infections, the lungs are the most common site of infection. Involvement of the gastrointestinal tract is less frequently encountered. The clinical presentation is often nonspecific, and cultures typically yield no growth, making the diagnosis challenging. CASE REPORT We present a case of isolated hepatic mucormycosis in the setting of neutropenic fever and abdominal pain following induction chemotherapy for the treatment of acute myeloid leukemia. The patient was treated with combination antifungal therapy with amphotericin and posaconazole without surgical resection, given the presence of multiple liver lesions. After a prolonged course of dual antifungal therapy, the size of her liver lesions improved. Unfortunately, her lymphoproliferative disorder proved fatal, following approximately 13 months of antifungal therapy. CONCLUSIONS Among patients with mucormycosis, mortality remains high, especially in the setting of gastrointestinal involvement. Although surgical resection along with dual antifungal therapy can improve outcomes, the high mortality rate necessitates further investigation into improved diagnostic and treatment strategies including optimal antifungal therapy.

Topics: Amphotericin B; Antifungal Agents; Chemotherapy, Adjuvant; Fatal Outcome; Female; Humans; Immunocompromised Host; Leukemia, Myeloid, Acute; Liver Diseases; Middle Aged; Mucormycosis; Risk Factors; Treatment Failure; Treatment Outcome; Triazoles

Topics: Adolescent; Adult; Amphotericin B; Antifungal Agents; Child; Child, Preschool; Coccidioides; Coccidioidomycosis; Colon; Cryptococcosis; Cryptococcus; Duodenal Ulcer; Endemic Diseases; Female; Histoplasma; Histoplasmosis; Humans; Itraconazole; Job Syndrome; Male; Middle Aged; Mutation; STAT3 Transcription Factor; Treatment Outcome; Triazoles; United States

Invasive aspergillosis remains an often fatal, difficult-to treat infection in immunocompromised patients. Patients not classically defined as immunocompromised, especially those in an intensive care unit setting, also develop invasive aspergillosis. Clinical clues suggesting angioinvasion and radiographic modalities, especially computed tomographic scans, combined with newer non-culture-based diagnostic techniques, have allowed earlier recognition of invasive aspergillosis. Although mortality remains high, it has greatly decreased over the past 15 years. Voriconazole has supplanted amphotericin B, with its various toxicities, as primary treatment for invasive aspergillosis. Combination therapy with voriconazole and an echinocandin for initial therapy, based on results from a recent controlled clinical trial, could become the standard of care in high-risk patients.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Combined Modality Therapy; Drug Therapy, Combination; Echinocandins; Hematopoietic Stem Cell Transplantation; Humans; Lung Transplantation; Magnetic Resonance Imaging; Risk Factors; Tomography, X-Ray Computed; Treatment Outcome; Triazoles; Voriconazole

Mucormycosis is a rare, though increasingly prevalent, life-threatening fungal disease caused by Mucorales. The incidence has increased over the last decade and its mortality remains high at around 50%. Mucormycosis occurs mostly in patients with diabetes mellitus and/or in the context of immunosuppression resulting from chemotherapy for hematological malignancy, hematopoietic stem cell transplantation, or solid-organ transplantation. In this situation, lung and rhino-orbito-cerebral infections are the most frequent localizations of the disease. Prompt initiation of an effective treatment is essential to decrease mortality. However, mucormycosis and aspergillosis share close clinical and radiological features. Invasive procedures such as bronchial endoscopy and/or lung biopsy are necessary to confirm diagnosis, as no indirect tests are yet validated. Therefore, the challenge is to minimize the delay in diagnosis. When present, the reversed halo sign on CT scan is suggestive of mucormycosis. Quantitative polymerase chain reaction is a new promising approach to detect Mucorales DNA in serum and new molecular tools are available to detect Mucorales in tissues as well as to specify species. Recommendations from ECIL and ECMM/ESCMID have recently been published on management of mucormycosis. The recommended treatment is an amphotericin B lipid formulation in combination with surgery and modification of risk factors. High-dose (10 mg/kg) of liposomal amphotericin B is recommended in case of neurological involvement and posaconazole for maintenance therapy. Place of isavuconazole as well as posaconazole new formulations (tablets and intravenous) in first line treatment have to be defined. Improved radiologic descriptions of mucormycosis and new molecular tools may be key elements to help with rapid diagnosis in the future. Clinical trials are warranted to improve therapeutic success and hopefully survival.

Topics: Amphotericin B; Antifungal Agents; Combined Modality Therapy; Debridement; Hematopoietic Stem Cell Transplantation; Humans; Lung Diseases, Fungal; Mucorales; Mucormycosis; Nitriles; Pyridines; Triazoles

Mucormycosis, previously termed as zygomycosis, is caused by fungi belonging to the order Mucorales and is a very severe disease in immunocompromised patients with an often unfavourable outcome. Given the high morbidity and mortality of mucormycosis, establishing a timely diagnosis followed by immediate treatment is of major importance. As randomised clinical trials are lacking, we present our current diagnostic and treatment pathways for mucormycosis in the immunocompromised host. Due to the difficulty to distinguish mucormycosis from other filamentous fungi, mucormycosis always has to be considered as differential diagnosis in predisposed patients. Diagnostic procedures comprise imaging, microscopy, culture and histopathology and need to be rigorously used. In patients with a high suspicion of mucormycosis, e.g. reversed halo sign on computed tomography scanning, our approach combines liposomal amphotericin B (LAmB) with surgical debridement. In light of the rapid deterioration and poor prognosis of these patients, we prefer a daily dose of LAmB of at least 5 mg kg(-1) despite nephrotoxicity. In patients with stable disease we switch to posaconazole 200 mg four times per day. In case of progression antifungal combination is an option.

Topics: Amphotericin B; Antifungal Agents; Debridement; Humans; Immunocompromised Host; Mucorales; Mucormycosis; Triazoles

Mucormycosis is an emerging mycotic infection with high mortality. We described the clinical presentation, evolution and treatment of 5 patients with diagnosis of mucormycosis.. La mucormicosis es una micosis emergente, de elevada mortalidad. El objetivo del estudio es presentar las características clínicas y evolución de los casos asistidos en el Sanatorio Allende, de la Ciudad de Córdoba República Argentina y hacer una actualización bibliografíca. Se presentan 5 pacientes con mucormicosis con diferentes formas clínicas de presentación. El diagnóstico clínico se confirmó por histopatología y/o cultivo de los tejidos. Concluimos que en la actualidad la sospecha clínica basada en la forma de presentación y los factores de riesgo siguen siendo claves para establecer la sospecha clínica y realizar el diagnóstico temprano. En cuanto al tratamiento se basa fundamentalmente en el desbridamiento quirúrgico para eliminación del tejido necrótico y Anfotericina liposomal como antifúngico de elección. El posaconazol nuevo triazol tendría un rol importante en la consolidación del tratamiento una vez que el paciente logra la estabilización clínica o como tratamiento de rescate.

Topics: Adolescent; Adult; Amphotericin B; Antifungal Agents; Fatal Outcome; Female; Humans; Male; Middle Aged; Mucormycosis; Rifampin; Risk Factors; Triazoles; Young Adult

Mucormycosis is a life-threatening invasive fungal infection that arises among immunocompromised patients (haematological malignancies, solid organ transplantation, diabetes mellitus). The most frequent sites of infection are pulmonary, rhinocerebral, cutaneous and disseminated. Reversal of the underlying conditions is mandatory for controlling mucormycosis. Another cornerstone of mucormycosis treatment is prompt and aggressive surgery. It is achieved by extensive surgical debridement of necrotic tissues. Finally an antifungal therapy is needed. The first-line chemotherapy of mucormycosis includes high-dose liposomal amphotericin B (≥ 5 mg/kg/day). The duration of antifungal chemotherapy is not defined but guided by the resolution of all associated symptoms and findings (usually 6-8 weeks). Maintenance therapy/secondary prophylaxis by posaconazole has to be considered in persistently immuno compromised patients.

Topics: Amphotericin B; Antifungal Agents; Debridement; Humans; Immunocompromised Host; Mucormycosis; Triazoles

Candida infections are a source of significant mortality and morbidity in the neonatal intensive care unit. Treatment strategies continue to change as additional antifungals become available and studies in neonates are performed. Amphotericin B deoxycholate has been favored for many years, but fluconazole has the most data supporting its use in neonatal Candida infections and is often employed for prophylaxis as well as treatment. Voriconazole and posaconazole have limited utility in the nursery and are rarely used. The echinocandins are increasingly administered for invasive Candida infections, although higher doses are required in neonates than in older children and adults.

Topics: Amphotericin B; Antifungal Agents; Candidiasis; Deoxycholic Acid; Dose-Response Relationship, Drug; Drug Combinations; Echinocandins; Fluconazole; Humans; Infant, Newborn; Infant, Newborn, Diseases; Intensive Care Units, Neonatal; Neonatology; Pyrimidines; Triazoles; Voriconazole

Invasive aspergillosis (IA) is a major cause of morbidity and mortality in immunocompromised hosts. Economic expenditures prompted by this invasive fungal infection (IFI) are significant. Although, the duration and associated costs of hospitalization comprise the largest proportion of costs in large surveillance studies, the newer oral antifungal agents may impact significantly on these costs. A review of the pharmacoeconomic (PE) studies is provided focussing on primary therapy, salvage therapy, empiric therapy and prophylaxis for IA. PE evaluations have demonstrated the cost effectiveness and dominance of voriconazole for targeted primary treatment of IA compared with other available agents. Differences in the drug choice and analytic methodology of the PE analyses of empiric antifungal strategy hamper definitive conclusions about the agents employed as empiric antifungal that may be directed at suspected IA although both caspofungin and voriconazole appear to be cost effective and dominant over liposomal amphotericin B (LAmB), whereas LAmB is more costly than conventional amphotericin B. Posaconazole is the most cost-effective agent for antifungal prophylaxis against IFI and IA.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Clinical Trials as Topic; Cost-Benefit Analysis; Empirical Research; Humans; Length of Stay; Pyrimidines; Treatment Outcome; Triazoles; Voriconazole

Topics: Aged; Amphotericin B; Antifungal Agents; Caspofungin; Diabetes Mellitus, Type 2; Disease Susceptibility; Drug Resistance, Multiple, Fungal; Drug Therapy, Combination; Echinocandins; Endophthalmitis; Eye Enucleation; Eye Infections, Fungal; Glaucoma; Humans; Hypertension; Intravitreal Injections; Lipopeptides; Male; Phialophora; Pyrimidines; Triazoles; Vitrectomy; Voriconazole

Major progress for the management of invasive aspergillosis has come from the introduction of new antifungals since the late 1990s. Although mortality of invasive aspergillosis remains as high as 30-50%. Backbone of management are prophylaxis, early diagnosis and early initiation of antifungals for reduction of invasive aspergillosis related mortality. Randomized trials have been undertaken for the prophylaxis as well as treatment of invasive aspergillosis in the last two decades. Posaconazole is recommended for prophylaxis against aspergillosis in patients treated for acute myelogenous leukemia, myelodysplastic syndrome or patients with graft versus host disease after allogeneic transplantation. Efficacy has been shown for first-line therapy of invasive aspergillosis with voriconazole and liposomal amphotericin B. Gastrointestinal resorption for the azoles posaconazole, voriconazole and itraconazole differ considerably. While oral voriconazole resportion is reduced when taken with food, posaconazole has to be taken with fatty food for optimal intestinal resorption. Beside all advances in the management of invasive aspergillosis important questions remain unresolved. This article reviews the current state of prophylaxis and treatment of invasive aspergillosis and points out clinicians unmet needs.

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Clinical Trials as Topic; Drug Therapy, Combination; Echinocandins; Evidence-Based Medicine; Humans; Invasive Pulmonary Aspergillosis; Itraconazole; Lipopeptides; Pyrimidines; Risk Factors; Triazoles; Voriconazole

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 mycoses continue to be a major problem in the growing population of immunosuppressed patients. More antifungal agents are now available than ever. The options are many, with more efficacies and less toxicity than in the past. These agents differ in terms of spectrum of activity, pharmacologic properties, and indications. In this article we discuss the three major classes of antifungal agents: the polyens, the triazoles, and the echinocandins. The emphasis is placed on their clinical use, side effects, drug interactions, and other practical issues.

Topics: Amphotericin B; Anidulafungin; Antifungal Agents; Caspofungin; Drug Therapy, Combination; Echinocandins; Fluconazole; Humans; Itraconazole; Lipopeptides; Micafungin; Pyrimidines; Triazoles; Voriconazole

Topics: Administration, Oral; Adolescent; Amphotericin B; Antifungal Agents; Cunninghamella; Dermatomycoses; Female; Humans; Injections, Intravenous; Mucormycosis; Transplants; Triazoles

Invasive fungal infections cause significant morbidity and mortality in immunocompromised children. The prevalence of invasive aspergillosis (IA) is increasing as a reflection of the rising numbers of immunocompromised patients and the increasing use of aggressive immunosuppressive treatment regimes for hematologic malignancies and transplantation. IA is almost exclusively seen in severely immunocompromised or critically ill children, including those with the classic risk factors (particularly neutropenia, hematopoietic stem cell transplant or solid-organ transplantation, hematological malignancies, use of systemic immunosuppressive agents or cytotoxic therapies). Early treatment improves survival rates, but the diagnosis of aspergillosis remains difficult and, while IA has been relatively well-characterized in adults, far fewer studies have described optimal treatment for the pediatric population. This article reviews and compares the newer, less-invasive diagnostic techniques that are becoming available and focuses on the data specifically from pediatric trials regarding efficacy, safety and pharmacokinetics of the antifungals used for IA.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Caspofungin; Child; Echinocandins; Fungal Vaccines; Genomics; Humans; Immunocompromised Host; Lipopeptides; Micafungin; Pyrimidines; Risk Factors; Triazoles; Voriconazole

Recent therapeutic advances have the potential to improve outcomes of mucormycosis. Lipid formulations of amphotericin B (LFAB) have evolved as the cornerstone of primary therapy for mucormycosis. Posaconazole may be useful as salvage therapy, but it cannot be recommended as primary therapy for mucormycosis on the basis of available data. Preclinical and limited retrospective clinical data suggest that combination LFAB-echinocandin therapy may improve survival during mucormycosis. A definitive trial is needed to confirm these results. Combination therapy with LFAB and the iron chelator, deferasirox, also improved outcomes in animal models of mucormycosis. In contrast, combination polyene-posaconazole therapy was of no benefit in preclinical studies. Adjunctive therapy with recombinant cytokines, hyperbaric oxygen, and/or granulocyte transfusions can be considered for selected patients. Early initiation of therapy is critical to maximizing outcomes; recent developments in polymerase chain reaction technology are advancing early diagnostic strategies. Prospective, randomized clinical trials are needed to define optimal management strategies for mucormycosis.

Topics: Amphotericin B; Antifungal Agents; Benzoates; Case Management; Clinical Trials as Topic; Deferasirox; Drug Therapy, Combination; Echinocandins; Humans; Immunologic Factors; Mucormycosis; Polyenes; Triazoles

Zygomycosis is an invasive infection that can occur particularly in patients with haematological malignancy. The causative fungi are members of the order Mucorales, and individual species within this group require a high level of laboratory skill to be identified. Zygomycosis can present as rhinocerebral, pulmonary, or disseminated disease, with a rapid clinical course. The optimal management of these cases requires early diagnosis, aggressive antifungal therapy and, when possible, surgical debridement. Founded on clinical experience, but without the benefit of comparative studies, liposomal amphotericin B has become the therapeutic agent of choice. Posaconazole is an orally administered triazole with a demonstrated in vitro and in vivo activity against most Zygomycetes that is comparable to that of amphotericin B. Studies on salvage therapy with posaconazole have yielded promising results, and successful case reports are also available. As an adjuvant approach, iron chelation with deferasirox has shown promising results, although clinical experience is still limited.

Topics: Amphotericin B; Antibiotic Prophylaxis; Antifungal Agents; Granulocytes; Hematologic Neoplasms; Humans; Hyperbaric Oxygenation; Iron Chelating Agents; Neutrophils; Risk Factors; Triazoles; Zygomycosis

Invasive opportunistic fungal infections caused by agents of Mucorales that involve the gastrointestinal tract are uncommon but aggressive. These ubiquitous fungal spores typically are inhaled and can germinate in immunocompromised hosts. Standard therapy for invasive mucormycosis includes parenteral amphotericin B (AMB) in combination with radical debridement of infected tissues. Early diagnosis and treatment are of paramount importance. Unfortunately, long-term survival is poor owing to the prohibitive morbidity and mortality rates associated with the medical and surgical therapies. Posaconazole is a novel, extended-spectrum triazole oral antifungal agent with documented success in the treatment of patients with invasive mucormycosis.. Case report and literature review.. A 50-year-old man presented with invasive mucormycosis of the lower esophagus, stomach, and liver, resulting in gastrointestinal hemorrhage. The infection did not respond to AMB but was treated successfully with a combination of posaconazole and liposomal AMB (LAMB) without surgical debridement.. To our knowledge, this is the first reported case of extensive gastric and intrahepatic mucormycosis that responded to combination posaconazole and LAMB without surgical debridement. This approach may be an alternative to surgery in patients who are precluded from extensive surgical intervention.

Topics: Amphotericin B; Antifungal Agents; Drug Therapy, Combination; Gastrointestinal Diseases; Humans; Male; Middle Aged; Mucor; Mucormycosis; Treatment Outcome; Triazoles

Zygomycosis of the central nervous system (CNS) can manifest in three distinct clinical forms, as rhinocerebral zygomycosis, as disseminated zygomycosis with CNS involvement, and as isolated cerebral zygomycosis. We present a case of a 2-year-old boy with leukaemia and disseminated zygomycosis, caused by Absidia corymbifera, involving the brain, spinal cord, lung and liver. The child received treatment with liposomal amphotericin B and posaconazole for 6 months. Although the lesions of the lungs and liver resolved, those of the CNS persisted and the child is in a vegetative state. A review of the literature after 2004 identified ten additional cases of disseminated zygomycosis with cerebral involvement, all but one of which had concurrent lung infection. The most common underlying disease in these cases was haematological malignancy and the mortality rate was 70%. Disseminated zygomycosis with cerebral involvement is a fatal disease. Early recognition and prompt intervention with combined medical and surgical treatment may improve the outcome.

Topics: Absidia; Amphotericin B; Antifungal Agents; Brain; Central Nervous System Fungal Infections; Child, Preschool; Humans; Liver; Lung; Male; Mucormycosis; Spinal Cord; Triazoles

To date, no reference standard for therapy for zygomycosis has been established because there are insufficient clinical data with which to make such a judgement. Knowledge of the species responsible for the infection and its antifungal susceptibility profile has become increasingly important in the management of patients. Amphotericin B is the most active drug against all the species involved, followed by posaconazole, whereas voriconazole has no activity. Echinocandins are completely inactive in vitro, but may be an interesting option when used in combination with other drugs.

Topics: Amphotericin B; Antifungal Agents; Echinocandins; Humans; Microbial Sensitivity Tests; Mucorales; Mucormycosis; Pyrimidines; Triazoles; Voriconazole

The treatment of zygomycosis has two cornerstones, namely, surgery and antifungal drugs. In many patients, both need to be applied to achieve treatment success; without treatment, the mortality rate of zygomycosis approaches 100%. Because treatment options are limited, no well-designed randomized clinical trial has been conducted and data are predominantly derived from compassionate-use programmes or case reports. Amphotericin B (AmB) lipid complex (ABLC) was clinically evaluated for efficacy against zygomycosis in a single series and resulted in cure or improvement in 52% and in the stabilizing of disease in 20% of patients. Liposomal AmB (L-AmB) is frequently used, but no large series have yet been published. Posaconazole has demonstrated in vitro and in vivo activity against Zygomycetes. Two series demonstrated salvage treatment response rates of 60% and 79%, respectively. Antifungal combinations have not been evaluated thoroughly enough to warrant recommendations outside of clinical trials. Survival is usually associated with surgical debridement and improvement in underlying diseases. Currently, surgical debridement should be performed. Antifungal treatment should consist of either ABLC > or =5 mg/kg once per day or L-AmB > or =3 mg/kg once per day. When toxicity occurs or stable fungal disease is achieved, treatment can be switched to oral posaconazole 200 mg four times per day. If impaired kidney function is overt or expected on the grounds of, for example, uncontrolled diabetes, primary treatment of zygomycosis with posaconazole is an option.

Topics: Amphotericin B; Antifungal Agents; Debridement; Humans; Triazoles; Zygomycosis

Zygomycetes are increasingly reported as a cause of life-threatening invasive fungal infections in profoundly immunocompromised patients and in those with diabetic ketoacidosis. Zygomycosis, typically presents as soft tissue, rhino-orbitocerebral, pulmonary or disseminated disease and is characterized by rapid clinical progression and high mortality rates. Treatment with amphotericin B lipid formulations in combination with surgery and, perhaps, the addition of caspofungin offers the best chance for survival; posaconazole, a new antifungal triazole, is increasingly used for consolidation or maintenance therapy. Because of the poor prognosis of zygomycosis, particularly in immunocompromised cancer patients, adjunctive treatments such as hyperbaric oxygen therapy, use of immunomodulatory cytokines, and in vivo iron starvation continue to be explored. However, although each of these modalities is based on a plausible scientific rationale and has been helpful in the management of individual patients, there is no clinical evidence for their general effectiveness as adjunctive treatments in patients with zygomycosis. Further experimental and clinical investigations are necessary to determine whether and how these treatments can impact on outcome and to determine which patients and which types of infection may benefit from them.

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Debridement; Echinocandins; Humans; Hyperbaric Oxygenation; Immunologic Factors; Lipopeptides; Oxygen; Triazoles; Zygomycosis

Invasive candidiasis is a common nosocomial infection among critically ill patients, constitutes an important cause of sepsis, and is associated with significant morbidity and mortality. The Infectious Diseases Society of America (IDSA) has created evidence-based guidelines for the management of invasive candidiasis. However, several new antifungal agents with excellent activity against Candida spp. and favourable safety profiles have been introduced successfully in the clinical setting since the IDSA guidelines were published in late 2003. Further, the role of antifungals is not entirely clear in the intensive care unit (ICU) setting. Therefore, this article discusses daily problems in the prophylaxis and treatment of invasive candidasis in interdisciplinary ICUs.

Topics: Amphotericin B; Antifungal Agents; Candida; Candidiasis; Cross Infection; Deoxycholic Acid; Drug Combinations; Drug Therapy, Combination; Echinocandins; Fluconazole; Humans; Intensive Care Units; Itraconazole; Pyrimidines; Risk Factors; Triazoles; Voriconazole

A 57-year-old woman with end-stage kidney disease secondary to autosomal dominant polycystic kidney disease developed peritoneal dialysis-related Mucor peritonitis after her pet cockatoo bit through her transfer set. The infection persisted despite more than 8 weeks of treatment with liposomal amphotericin B. On a compassionate basis, she then received oral posaconazole, 800 mg/d, in divided doses for 6 months. She experienced complete remission and has remained disease free since then, for more than 2 years. We review the medical literature about mucormycosis peritonitis which, albeit rare, carries very high mortality. The treatment of choice is liposomal amphotericin B, which failed in our patient. Our case report suggests that posaconazole is an attractive treatment option in patients with peritoneal dialysis-related Mucor peritonitis.

Topics: Amphotericin B; Antifungal Agents; Female; Humans; Kidney Failure, Chronic; Liposomes; Middle Aged; Mucormycosis; Peritoneal Dialysis; Peritonitis; Polycystic Kidney, Autosomal Dominant; Treatment Failure; Treatment Outcome; Triazoles

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

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

Topics: Acute Disease; Amphotericin B; Antifungal Agents; Humans; Leukemia, Myeloid; Rhizopus; Triazoles; Zygomycosis

During the last decade the incidence of invasive aspergillosis has substantially grown due to the increasing use of powerful immunosupressive drugs in more patients. Unfortunately, the associated mortality with this infection is still very high and has not decreased in recent years. Pulmonary aspergillosis is by far the most frequent clinical picture of this infection, followed by sinus, tracheo-bronchial and central nervous system disease. The degree of immunosupression is the main factor influencing the evolution and dissemination of aspergillosis. Conventional amphotericin B has been the first-line therapy of invasive aspergillosis for the last 30 years, and most authors have long considered amphotericin B related toxicity as one of the main causes for the poor results obtained in the outcome of patients who developed this infection. Fortunately, in the last few years new safer and more effective drugs have been developed for the treatment of this entity. However, if we are really trying to substantially decrease invasive aspergillosis associated-mortality we should use these drugs earlier in the development of the infection, using new more sensitive diagnostic tests and/or a riskbase strategy which could identify patients at the highest risk to develop this infection.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillosis, Allergic Bronchopulmonary; Caspofungin; Dermatomycoses; Drug Therapy, Combination; Echinocandins; Humans; Immunocompromised Host; Immunologic Factors; Itraconazole; Lipopeptides; Neuroaspergillosis; Neutropenia; Peptides; Peptides, Cyclic; Pyrimidines; Respiratory Tract Infections; Triazoles; Voriconazole

A severely neutropenic patient with chronic lymphocytic leukemia developed a diffuse bilateral pulmonary infection while receiving a therapeutic daily dosage of intravenous amphotericin B for Candida glabrata esophagitis. Computed tomography of the chest showed numerous lung nodules, ground glass areas and a pleural effusion. Biopsy of one nodule demonstrated hyaline septate hyphae. Multiple sputum cultures grew Acremonium strictum. Increasing the dose of amphotericin B and the addition of itraconazole did not resolve the infection. Change of treatment to posaconazole given orally at 200 mg four times/d resulted in progressive improvement leading finally to cure after 24 weeks of therapy. Treatment with posaconazole was clinically and biologically well tolerated.

Topics: Acremonium; Administration, Oral; Amphotericin B; Antifungal Agents; Biopsy, Needle; Female; Follow-Up Studies; Humans; Immunocompromised Host; Lung Diseases, Fungal; Microbial Sensitivity Tests; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Risk Assessment; Tomography, X-Ray Computed; Treatment Failure; Treatment Outcome; Triazoles

Histoplasmosis is an endemic mycosis, which is most prevalent in the Ohio and Mississippi valleys of North America. The causative organism is a dimorphic fungus, Histoplasma capsulatum. Histoplasmosis can present as a self-limited disease or cause life-threatening diseases resulting in considerable morbidity and mortality. Treatment is appropriate in patients with diffuse acute pulmonary infection, chronic pulmonary infection, mediastinal granuloma causing obstruction of important structures, or disseminated infection. Other chronic forms of disease such as fibrosing mediastinitis and broncholithiasis are unresponsive to pharmacologic treatment. Options for therapy include amphotericin B or one of its lipid formulations, and ketoconazole, itraconazole, or fluconazole. Recently, newer antifungal agents have been evaluated in animals models of histoplasmosis. Of these, a new triazole, posaconazole (SCH56592) appears most promising. Generally, amphotericin B or one of the lipid formulations is recommended as initial treatment in patients with more extensive diseases, felt to be ill enough to require hospitalization, and itraconazole for those who have milder illness, or to complete treatment after patients respond to amphotericin B. The role of intravenous formulation of itraconazole for severe histoplasmosis is unknown because studies comparing it with amphotericin B have not been conducted.

Topics: Amphotericin B; Antifungal Agents; Histoplasmosis; Humans; Triazoles

First-line antifungal treatment for invasive mucormycosis (IM) consists of liposomal amphotericin B. Salvage treatment options are limited and often based on posaconazole oral suspension. With the approval of posaconazole new formulations, patients could benefit from improved pharmacokinetics, safety and tolerability.. Our aim was to assess the effectiveness of posaconazole new formulations for IM treatment.. We performed a case-matched analysis with proven or probable IM patients from the FungiScope® Registry. First-line posaconazole new formulations (1st-POSnew) and first-line amphotericin B plus posaconazole new formulations (1st-AMB+POSnew) cases were matched with first-line amphotericin B-based (1st-AMB) treatment controls. Salvage posaconazole new formulations (SAL-POSnew) cases were matched with salvage posaconazole oral suspension (SAL-POSsusp) controls. Each case was matched with up to three controls (based on severity, haematological/oncological malignancy, surgery and/or renal dysfunction).. Five patients receiving 1st-POSnew, 18 receiving 1st-AMB+POSnew and 22 receiving SAL-POSnew were identified. By day 42, a favourable response was reported for 80.0% (n = 4/5) of patients receiving 1st-POSnew, for 27.8% (n = 5/18) receiving 1st-AMB+POSnew and for 50.0% (n = 11/22) receiving SAL-POSnew. Day 42 all-cause mortality of patients receiving posaconazole new formulations was lower compared with controls [20.0% (n = 1/5) in 1st-POSnew versus 53.3% (n = 8/15) in 1st-AMB; 33.3% (n = 6/18) in 1st-AMB+POSnew versus 52.0% (n = 26/50) in 1st-AMB; and 0.0% (n = 0/22) in SAL-POSnew versus 4.4% (n = 2/45) in SAL-POSsusp].. Posaconazole new formulations were effective in terms of treatment response and associated mortality of IM. While posaconazole new formulations may be an alternative for treatment of IM, the limited sample size of our study calls for a cautious interpretation of these observations.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Child; Child, Preschool; Drug Compounding; Female; Humans; Infant; Infant, Newborn; Invasive Fungal Infections; Male; Matched-Pair Analysis; Middle Aged; Mucorales; Mucormycosis; Prospective Studies; Registries; Triazoles; Young Adult

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

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

In patients with hematologic malignancy, invasive aspergillosis continues to be associated with high mortality even when treated with conventional antifungal therapy. To investigate novel antifungal agents, we compared 53 patients who received posaconazole salvage therapy to 52 contemporary control patients who received high-dose lipid formulation of amphotericin B (HD-LPD/AMB at > or = 7.5 mg kg(-1) per day) and 38 other control patients who received caspofungin plus HD-LPD/AMB. Patients in the three groups had similar. The overall response rate to salvage therapy was 40% for posaconazole, 8% for HD-LPD/AMB (P < or = 0.001) and 11% for combination therapy (P < 0.002). Aspergillosis contributed to the death of 40% of posaconazole group, 65% of the HD-LPD/AMB group and 68% of the combination group (P < or = 0.008). By multivariate analysis, posaconazole therapy independently improved response (9.5; 95% confidence interval, 2.8-32.5; P < 0.001). HD-LPD/AMB alone or in combination was associated with a significantly higher rate of nephrotoxicity (P < or = 0.02) and hepatotoxicity (P < 0.03). In conclusion, posaconazole salvage therapy demonstrated greater efficacy and safety than HD-LPD/AMB alone or in combination with caspofungin in the salvage therapy of invasive aspergillosis in hematologic malignancy.

Topics: Adult; Amphotericin B; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Aspergillosis; Caspofungin; Combined Modality Therapy; Drug Combinations; Drug Therapy, Combination; Echinocandins; Female; Fungemia; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Itraconazole; Lipopeptides; Male; Middle Aged; Neutropenia; Phosphatidylcholines; Phosphatidylglycerols; Pyrimidines; Salvage Therapy; Treatment Outcome; Triazoles; Voriconazole

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

Although Fusarium spp. rarely cause infections in healthy people, they can cause fusariosis, particularly in neutropenic hematological malignancies, bone marrow transplant patients, and immunocompromised patients, such as those with acquired immune deficiency syndrome (AIDS), and rarely in solid organ transplant recipients. Here, we present a case of a liver transplant recipient with F. solani species complex (FSSC) infection treated with posaconazole. A 61-year-old man presented with multiple itchy, painful, palpable, irregular, subcutaneous nodules on the right leg and total dystrophic onychomycosis in the right toenails. Incisional skin biopsies of the lesions were performed, and the samples were sent to the pathology and mycology laboratories for analysis. The clinical isolate was identified as FSSC using phenotypic, matrix-assisted laser desorption/ionization-time of flight mass spectrometry, and genotypic methods. Liposomal amphotericin B could not be administered owing to the development of side effects; hence, the patient was treated with posaconazole for 4 months. While some nodular lesions disappeared completely under this treatment, the others showed dimensional regression. This is the first case of FSSC infection with skin and nail involvement in a non-neutropenic, liver transplant patient in Turkey. Fusariosis may develop with rare species, such as FSSC, as first reported in this case of a liver transplant patient. Regardless of the species, amphotericin B is the first choice for treating fusariosis; however, posaconazole is an effective and safe alternative to amphotericin B.

Topics: Amphotericin B; Antifungal Agents; Fusariosis; Fusarium; Humans; Liver Transplantation; Male; Middle Aged

We compared the antifungal susceptibility of 92 Mucorales isolates obtained by visual inspection and spectrophotometric readings following EUCAST (European Committee on Antimicrobial Susceptibility Testing) testing. Amphotericin B minimum inhibitory concentrations (MICs) were up to 1 mg/l against most isolates and variable among species, except for Cunninghamella bertholletiae. Posaconazole MICs against most isolates were up to 1 mg/l and high against Mucor circinelloides, some Rhizopus arrhizus, and Rhizopus microsporus. Isavuconazole MICs ranged between 1 and 8 mg/l but were invariably >8 mg/l against M. circinelloides and C. bertholletiae. The agreement between MICs obtained by visual endpoint or spectrophotometric readings was moderate and higher when using the ≥90% fungal growth inhibition endpoint.. The agreement between minimum inhibitory concentration (MIC) values obtained by visual inspection or spectrophotometric readings was moderate and higher when the ≥90% fungal growth inhibition endpoint was chosen. Isavuconazole presented higher MICs than posaconazole, regardless of the inhibition endpoint used.

Topics: Amphotericin B; Animals; Antifungal Agents; Itraconazole; Microbial Sensitivity Tests; Mucorales

To evaluate the efficacy and safety of short-course intravenous amphotericin B followed by sustained release posaconazole tablets for diabetes or COVID-19-associated rhino-orbito-cerebral mucormycosis.. This prospective, pragmatic study included adults with diabetes or COVID-19-associated rhino-orbito-cerebral mucormycosis. Patients received short (7-14 days) or long (15-28 days) intravenous antifungal therapy (short intravenous antifungal treatment [SHIFT] or long intravenous antifungal treatment [LIFT], respectively) depending on the presence or absence of brain involvement. All patients received step-down posaconazole tablets, debridement, and glycemic control. The primary outcome was the treatment success at week 14, which was determined by assessing survival and the absence of disease progression through clinical evaluation and nasal endoscopy. Log-binomial regression analysis (risk ratio and 95% CI) was performed to assess factors associated with the primary outcome.. Intravenous therapy was administered to 251 participants: SHIFT, 205 (median duration, 13 days); LIFT, 46 (median duration, 22 days). Treatment success at 3 months was 88% (217/248; 95% CI, 83-91%): SHIFT group, 93% (189/203; 89-96%); LIFT group, 62% (28/45; 47-76%). All-cause mortality was 12% (30/251): SHIFT group, 6% (13/205); LIFT group, 37% (17/46). Age (aRR [95% CI]: 1.02 [1.00-1.05]; p 0.027), diabetic ketoacidosis at presentation (2.32 [1.20-4.46]; p 0·012), glycated haemoglobin A1c (1.19 [1.03-1.39]; p 0.019), stroke (3.93 [1.94-7.95]; p 0·0001), and brain involvement (5.67 [3.05-10.54]; p < 0.0001) were independently associated with unsuccessful outcomes.. Short intravenous amphotericin B with step-down posaconazole tablets should be further studied as primary treatment option for diabetes or COVID-19-associated mucormycosis in randomized controlled trials.

Topics: Adult; Amphotericin B; Antifungal Agents; COVID-19; Diabetes Mellitus; Humans; Mucormycosis; Orbital Diseases; Prospective Studies

We evaluated the activity of amphotericin B, itraconazole, posaconazole, voriconazole and caspofungin against 1468 invasive moulds collected worldwide from 2018 to 2021. Most (>92%) of the Aspergillus spp. isolates were wildtype (WT) to amphotericin B, caspofungin and the azoles. Azole-non-wildtype A. fumigatus rates were higher in Europe (9.5%) and North America (9.1%) than Latin America (0.0%; only 12 isolates) and the Asia-Pacific region (5.3%). Amphotericin B and caspofungin were active against azole-non-wildtype A. fumigatus isolates. Posaconazole and amphotericin B were the most active agents against the Mucorales. Among the less common moulds, several expressed a pan-azole-resistant phenotype; many of these species also showed elevated MIC values (MIC, >2 mg/L) for amphotericin B and caspofungin. Although most isolates of Aspergillus spp. remain WT to the azoles, azole resistance is increasing in both North America and Europe. Amphotericin B and caspofungin exhibit potentially useful activity against azole-resistant A. fumigatus.

Topics: Amphotericin B; Antifungal Agents; Aspergillus; Azoles; Caspofungin; Drug Resistance, Fungal; Fungi; Itraconazole; Microbial Sensitivity Tests; Voriconazole

The dimorphic fungus Sporothrix globosa is the predominant etiologic agent causing sporotrichosis in China, particularly in the northeast. It has been demonstrated that the incubation temperature and growth phase can influence in vitro antifungal susceptibility profiles of S. schenckii sensu stricto and S. brasiliensis (sibling species of S. globosa). Few studies have reported on the antifungal susceptibility of S. globosa, especially using large numbers of isolates. In this study, we assessed the susceptibility of 80 isolates of S. globosa originating from Jilin Province, northeastern China, to six antifungal agents (itraconazole, terbinafine, voriconazole, posaconazole, fluconazole, and amphotericin B), at varying incubation temperatures and in different fungal growth phases. The isolates were most sensitive to terbinafine (geometric mean [GM] of the minimum inhibitory concentration [MIC]: 0.0356 μg/ml for the mycelial phase at 30 °C, 0.0332 μg/ml for the mycelial phase at 35 °C, and 0.031 μg/ml for the yeast phase, respectively), followed by posaconazole (GM of the MIC: 4.2501 μg/ml for the mycelial phase at 30 °C, 1.4142 μg/ml for the mycelial phase at 35 °C, and 0.7195 μg/ml for the yeast phase, respectively) and itraconazole (GM of the MIC: 6.8448 μg/ml for the mycelial phase at 30 °C, 3.1383 μg/ml for the mycelial phase at 35 °C, and 1.0263 μg/ml for the yeast phase, respectively). The isolates were relatively resistant to fluconazole (GM of the MIC: 76.7716 μg/ml for the mycelial phase at 30 °C, 66.2570 μg/ml for the mycelial phase at 35 °C, and 24.4625 μg/ml for the yeast phase, respectively) and voriconazole (GM of the MIC: 26.2183 μg/ml for the mycelial phase at 30 °C, 13.6895 μg/ml for the mycelial phase at 35 °C, and 1.3899 μg/ml for the yeast phase, respectively). For all the tested azole drugs, the MICs at 30 °C were significantly higher than those at 35 °C (P < 0.001); for all agents except terbinafine, the MICs of S. globosa in the yeast phase were significantly lower than those of the strains in the mycelial phase (P < 0.001). These results show that the sensitivities of S. globosa to antifungal compounds are dependent on incubation temperature and growth phase. To the best of our knowledge, this is the largest study of antifungal susceptibility of S. globosa isolates reported to date. To establish epidemiological cutoff values for S. globosa, further antifungal susceptibility testing studies by independent laboratories located in differ

Topics: Amphotericin B; Antifungal Agents; China; Fluconazole; Humans; Itraconazole; Microbial Sensitivity Tests; Mycelium; Phylogeny; Saccharomyces cerevisiae; Sporothrix; Sporotrichosis; Terbinafine; Triazoles

The emergence of azole resistance in non-fumigatus Aspergillus strains is on the raise.. To study the susceptibility profiles and the molecular mechanisms of azole resistance of environmental and clinical strains of Aspergillus flavus from Argentina.. Thirty-five A flavus isolates (18 from soybean seeds and chickpea seeds and 17 from the clinic) were analysed for amphotericin B and azole resistance using the standard microbroth dilution method according to CLSI M38-A2 guidelines. Sequencing analysis of the cyp51 genes was conducted in those isolates displaying high MICs values to itraconazole, voriconazole and/or posaconazole.. Among the environmental isolates, 33.3% of them showed high MIC values for at least one triazole whereas 23.5% of the clinical isolates displayed high MIC values for amphotericin B. Point mutations in the Cyp51C gene were recorded in most environmental isolates with non-wild-type MIC values.. Susceptibility differences among environmental A flavus isolates might suggest the possibility of native resistance to certain triazole antifungals used in the clinic. To the best of our knowledge, this is the first report of antifungal screening of environmental strains of A flavus in soybean seeds and chickpea seeds from Argentina that showed increased resistance to voriconazole and itraconazole in comparison to clinical strains.

Topics: Amphotericin B; Antifungal Agents; Argentina; Aspergillosis; Aspergillus flavus; Cytochrome P450 Family 51; Drug Resistance, Fungal; Environmental Microbiology; Environmental Monitoring; Genes, Fungal; Humans; Itraconazole; Microbial Sensitivity Tests; Mutation; Triazoles; Voriconazole

Mucorales are opportunistic pathogens that can cause life-threatening diseases predominantly in immunocompromised patients.. This study aimed to investigate the frequency, seasonal variation and antifungal susceptibility of pathogenic Mucorales in the soil collected from seven hospitals in Urmia, Iran, between November 2017 and July 2018 in four different seasons.. Mucorales isolates obtained from soil were characterised based on conventional and molecular assays. In addition, in vitro antifungal susceptibility was performed using the CLSI M38Ed3 procedure.. Out of 196 tested soil samples, 80 (40.8%) samples were positive for mucoralean fungi. Rhizopus arrhizus var. arrhizus (n = 47) was the most frequent species followed by Mucor circinelloides (n = 21) and Cunninghamella echinulata (n = 6). A seasonal variation in the frequency of Mucorales in soil was detected with a maximum of culture-positive soil samples detected in wet autumn (43.2%) followed by winter (23.4%), summer (19.7%) and spring (13.6%). In vitro antifungal susceptibility testing for 80 environmental isolates exhibited MIC of ≤2 μg/ml for amphotericin B indicating the smallest range of MIC variation among the tested Mucorales (range: 0.125-2 μg/ml). Among the azoles, posaconazole was the most effective antifungals (GM MIC, 0.724 μg/ml).. We considered associations of species and seasonal frequencies between soil mucoralean fungi and mucormycosis. The effect of opportunistic Mucorales dominating in the soil and prevalent causative agents of mucormycosis in Iran reported in the literatures but more comprehensive studies are needed to confirm this conclusion.

Topics: Amphotericin B; Antifungal Agents; Cunninghamella; Hospitals; Humans; Iran; Microbial Sensitivity Tests; Mucor; Mucorales; Mucormycosis; Opportunistic Infections; Rhizopus; Seasons; Soil; Soil Microbiology; Triazoles

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

The aim of the study was to report clinical features, contributing factors and outcome of patients with coronavirus disease 2019 (COVID-19)-associated mucormycosis (CAM).. A cross-sectional descriptive multicentre study was conducted on patients with biopsy-proven mucormycosis with RT-PCR-confirmed COVID-19 from April to September 2020. Demographics, the time interval between COVID-19 and mucormycosis, underlying systemic diseases, clinical features, course of disease and outcomes were collected and analysed.. Fifteen patients with COVID-19 and rhino-orbital mucormycosis were observed. The median age of patients was 52 years (range 14-71), and 66% were male. The median interval time between COVID-19 disease and diagnosis of mucormycosis was seven (range: 1-37) days. Among all, 13 patients (86%) had diabetes mellitus, while 7 (46.6%) previously received intravenous corticosteroid therapy. Five patients (33%) underwent orbital exenteration, while seven (47%) patients died from mucormycosis. Six patients (40%) received combined antifungal therapy and none that received combined antifungal therapy died.. Clinicians should be aware that mucormycosis may be complication of COVID-19 in high-risk patients. Poor control of diabetes mellitus is an important predisposing factor for CAM. Systematic surveillance for control of diabetes mellitus and educating physician about the early diagnosis of CAM are suggested.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Caspofungin; Coinfection; Comorbidity; COVID-19; COVID-19 Drug Treatment; Cross-Sectional Studies; Diabetes Complications; Diabetes Mellitus; Drug Therapy, Combination; Female; Humans; Iran; Male; Middle Aged; Mucormycosis; Respiratory Distress Syndrome; Triazoles; Young Adult

There is a worldwide concern regarding the antimicrobial resistance and the inappropriate use of antifungal agents, which had led to an ever-increasing antifungal resistance. This study aimed to identify the antifungal susceptibility of colonized Candida species isolated from pediatric patients with cancer and evaluate the clinical impact of antifungal stewardship (AFS) interventions on the antifungal susceptibility of colonized Candida species. Candida species colonization was evaluated among hospitalized children with cancer in a tertiary teaching hospital, Shiraz 2017-2018. Samples were collected from the mouth, nose, urine, and stool of the patients admitted to our center and cultured on sabouraud dextrose agar. The isolated yeasts identified by polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP). DNA Extracted and PCR amplification was performed using the ITS1 and ITS4 primer pairs and Msp I enzyme. The broth microdilution method was used to determine the minimum inhibitory concentrations (MICs) for amphotericin B, caspofungin, and azoles. The prevalence of Candida albicans in the present study was significantly higher than other Candida species. Candida albicans species were completely susceptible to the azoles. The susceptibility rate of C. albicans to amphotericin B and caspofungin was 93.1% and 97.1%, respectively. The fluconazole MIC values of Candida albicans decreased significantly during the post-AFS period (P < 0.001; mean difference: 72.3; 95% CI of the difference: 47.36-98.62). We found that ‏52.5% (53/117) of the isolated C. albicans were azole-resistant before AFS implementation, while only 1.5% (2/102) of the isolates were resistant after implementation of the AFS program (P < 0.001). C. albicans fluconazole and caspofungin resistant rate also decreased significantly (P < 0.001) after implementation of the AFS program [26 (32.9%) versus 0 (0.0%) and 11 (10.9%) versus 1 (0.9%), respectively]. Besides, fluconazole use (p < 0.05) and fluconazole expenditure reduced significantly (about one thousand US$ per year) after the AFS program. Our results confirm the positive effect of optimized antifungal usage and bedside intervention on the susceptibility of Candida species after the implementation of the AFS program. C. albicans and C. glabrata exhibited a significant increase in susceptibility after the execution of the AFS program.

Topics: Adolescent; Amphotericin B; Antifungal Agents; Antimicrobial Stewardship; Candida; Caspofungin; Child; Child, Preschool; Colony Count, Microbial; Disease Susceptibility; Drug Resistance, Fungal; Female; Fluconazole; Humans; Male; Microbial Sensitivity Tests; Neoplasms; Triazoles

A 5-year-old patient treated for acute lymphoblastic leukaemia (ALL) developed proven pulmonary invasive fungal disease (IFD) due to Actinomucor elegans. While completing ALL treatment according to AIEOP ALL protocol 2009 for further 15 months, antifungal treatment with liposomal amphotericin B and intermittent additional posaconazole was continued until immune reconstitution 7 months after the end of ALL treatment. Repeated imaging guided treatment decisions. Twenty-six and 19 months after the end of ALL treatment and antifungal treatment, respectively, the patient is still in the first complete remission and shows no signs of active invasive fungal disease (IFD).

Topics: Amphotericin B; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Humans; Invasive Fungal Infections; Lung Diseases, Fungal; Male; Mercaptopurine; Methotrexate; Mucorales; Mucormycosis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Remission Induction; Triazoles; Vincristine

Topics: Adult; Amphotericin B; Antifungal Agents; Debridement; Drug Substitution; Humans; Male; Mouth Diseases; Mucormycosis; Nose Diseases; Orbital Diseases; Palate; Pancytopenia; Triazoles

A case of fungal keratitis due to Coprinellus radians is reported. To our knowledge, fungal keratitis caused by this species was rare. Fungal hyphae were detected in corneal scrapings, and isolates were identified by morphology and by sequencing the internal transcribed spacer region of ribosomal DNA. The patient was treated with systemic and local antifungal therapy for 5 days, and lamellar keratoplasty was performed after no obvious improvement in symptoms. The in vitro antifungal susceptibilities of the case strain were tested for six antifungal agents. The results showed that 5-fluorouracil was resistant, fluconazole was moderately sensitive, and the other drugs assayed (amphotericin B, posaconazole, itraconazole and voriconazole) were highly effective against this fungus.

Topics: Agaricales; Amphotericin B; Antifungal Agents; Corneal Transplantation; Corneal Ulcer; DNA, Fungal; DNA, Ribosomal Spacer; Eye Infections, Fungal; Female; Humans; Hyphae; Keratitis; Microbial Sensitivity Tests; Middle Aged; Triazoles

Cerebral abscess due to pigmented molds is a rare but usually fatal infection occasionally seen in transplant recipients. A 67-year-old man of Iraqi origin underwent a deceased donation renal transplant for renal failure and 2 months later was diagnosed with an abscess in the left posterior frontal lobe of his brain. Subsequent biopsy proved this to be due to the mold Rhinocladiella mackenziei. Further interventions included two operations to aspirate the lesion, voriconazole, then liposomal amphotericin B, then a combination of posaconazole and flucytosine which he continued for over 4 years. He also suffered from right ankle pain and was diagnosed with septic arthritis; R mackenziei was isolated from pus aspirated from the ankle joint. He responded well to the treatment and has had little loss of function, and on CT, the cerebral lesion has stabilized. Beta-D-glucan, initially at very high levels proved useful to monitor response over the 5 years and the latest sample was negative (38 pg/mL). This case is notable for the first disseminated case of this infection, its favorable outcome on a novel antifungal combination and a new approach to monitoring the course of disease.

Topics: Aged; Amphotericin B; Antifungal Agents; Arthritis, Infectious; Ascomycota; Brain Abscess; Central Nervous System Fungal Infections; Humans; Immunocompromised Host; Invasive Fungal Infections; Kidney Transplantation; Male; Treatment Outcome; Triazoles

Posaconazole is a triazole antifungal with activity against Rhizopus, but data on its use and pharmacokinetics in preterm infants are scarce. In this case, a 24 4/7-week neonate's Rhizopus infection is successfully treated with debridement and combination antifungal therapy with amphotericin B, micafungin and enteral posaconazole. This is the first reported posaconazole use in a preterm neonate with Rhizopus.

Topics: Amphotericin B; Antifungal Agents; Drug Therapy, Combination; Humans; Infant, Newborn; Infant, Premature; Male; Micafungin; Microbial Sensitivity Tests; Mucormycosis; Rhizopus; Triazoles

Topics: Amphotericin B; Antifungal Agents; Humans; Mucormycosis; Triazoles

Some species of fusaria are well-known pathogens of humans, animals and plants.

Topics: Amphotericin B; Antifungal Agents; Drug Resistance, Fungal; Fungal Proteins; Fusarium; Gene Expression Regulation, Bacterial; Reproducibility of Results; Species Specificity; Transcriptome; Triazoles

Mucormycosis is one of the most complicated to diagnose and treat invasive fungal diseases. Diagnostic techniques have not significantly advanced in years, and recent international consensus treatment guidelines offer some insight into the current best approaches to treating this deadly invasive mold.

Topics: Amphotericin B; Antifungal Agents; Biopsy; Child; Debridement; Humans; Immunocompromised Host; Invasive Fungal Infections; Mucorales; Mucormycosis; Salvage Therapy; Tomography, X-Ray Computed; Triazoles

Mucormycosis is an invasive mould that can cause aggressive infection, particularly in immunocompromised patients. Though oesophageal mucormycosis is relatively rare, it remains an elusive and devastating manifestation of this disease. The management is also challenging, due to surgical morbidity and contraindications such as thrombocytopenia in immunocompromised hosts. In this report, we present the case of a 60-year-old Lebanese man with newly diagnosed acute myeloid leukaemia who developed oesophageal mucormycosis after induction chemotherapy with idarubicin/cytarabine (7+3). The diagnosis was made when the patient developed febrile neutropenia and odynophagia. CT scan of the chest revealed a thickened oesophagus. Oesophagogastroduodenoscopy with biopsy, histopathology and PCR were performed, resulting in the diagnosis of

Topics: Amphotericin B; Antifungal Agents; Cytarabine; Esophageal Diseases; Esophagus; Humans; Idarubicin; Immunocompromised Host; Induction Chemotherapy; Leukemia, Myeloid, Acute; Male; Middle Aged; Mucormycosis; Rhizopus; Triazoles

Luliconazole is an imidazole antifungal agent used in topical form for the treatment of onychomycosis and dermatophytosis. In vitro activity of luliconazole against dermatophytes, Candida, black fungi, Fusarium and Aspergillus species have been investigated. Rhodotorula spp. are environmental yeasts and emerged as opportunistic pathogens among immunocompromised patients. Rhodotorula's human infections are usually resistant to treatment with antifungal drugs especially triazoles and echinocandins. The present study aimed at the molecular detection of environmental isolates of Rhodotorula spp. Then, antifungal efficacy of luliconazole was evaluated against isolates and compared to other routine systemic antifungals including; caspofungin, posaconazole, fluconazole, itraconazole, amphotericin B, and voriconazole. The biofilm production of Rhodotorula isolates was also evaluated. In this study, 39 isolates of Rhodotorula spp. were isolated from the environment, detected using molecular methods, and tested against luliconazole. Then, the anti-fungal activity of luliconazole compared with several routine antifungals. Also, biofilm formation by using a crystal violet staining assay was performed. Our finding showed that luliconazole has a very high minimum inhibitory concentration (MIC) value (1-8 µg/ml) against Rhodotorula spp. Besides, 100% of Rhodotorula strains were resistant to caspofungin, followed by fluconazole 94.7% and voriconazole 74.4%. Amphotericin B was demonstrated excellent in vitro activity against this genus. Our result indicated that 59% of Rhodotorula spp. were in the mid-range of biofilm production. Our results indicated that luliconazole does not effective against the genus Rhodotorula. Furthermore, amphotericin B is the best drug against this genus in comparison to caspofungin and other azole drugs.

Topics: Amphotericin B; Antifungal Agents; Biofilms; Caspofungin; DNA, Fungal; DNA, Ribosomal Spacer; Fluconazole; Humans; Imidazoles; Itraconazole; Microbial Sensitivity Tests; Phylogeny; Rhodotorula; Species Specificity; Triazoles; Voriconazole

Topics: Amphotericin B; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; Blood-Brain Barrier; Brain; Cryptococcus neoformans; Dibenzocycloheptenes; Diketopiperazines; Disease Models, Animal; Heterocyclic Compounds, 4 or More Rings; Humans; Male; Meningitis, Cryptococcal; Mice; Molecular Docking Simulation; Quinolines; Serum Albumin; Tissue Distribution; Triazoles

Pemphigus vulgaris is an autoimmune disease that mostly affects the mucosa and oral cavity. Candida species can invade the mucosal lesions of these patients and cause diseases. The aim of this study was to identify the fungal agents isolated from mucosal lesions and evaluate antifungal activity profile against the isolates. A total of 25 patients with pemphigus vulgaris with active oral lesions and 25 healthy people serving as a control group were included in this study. Identification of the fungal isolates was performed based on conventional methods and DNA sequence analysis of the internal transcribed spacer (ITS) rDNA gene region. The sequence results were deposited in the NCBI database using the Basic Local Alignment Search Tool. Antifungal activity of fluconazole, itraconazole, ketoconazole, posaconazole, econazole, and amphotericin B against the isolates were evaluated based on the CLSI M-44 A protocol. Oral candidiasis was detected in 20% of the patients. Candida species isolated from oral lesions of patients with pemphigus were identified as Candida albicans 22/25, Candida glabrata 2/25, and Candida dubliniensis 1/25. All of the isolates were sensitive to amphotericin and econazole, 96% to fluconazole and posaconazole, and 92% to ketoconazole and itraconazole. One patient showed a profile resistant to fluconazole, posaconazole, and ketoconazole, simultaneously. Ninety six percent of control group isolates were sensitive to six antifungals. Candida albicans was the most prevalent species isolated from oral lesions of patients with pemphigus vulgaris and the control group. Amphotericin B and econazole were the most effective antifungals against the isolates.

Topics: Adult; Amphotericin B; Antifungal Agents; Candida; Candidiasis, Oral; Disk Diffusion Antimicrobial Tests; Econazole; Female; Fluconazole; Humans; Itraconazole; Ketoconazole; Male; Pemphigus; Triazoles

Topics: Amphotericin B; Antifungal Agents; Drug Resistance, Fungal; Fluconazole; Fungi; Humans; Itraconazole; Microbial Sensitivity Tests; Mycoses; Triazoles; Voriconazole

Surgical-site mucormycosis infections in solid-organ transplant recipients are rare conditions, with only 15 previously reported cases. We describe a case of a 49-year-old man who received a liver transplant due to alcoholic cirrhosis. On postoperative day 14, necrosis was noticed at the surgical site. After mucormycosis was diagnosed, monotherapy with amphotericin was started along with surgical debridements. Due to continued clinical deterioration, triple antifungal therapy was started with amphotericin, micafungin and posaconazole. Treatment with a granulocyte-macrophage colony-stimulating factor was also started. Despite therapy, the patient expired on postoperative day 31. We review the risk factors for mucormycosis infection in solid-organ transplant recipients as well as evidence for current treatment options. We also review the 15 previously reported cases of surgical-site mucormycosis infections in solid-organ transplant recipients, including time to infection, infecting organisms, mortality and treatments.

Topics: Amphotericin B; Antifungal Agents; Debridement; Fatal Outcome; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Mucormycosis; Shock, Septic; Surgical Wound Infection; Transplant Recipients; Triazoles

Mucorales can cause cutaneous to deep-seated infections, mainly in the immunocompromised host, resulting in high mortality rates due to late and inefficient treatment. In this study, Galleria mellonella larvae were evaluated as a heterologous invertebrate host to study pathogenicity of clinically relevant mucormycetes (Rhizopus spp., Rhizomucor spp., Lichtheimia spp., Mucor spp.). All tested species were able to infect G. mellonella larvae. Virulence potential was species-specific and correlated to clinical relevance. Survival of infected larvae was dependent on (a) the species (growth speed and spore size), (b) the infection dose, (c) the incubation temperature, (d) oxidative stress tolerance, and (e) iron availability in the growth medium. Moreover, we exploited the G. mellonella system to determine antifungal efficacy of liposomal amphotericin B, posaconazole, isavuconazole, and nystatin-intralipid. Outcome of in vivo treatment was strongly dependent upon the drug applied and the species tested. Nystatin-intralipid exhibited best activity against Mucorales, followed by posaconazole, while limited efficacy was seen for liposomal amphotericin B and isavuconazole. Pharmacokinetic properties of the tested antifungals within this alternative host system partly explain the limited treatment efficacy. In conclusion, G. mellonella represents a useful invertebrate infection model for studying virulence of mucormycetes, while evaluation of treatment response was limited.

Topics: Amphotericin B; Animals; Antifungal Agents; Disease Models, Animal; Drug Resistance, Fungal; Larva; Lepidoptera; Microbial Sensitivity Tests; Mucor; Mucorales; Mucormycosis; Nitriles; Pyridines; Rhizopus; Triazoles; Virulence

Mucormycosis is a rare fungal infection often seen in immunocompromised hosts. Isolated renal mucormycosis may however present in immunocompetent children as renal failure and has a uniformly poor prognosis if not detected and treated early into the course of illness. We present a 3-year-old boy with unrelenting pyelonephritis in whom serial urine cultures done were negative. A final diagnosis of isolated renal mucormycosis was made by magnetic resonance imaging and renal biopsy.

Topics: Abdominal Pain; Amphotericin B; Antifungal Agents; Child, Preschool; Dialysis; Fever; Humans; Kidney; Kidney Failure, Chronic; Magnetic Resonance Imaging; Male; Mucorales; Mucormycosis; Pyelonephritis; Treatment Outcome; Triazoles; Urinary Tract Infections; Vomiting

Naegleria fowleri is the causative agent of primary amoebic meningoencephalitis (PAM), which is fatal in >97% of cases. In this study, we aimed to identify new, rapidly acting drugs to increase survival rates. We conducted phenotypic screens of libraries of Food and Drug Administration-approved compounds and the Medicines for Malaria Venture Pathogen Box and validated 14 hits (defined as a 50% inhibitory concentration of <1 μM). The hits were then prioritized by assessing the rate of action and efficacy in combination with current drugs used to treat PAM. Posaconazole was found to inhibit amoeba growth within the first 12 hours of exposure, which was faster than any currently used drug. In addition, posaconazole cured 33% of N. fowleri-infected mice at a dose of 20 mg/kg and, in combination with azithromycin, increased survival by an additional 20%. Fluconazole, which is currently used for PAM therapy, was ineffective in vitro and vivo. Our results suggest posaconazole could replace fluconazole in the treatment of PAM.

Topics: Amphotericin B; Animals; Antiprotozoal Agents; Azithromycin; Central Nervous System Protozoal Infections; Disease Models, Animal; Drug Combinations; Drug Discovery; Drug Synergism; Female; Fluconazole; Humans; Inhibitory Concentration 50; Mice; Naegleria fowleri; Phenotype; Time Factors; Triazoles; United States; United States Food and Drug Administration

Despite the availability of new antifungal compounds, invasive aspergillosis carries high morbidity and mortality in hematopoietic stem cell transplant recipients.

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Cell Survival; Deoxycholic Acid; Doxorubicin; Drug Combinations; Fluconazole; Humans; Killer Cells, Natural; Microbial Sensitivity Tests; Polyethylene Glycols; Triazoles; Voriconazole

Topics: Aminopyridines; Amphotericin B; Animals; Antifungal Agents; Coccidioides; Disease Models, Animal; Female; Fluconazole; Isoxazoles; Mice; Mice, Inbred C57BL; Microbial Sensitivity Tests; Pneumonia; Prodrugs; Triazoles

To report the frequency and factors affecting patients', globe and vision survivals in rhino-orbito-cerebral mucormycosis (ROCM).. This is a retrospective study of 63 patients (79 eyes) with biopsy-proven ROCM at a university hospital 2008-2016. Systemic and ophthalmic manifestations, imaging, management and final outcomes were recorded. Globe survival was defined as no exenteration and vision survival as final visual acuity of light perception and more.. Mean age was 55.5 (SD 12.9) years with no gender preference. Diabetes was the most common underlying disease (68.3%). Patient survival was observed in 57.1 % (36/63). Presence of frozen eye (OR 4.6), nasal mucosal involvement (OR 7.3) and shorter duration of antifungal therapy (OR 1.03) were significantly associated with lower patient survival. Exenteration did not significantly change the survival. Globe survival was detected in 43% (34/79). Higher white blood cell (WBC) count was associated with a lower globe survival (p=0.02). Vision survival was observed in 25.3% (20/79) in whom younger age was significantly associated with a worse vision survival.. Patient, globe and vision survivals were 57%, 43% and 25%, respectively. Exenteration did not affect the patients' survival. While frozen eye and nasal mucosal involvement were significantly associated with a lower survival, higher WBC count significantly increased the risk of exenteration.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Brain Diseases; Combined Modality Therapy; Debridement; Deoxycholic Acid; Eye Infections, Fungal; Female; Humans; Male; Middle Aged; Mucormycosis; Natural Orifice Endoscopic Surgery; Orbital Diseases; Paranasal Sinus Diseases; Retrospective Studies; Treatment Outcome; Triazoles; Young Adult

Mucormycosis is an aggressive invasive fungal infection that occurs rarely in immunocompetent but frequently in immunocompromised patients. We present a case of a 68-year-old patient with cutaneous mucormycosis due to Rhizopus pusillus. He was initially hospitalized for invasive pulmonary aspergillosis and diabetes mellitus secondary to acute graft-versus-host treatment with glucocorticoids after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia. Treatment with liposomal amphotericin B and posaconazole was initiated but the patient developed septic shock with multiple organ failure and died 5 days later. The risk factors, clinical presentation, treatment, and prognosis of cutaneous mucormycosis in hematopoietic stem cell and solid organ transplant patients are discussed.

Topics: Aged; Amphotericin B; Antifungal Agents; Fatal Outcome; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Invasive Fungal Infections; Male; Mucormycosis; Multiple Organ Failure; Rhizopus; Shock, Septic; Skin; Triazoles

Candida albicans is the most frequently isolated fungal species in hospital settings worldwide. However, non-albicans Candida species with decreased susceptibility to antifungals have emerged as an important cause of fungemia. The aims of this study were to determine the species distribution of fungi isolated from the blood samples of patients at a Swedish University Hospital and to define the in vitro susceptibilities of these isolates to nine antifungal agents. In total, 233 yeast isolates from 143 patients were included in this study. Antifungal susceptibility testing was performed using broth dilution Sensititre YeastOne panels, which comprised amphotericin B, 5-flucytosine, fluconazole, itraconazole, voriconazole, posaconazole, anidulafungin, micafungin, and caspofungin. The most common species in all age groups was C. albicans (n = 93, 65%), followed by C. glabrata (n = 27, 19%) and C. parapsilosis (n = 15, 10%). C. glabrata was mostly found in elderly individuals, while C. parapsilosis was found mainly in young children (p = 0.008). Antifungal resistance was low in the Candida species, except for reduced susceptibility to fluconazole among C. glabrata strains. C. albicans is the most frequent colonizer of Swedish patients. In general antifungal resistance is uncommon in Candida species. Nevertheless, reduced susceptibilities to fluconazole and echinocandins were found in C. glabrata and C. parapsilosis, respectively.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Anidulafungin; Antifungal Agents; Candida; Candida albicans; Candida glabrata; Candida parapsilosis; Candidemia; Caspofungin; Child; Child, Preschool; Female; Fluconazole; Flucytosine; Humans; Itraconazole; Male; Micafungin; Microbial Sensitivity Tests; Middle Aged; Triazoles; Voriconazole; Young Adult

Pulmonary coinfection with Mucor and Aspergillus species has not been reported in organ transplant recipients. Here, we report a rare case of pulmonary coinfection with invasive fungal species in a renal transplant recipient with delayed graft function. The patient was first treated with a regime containing voriconazole, but the infection only worsened. Then, bronchoalveolar lavage fluid culture and internal transcribed spacer region sequencing were performed, and simultaneous pulmonary infection by Lichtheimia ramosa and Aspergillus fumigatus was clearly diagnosed. Susceptibility testing determined that the fungi were sensitive to amphotericin B and posaconazole. Therefore, a therapeutic regime containing posaconazole and amphotericin B liposome, which are less toxic to the kidney, was planned and resulted in resolution of the infectious symptoms. The present case demonstrates the importance of identifying fungal pathogens early and definitively, determining the effective anti-fungal medications, and administering the properly planned therapeutic regime in a timely manner to treat cases of coinfection in transplant recipients.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Coinfection; Delayed Graft Function; Humans; Immunocompromised Host; Kidney Transplantation; Male; Mucorales; Mucormycosis; Respiratory Tract Infections; Triazoles

Mucormycosis is an emerging disease with high mortality rates. Few antifungal drugs are active against Mucorales. Considering the low efficacy of monotherapy, combination-therapy strategies have been described. It is known that fungi are susceptible to zinc deprivation, so we tested the

Topics: Amphotericin B; Antifungal Agents; Chelating Agents; Clioquinol; Microbial Sensitivity Tests; Mucorales; Phenanthrolines; Triazoles; Zinc

There is a growing body of evidence for immunomodulatory side effects of antifungal agents on different immune cells, e.g., T cells. Therefore, the aim of our study was to clarify these interactions with regard to the effector functions of polymorphonuclear neutrophils (PMN). Human PMN were preincubated with fluconazole (FLC), voriconazole (VRC), posaconazole (POS), isavuconazole (ISA), caspofungin (CAS), micafungin (MFG), conventional amphotericin B (AMB), and liposomal amphotericin B (LAMB). PMN then were analyzed by flow cytometry for activation, degranulation, and phagocytosis and by dichlorofluorescein assay to detect reactive oxygen species (ROS). Additionally, interleukin-8 (IL-8) release was measured by enzyme-linked immunosorbent assay. POS led to enhanced activation, degranulation, and generation of ROS, whereas IL-8 release was reduced. In contrast, ISA-pretreated PMN showed decreased activation signaling, impaired degranulation, and lower generation of ROS. MFG caused enhanced expression of activation markers but impaired degranulation, phagocytosis, generation of ROS, and IL-8 release. CAS showed increased phagocytosis, whereas degranulation and generation of ROS were reduced. AMB led to activation of almost all effector functions besides impaired phagocytosis, whereas LAMB did not alter any effector functions. Independent from class, antifungal agents show variable influence on neutrophil effector functions

Topics: Amphotericin B; Antifungal Agents; Interleukin-8; Neutrophils; Nitriles; Phagocytosis; Pyridines; Triazoles; Voriconazole

Mucormycosis represents a real challenge in immunocompromised patients. This study aimed to describe the clinical characteristics, treatment outcome and infection-related mortality in our patients at the Children's Cancer Hospital 57357, Cairo, Egypt. This is a retrospective study during the period 2007-2017. Data analysis included demographic data, risk factors, diagnostic workup, treatment and outcome. During the study period, 45 patients developed proven mucormycosis according to EORTC/MSG criteria (2008). Ninety percentof cases were of haematological malignancies. Liposomal amphotericin B was the mainstay of treatment. Posaconazole was used as secondary prophylaxis in 35% of cases. Combination antifungal was used in three cases with progressive mucormycosis. Surgical intervention was achievable in 50% of cases. Therapy was successful in 35 patients (66%). Complications related to mucormycosis were seen in five cases with disfigurement and perforated hard palate. Chemotherapy delay with subsequent relapse of primary malignancy was reported in one case. Mucormycosis-related mortality was 33% (15 cases). Mucormycosis is a major cause of mortality among patients with haematological malignancies. Early diagnosis of Mucormycosis infection, with rapid initiation of appropriate antifungal therapy and surgical intervention, whenever feasible, is the backbone of mucormycosis treatment.

Topics: Adolescent; Amphotericin B; Antifungal Agents; Cancer Care Facilities; Child; Child, Preschool; Egypt; Female; Hematologic Neoplasms; Hospitals, Pediatric; Humans; Immunocompromised Host; Male; Mucormycosis; Neoplasms; Opportunistic Infections; Retrospective Studies; Risk Factors; Treatment Outcome; Triazoles

Topics: Adult; Amphotericin B; Antifungal Agents; Cavernous Sinus Thrombosis; Debridement; Delayed Diagnosis; Diabetes Complications; Humans; Magnetic Resonance Imaging; Male; Mucormycosis; Ophthalmoplegia; Opportunistic Infections; Orbit Evisceration; Orbital Cellulitis; Sinusitis; Triazoles

Recently, the species concept of opportunistic

Topics: Amphotericin B; Antifungal Agents; Humans; Itraconazole; Microbial Sensitivity Tests; Mucor; Mucormycosis; Natamycin; Nitriles; Pyridines; Rhizopus; Species Specificity; Terbinafine; Triazoles

MIC values for amphotericin B and three azoles determined by the EUCAST reference technique and by gradient concentration strips were compared for 30

Topics: Amphotericin B; Antifungal Agents; Azoles; Humans; Itraconazole; Microbial Sensitivity Tests; Mucorales; Nitriles; Pyridines; Triazoles

Invasive fungal infection (IFI) is a major cause of morbidity and mortality in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. A previous history of IFI is not an absolute contraindication for allo-HSCT, particularly in the era of secondary antifungal prophylaxis (SAP). Prompt diagnosis and therapy are essential for HSCT outcome.. The charts of 58 allo-HSCT recipients [median age:29.5 (16-62); M/F:41/17] who had a previous history of IFI were retrospectively reviewed.. Possible IFI was demonstrated in 32 (55.2%), probable in 13 (22.4%) and proven in 13 patients (22.4%). All patients received SAP [liposomal amphoterisin B (n ꞊ 35), voriconazole (n ꞊ 17), caspofungin (n ꞊ 2), posaconazole (n ꞊ 1), combination therapy (n = 3)] which was started on the first day of the conditioning regimen. Treatment success was better in the voriconazole group when compared to the amphotericin B arm (100% vs 69.2%; p = 0.029). Development of breakthrough IFI was more frequent in patients on amphotericin B prophylaxis (42.4% vs 23.1%; p = 0.036). Clinical and radiological response were achieved in 13 of 18 patients (72.2%) who developed breakthrough infection. Overall survival of the study population was 13.5% at a median follow-up of 154 (7-3285) days. Fungal mortality was found to be 23%. Overall survival was better in the voriconazole arm, without statistical significance (90% vs 65.8%, p > 0.05).. Secondary antifungal prophylaxis is considered to be an indispensible strategy in patients with pre-HSCT IFI history. Voriconazole seems to be a relatively better alternative despite an underlying necessity of larger prospective trials.

Topics: Adolescent; Adult; Allografts; Amphotericin B; Antibiotic Prophylaxis; Antifungal Agents; Caspofungin; Drug Therapy, Combination; Female; Hematopoietic Stem Cell Transplantation; Humans; Invasive Fungal Infections; Male; Middle Aged; Retrospective Studies; Treatment Outcome; Triazoles; Voriconazole; Young Adult

Recent years have seen important advances in the diagnosis of invasive pulmonary aspergillosis (IPA), complemented by the introduction of new therapies. Despite this, IPA remains a major cause of infection-related mortality in patients with haematological diseases. There are two main reasons for this. First, diagnosis of IPA remains a challenge, since risk factors and the clinical, radiological and mycological presentations vary not only by fungal disease stage, but also by patient group (eg neutropenic vs non-neutropenic patients). Diagnosis is particularly challenging in patients receiving mould-active prophylactic or empirical treatment, which reduces the sensitivity of all diagnostic tests for IPA. Second, treatment of IPA is complex due to unpredictable pharmacokinetic profiles of antifungal agents, small therapeutic window in terms of exposure and adverse events, and multiple drug-drug interactions through the CYP450 system. Here we report a case of a 23-year-old male with severe aplastic anaemia and subpleural nodules. Diagnostic tests for IPA obtained during ongoing mould-active empirical treatment were negative. Intravenous voriconazole was stopped after visual disturbances and hallucinations. The patient then had an anaphylactic reaction to liposomal amphotericin B and was switched to intravenous posaconazole, which had to be discontinued due to a significant increase in transaminase levels. He was treated with oral isavuconazole with reduced dosage, triggered by increasing transaminases under the standard dosage. Even under reduced dosage, blood concentrations of isavuconazole were high and treatment was successful. The case illustrates real-world challenges and unmet needs in the diagnosis and treatment of IPA in patients with haematological diseases.

Topics: Amphotericin B; Anemia, Aplastic; Antifungal Agents; Aspergillus; Hematologic Diseases; Humans; Invasive Pulmonary Aspergillosis; Male; Neutropenia; Nitriles; Pyridines; Transaminases; Treatment Outcome; Triazoles; Voriconazole; Young Adult

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

Endophthalmitis is a rare infection of the vitreous and/or aqueous. It can be bacterial or fungal. Exogenous endophthalmitis is the most common form and results from direct inoculation of a pathogen after eye surgery or penetrating trauma. Endophthalmitis can also be endogenous, secondary to disseminated infection. Fungal endophthalmitis is associated with poor prognosis and treatment is difficult given the low penetration of most of the antifungal agents available and the emergence of resistant filamentous fungi like Fusarium. To our knowledge, we describe the first endogenous fungal endophthalmitis due to Fusarium dimerum, a ubiquitous pathogen found in soil and plants. A 71-year-old woman, diagnosed with acute myeloid leukemia, was hospitalized for surveillance after induction chemotherapy. Prophylaxis by antibiotics and posaconazole was ongoing when she complained of pain and decreased vision in the left eye. A voluminous chorioretinal abscess developed and after multiple sterile aqueous humour samples, only vitrectomy allowed diagnosis with fungal hyphae seen on May-Grünwald Giemsa stained smear and positive cultures. The fungus was identified as Fusarium dimerum. The treatment, that included intravitreal injections of voriconazole and amphotericin B associated with systemic administration of voriconazole, allowed complete control of the infection. The source of this infection could not be confirmed despite the discovery of several possible infection sites including a periungual whitlow on the left hand and a lesion on a nail, from which samples were negative in microbiology laboratories. Unfortunately, damages of the retina were too important and the patient did not recover sight of her left eye.

Topics: Aged; Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Endophthalmitis; Eye; Female; Fusarium; Humans; Hyphae; Immunocompromised Host; Leukemia, Myeloid, Acute; Treatment Outcome; Triazoles; Vitrectomy; Voriconazole

Mucormycosis is a rare but fulminant opportunistic fungal infection, which occurs most often in diabetic and immunocompromised patients. Dental extractions may create a portal of entry for the fungal infection. The mucormycosis may be the original cause of the pain and can be misdiagnosed as dental pain. In this paper, two cases of mucormycosis are reported after dental extractions and successfully treated with amphotericin B (case #1) and combined with posaconazole (case #2). The two cases we describe exemplify the fulminant mucormycosis of maxillary sinuses after dental extraction inpatients with uncontrolled diabetic support the findings that this predisposing condition created a suitable environment for the Mucorales growth. These case reports emphasize early recognition and urgent treatment of mucormycosis is necessary to prevent the spread of infection Therefore, dental surgeons and healthcare practitioners should become familiar with mucormycosis.

Topics: Adult; Amphotericin B; Antifungal Agents; Diabetes Complications; Diabetes Mellitus; Female; Humans; Immunocompromised Host; Male; Maxillary Sinus; Middle Aged; Mucorales; Mucormycosis; Opportunistic Infections; Sinusitis; Tooth Extraction; Treatment Outcome; Triazoles

Topics: Aged; Amphotericin B; Antifungal Agents; Humans; Immunocompromised Host; Leukemia, Myeloid, Acute; Lung Diseases; Male; Mucormycosis; Nose Diseases; Pancytopenia; Treatment Outcome; Triazoles

Exophiala dermatitidis is a melanized fungus isolated from many environmental sources. Infections caused by Exophiala species are typically seen in immunocompromised hosts and manifest most commonly as cutaneous or subcutaneous disease. Systemic infections are exceedingly rare and associated with significant morbidity and mortality CASE PRESENTATION: A 28-year-old female originally from India presented with fevers, chills, weight loss and increasing back pain. She had a recent diffuse maculopapular rash that resulted in skin biopsy and a tentative diagnosis of sarcoidosis, leading to administration of azathioprine and prednisone. An MRI of her spine revealed a large paraspinal abscess requiring surgical intervention and hardware placement. Cultures from the paraspinal abscess grew a colony of dark pigmented mold. Microscopy of the culture revealed a melanized fungus, identified as Exophiala dermatitidis. Voriconazole was initially utilized, but due to relapse of infection involving the right iliac crest and left proximal humerus, she received a prolonged course of amphotericin B and posaconazole in combination and required 7 separate surgical interventions. Prolonged disease stability following discontinuation of therapy was achieved.. Described is the first identified case of disseminated Exophiala dermatitidis causing osteomyelitis and septic arthritis in a patient on immunosuppressive therapy. A positive outcome was achieved through aggressive surgical intervention and prolonged treatment with broad-spectrum antifungal agents.

Topics: Adult; Amphotericin B; Antifungal Agents; Arthritis, Infectious; Exophiala; Female; Humans; Immunocompromised Host; Magnetic Resonance Imaging; Osteomyelitis; Phaeohyphomycosis; Triazoles; Voriconazole

Invasive mold diseases (IMDs) are associated with significant morbidity and mortality. Approved treatments include voriconazole (VORI), liposomal amphotericin B (L-AMB), posaconazole (POSA) and isavuconazole (ISAV). A UK-based economic model was developed to explore the cost of treating IMDs with ISAV versus L-AMB followed by POSA.. As indirect comparisons have demonstrated similar efficacy between the comparators, a cost-minimization approach was taken. Drug acquisition, administration & monitoring, and hospitalization costs were evaluated from the healthcare system perspective.. Per-patient costs were UK£14,842 with ISAV versus UK£18,612 with L-AMB followed by POSA. Savings were driven by drug acquisition, and administration & monitoring costs.. ISAV has the potential to reduce IMD treatment costs relative to L-AMB followed by POSA.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Costs and Cost Analysis; Drug Costs; Health Care Costs; Humans; Models, Economic; Mucormycosis; Nitriles; Pyridines; Treatment Outcome; Triazoles; United Kingdom

Topics: Aged; Amphotericin B; Antifungal Agents; Debridement; Dermatomycoses; Humans; Male; Mucormycosis; Triazoles

Targeting lanosterol 14α-demethylase (LDM) with azole drugs provides prophylaxis and treatments for superficial and disseminated fungal infections, but cure rates are modest for immunocompromised patients and individuals with comorbidities. The efficacy of azole drugs has also been reduced due to the emergence of drug-resistant fungal pathogens. We have addressed these problems by expressing in

Topics: Amphotericin B; Antifungal Agents; Azoles; Candida albicans; Candida glabrata; Drug Resistance, Fungal; Ergosterol; Fluconazole; Fungal Proteins; Humans; Itraconazole; Lanosterol; Microbial Sensitivity Tests; Saccharomyces cerevisiae; Sterol 14-Demethylase; Triazoles; Voriconazole

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

Necrotizing fasciitis is a life-threatening, rapidly progressing infection of fascia and subcutaneous cellular tissue typically caused by mixed aerobic and anaerobic bacteria. We present a case report of an immunocompromised 4-year-old female with necrotizing fasciitis from a rare fungal organism, Mucor indicus. The patient underwent multiple debridements and was treated for 10 months, first on liposomal amphotericin B (2 months) then posaconazole (8 months). Mucor indicus is a rarely described pathogen with only nine other cases described. Identification of this organism remains a challenge, and the need for further understanding of risk factors and organism susceptibility testing to help guide treatment is crucial.

Topics: Amphotericin B; Bone Marrow Transplantation; Child, Preschool; Debridement; Fasciitis, Necrotizing; Female; Humans; Immunocompromised Host; Magnetic Resonance Imaging; Mucor; Risk Factors; Treatment Outcome; Triazoles

Idiopathic CD4 lymphocytopenia (ICL) is characterised by a low CD4 +lymphocyte count in the absence of HIV or other underlying aetiologies. We report a case of a 17-year-old girl with ICL with autoimmune hepatitis who developed isolated renal mucormycosis, which, to our knowledge, is the first reported case described in literature. Combination therapy with antifungals and surgical resection was done, and the patient improved. This case report illustrates the importance of timely multidisciplinary approach to recognise this highly fatal disease at an early stage.

Topics: Adolescent; Amphotericin B; Antifungal Agents; Combined Modality Therapy; Diagnosis, Differential; Female; Humans; Kidney; Kidney Diseases; Mucormycosis; T-Lymphocytopenia, Idiopathic CD4-Positive; Triazoles

Invasive fungal infections in solid organ transplant recipients are associated with significant morbidity and mortality. Of these fungal infections, mucormycosis presents as an aggressive, frequently fatal angioinvasive infection. Immunocompromised hosts and diabetes are important risk factors. These infections are frequently difficult to diagnose. A high index of suspicion in the appropriate setting and early, aggressive treatment with the newer antifungal agents have altered the previously grave prognosis. We present the first reported case of cavitating pulmonary mucormycosis in a renal transplant recipient caused by an unusual species of Mucorales. The patient was treated with a combination of lobectomy and antifungal treatment comprising of amphotericin B and posaconazole. He remains free of disease recurrence on monotherapy with posaconazole.

Topics: Amphotericin B; Antifungal Agents; Humans; Immunocompromised Host; Kidney Transplantation; Lung Diseases, Fungal; Male; Middle Aged; Mucorales; Mucormycosis; Transplant Recipients; Triazoles

The incidence of candidemia is increasing in developing countries. Very little is known about the epidemiology of candidemia in Peru. The aim of this study is to describe the incidence, microbiology, clinical presentation and outcomes of Candida bloodstream infections in three Lima-Callao hospitals.. Candida spp. isolates were identified prospectively at participant hospitals between November 2013 and January 2015. Susceptibility testing for amphotericin B, fluconazole, posaconazole, voriconazole and anidulafungin was performed using broth microdilution method. Clinical information was obtained from medical records and evaluated.. We collected information on 158 isolates and 157 patients. Median age of patients was 55.0 yrs., and 64.1% were males. Thirty-eight (24.2%) episodes of candidemia occurred in those <18 yrs. The frequency of non-Candida albicans was 72.1%. The most frequently recovered species were C. albicans (n = 44, 27.8%), C. parapsilosis (n = 40, 25.3%), C. tropicalis (n = 39, 24.7%) and C. glabrata (n = 15, 9.5%). Only four isolates were resistant to fluconazole, 86.7% (n = 137) were susceptible and 17 were susceptible-dose dependent. Decreased susceptibility to posaconazole was also observed in three isolates, and one to voriconazole. All isolates were susceptible to anidulafungin and amphotericin B. The most commonly associated co-morbid conditions were recent surgery (n = 61, 38.9%), mechanical ventilation (n = 60, 38.2%) and total parenteral nutrition (n = 57, 36.3%). The incidence of candidemia by center ranged between 1.01 and 2.63 cases per 1,000 admissions, with a global incidence of 2.04. Only 28.1% of cases received treatment within 72 hrs. of diagnosis. Overall, the 30-day survival was 60.4% (treated subjects, 67.4%; not-treated patients, 50.9%).. We found a very high proportion of non-albicans Candida species. Despite this, the decreased susceptibility/resistance to fluconazole was only 13.3% and not seen in the other antifungals. Overall, the incidence of candidemia mortality was high when compared to other international studies. It is possible, that the delay in initiating antifungal treatment contributed to the elevated mortality rate, in spite of low antifungal resistance.

Topics: Adolescent; Adult; Aged; Amphotericin B; Anidulafungin; Antifungal Agents; Candida; Candidemia; Child; Child, Preschool; Drug Resistance, Fungal; Echinocandins; Female; Fluconazole; Humans; Incidence; Infant; Kaplan-Meier Estimate; Male; Middle Aged; Multivariate Analysis; Peru; Prospective Studies; Triazoles; Voriconazole; Young Adult

Mucormycosis is a highly lethal fungal infection especially in immunocompromised individuals.. In order to review the epidemiology, diagnosis, and treatment of mucormycosis in renal transplant recipients we searched publications of mucormycosis cases in renal transplant recipients in PUBMED database up to December 2015.. A total of 174 cases in renal transplant recipients were included in this review. Most of the cases (76%) were male. Major underlying diseases were diabetes mellitus (43.1%). Rhinocerebral was the most common site of infection (33.3%). Rhizopus species was the most frequent fungus (59.1%) in patients with pathogen identified to species level. The mortality rates of disseminated mucormycosis (76.0%) and graft renal (55.6%) were higher than infection in other sites. The overall survival in patients received surgical debridement combined with amphotericin B/posaconazole (70.2%) was higher than those who received antifungal therapy alone (32.4%), surgery alone (36.4%) or without therapy (0%) (p < 0.001). The overall survivals in patients receiving posaconazole and lipid amphoterincin B were higher than that receiving deoxycholate formulation (92.3% and 73.4% vs 47.4%).. Mucormycosis is a severe infection in renal transplant recipients. Surgical debridement combined with antifungals, especially liposomal amphotericin B and posaconazole, can significantly improve patient's overall survival.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Child; Debridement; Deoxycholic Acid; Diabetes Mellitus; Female; Humans; Immunocompromised Host; Kidney Transplantation; Male; Middle Aged; Mucormycosis; Rhizopus; Transplant Recipients; Triazoles; Young Adult

Sporothrix brasiliensis is the most virulent sporotrichosis agent. This species usually responds to antifungal drugs, but therapeutic failure can occur in some patients. Antifungal susceptibility tests have been performed on this species, but no clinical breakpoints (CBPs) are available. In this situation, minimal inhibitory concentration (MIC) distributions and epidemiological cutoff values (ECVs) support the detection of identification of resistant strains.. To study the MIC distributions of five antifungal drugs against S. brasiliensis and to propose tentative ECVs.. MICs of amphotericin B (AMB), itraconazole (ITR), ketoconazole (KET), posaconazole (POS), and terbinafine (TRB) against 335 S. brasiliensis strains were determined by the Clinical and Laboratory Standards Institute broth microdilution method.. The proposed ECV, in µg/mL, for AMB, ITR, KET, POS, and TRB were 4.0, 2.0, 1.0, 2.0, and 0.25, respectively. Percentages of wild-type strains in our population for the above antifungal drugs were 98.48, 95.22, 95.33, 100, and 97.67%, respectively.. These ECVs will be useful to detect strains with resistance, to define CBPs, and to elaborate specific therapeutic guidelines for S. brasiliensis. Rational use of antifungals is strongly recommended to avoid the emergence of resistant strains and ensure the therapeutic effectiveness of sporotrichosis.

Topics: Amphotericin B; Animals; Antifungal Agents; Cats; Drug Resistance, Fungal; Humans; Itraconazole; Ketoconazole; Microbial Sensitivity Tests; Naphthalenes; Sporothrix; Terbinafine; Triazoles

Mucormycosis is one of the rapidly progressing and lethal form of fungal infection which involves the nose and paranasal sinuses of the head and the neck regions. Mucormycosis also remains a threat to patients with uncontrolled diabetes or other predisposing systemic conditions. It manifests as rhinocerebral, pulmonary, gastrointestinal, cutaneous or disseminated form. The underlying conditions can influence clinical presentation and often delay diagnosis, with resultant poor outcomes.. We report a case of rhinocerebral mucormycosis in a 75 year-old diabetic patient with emphasise on diagnosis, treatment and survival options of patient from this potentially fatal fungal infection. Extra oral examination revealed mild non-tender swelling on the face, unable to see from left eye, impaired sense of smell, difficulty in speech and nasal stuffiness. Intra-oral examination showed necrosis of mucosa and underlying bone in relation to canine to the tuberosity area of the left vestibular region of the maxilla.. Timely diagnosis is critical to survival and minimization of morbidity. Institution of surgical and medical therapy is critical in maximizing the likelihood of good outcome.

Topics: Aged; Amphotericin B; Antifungal Agents; Humans; Male; Mucormycosis; Necrosis; Paranasal Sinuses; Tomography, X-Ray Computed; Triazoles

An 81-year-old man from rural Australia presented with right pretibial cellulitis 7 days after minor trauma against furniture. He failed to improve despite antibiotics and surgical debridement. Subsequent cultures grew the rare fungus

Topics: Aged, 80 and over; Amphotericin B; Antifungal Agents; Australia; Debridement; Humans; Leg Injuries; Male; Mucormycosis; Soft Tissue Infections; Treatment Outcome; Triazoles

Patients with hematologic malignancies as well as allogeneic hematopoietic stem cell transplantation (HSCT) patients are at high risk for invasive aspergillosis. Here, we report a culture- and autopsy-proven fatal invasive aspergillosis in an allogeneic HSTC patient which he developed despite posaconazole prophylaxis. The agent was determined to be an azole-resistant

Topics: Aged; Alleles; Amphotericin B; Antifungal Agents; Aspergillus fumigatus; Azoles; Caspofungin; Cytochrome P-450 Enzyme System; Drug Resistance, Multiple, Fungal; Echinocandins; Fungal Proteins; Humans; Invasive Pulmonary Aspergillosis; Leukemia, Myeloid, Acute; Lipopeptides; Male; Microbial Sensitivity Tests; Mutation; Treatment Outcome; Triazoles; Voriconazole

Scedosporium and Lomentospora species are the second most frequent colonizing, allergenic, or invasive fungal pathogens in patients with cystic fibrosis, and are responsible for infections varying from cutaneous and subcutaneous tissue infections caused by traumatic inoculation to severe systemic diseases in immunocompromised patients. The clinical relevance of fungal airway colonization for individual patients harboring Scedosporium and Lomentospora species is still an underestimated issue. The high resistance of Scedosporium and Lomentospora species to antifungal drugs has highlighted the need for alternative treatment modalities, and antimicrobial photodynamic therapy may be one such alternative. In this study, methylene blue was applied as a photosensitizing agent to 6 type strains of Scedosporium and Lomentospora species, and we irradiated the strains using a light-emitting diode (635 ± 10 nm, 12 J/cm

Topics: Amphotericin B; Antifungal Agents; Ascomycota; Humans; Immunocompromised Host; Itraconazole; Methylene Blue; Microbial Sensitivity Tests; Photochemotherapy; Photosensitizing Agents; Scedosporium; Triazoles; Voriconazole

To describe a case of Coccidioides endophthalmitis that resulted in a favorable visual outcome after a combined medical and surgical approach.. A 33-year-old previously healthy woman was referred for evaluation of dyspnea and left-sided vision loss, which began 3 months before, after a trip to Nevada. She was found to have a pulmonary cavitary lesion and fluffy white material in the anterior chamber. An aqueous and vitreous paracentesis grew Coccidioides species. She was managed medically with a total of 7 weekly intravitreal injections of amphotericin B and intravenous liposomal amphotericin B followed by transition to oral posaconazole. Seven months after presentation, to ensure ocular sterilization and to clear the visual axis, she underwent temporary keratoprosthesis implantation, anterior segment reconstruction, removal of a cyclitic membrane and the crystalline lens, pars plana vitrectomy, placement of a pars plana Ahmed drainage device, and penetrating keratoplasty.. After surgical intervention and with maintenance posaconazole therapy, the patient had resolution of her dyspnea and improved uncorrected (aphakic) vision with a clear corneal graft, quiet anterior chamber, and normal optic nerve and retina.. A combined medical and surgical approach resulted in a favorable visual outcome and avoided the need for enucleation.

Topics: Adult; Amphotericin B; Antifungal Agents; Aqueous Humor; Coccidioides; Coccidioidomycosis; Combined Modality Therapy; Endophthalmitis; Eye Infections, Fungal; Female; Humans; Intravitreal Injections; Ophthalmologic Surgical Procedures; Treatment Outcome; Triazoles; Vitreous Body

Antifungal susceptibility testing is a subject of interest in the field of medical mycology. The aim of the present study were the distributions and antifungal susceptibility patterns of various Candida species isolated from colonized and infected immunocompromised patients admitted to ten university hospitals in Iran.. In totally, 846 Candida species were isolated from more than 4000 clinical samples and identified by the API 20 C AUX system. Antifungal susceptibility testing was performed by broth microdilution method according to CLSI.. The most frequent Candida species isolated from all patients was Candida albicans (510/846). The epidemiological cutoff value and percentage of wild-type species for amphotericin B and fluconazole in Candida albicans, Candida tropicalis, Candida glabrata and Candida krusei were 0.5 μg/ml (95%) and 4 μg/ml (96%); 1 μg/ml (95%) and 8 μg/ml (95%); 0.5 μg/ml (99%) and 19 μg/ml (98%); and 4 μg/ml (95%) and 64 μg/ml (95%), respectively. The MIC90 and epidemiological cutoff values to posaconazole in Candida krusei were 0.5 μg/ml. There were significant differences between infecting and colonizing isolates of Candida tropicalis in MIC 90 values of amphotericin B, and isolates of Candida glabrata in values of amphotericin B, caspofungin, and voriconazole (P < 0.05).. Our findings suggest that the susceptibility patterns of Candida species (colonizing and infecting isolates) in immunocompromised patients are not the same and acquired resistance was seen in some species.

Topics: Amphotericin B; Antifungal Agents; Candida; Caspofungin; Cross-Sectional Studies; Drug Resistance, Fungal; Echinocandins; Female; Fluconazole; Hospitals, University; Humans; Immunocompromised Host; Iran; Lipopeptides; Microbial Sensitivity Tests; Triazoles; Voriconazole

We compared EUCAST and CLSI methods versus Etest for antifungal susceptibility testing of 20 clinically relevant Fusarium species against amphotericin B, posaconazole, and voriconazole. The median Etest amphotericin B and posaconazole MICs were 1 dilution higher than the median EUCAST and the CLSI MICs. The essential agreement (within ±1/±2 dilutions) was 60/90%, 80/95%, and 70/85% between the Etest and EUCAST methods and 80/95%, 75/95%, and 45/100% between the Etest and CLSI methods for amphotericin B, voriconazole, and posaconazole, respectively. The categorical agreement was >85%. Etest can be used for antifungal susceptibility testing of Fusarium species.

Topics: Amphotericin B; Antifungal Agents; Fungal Proteins; Fusarium; Microbial Sensitivity Tests; Triazoles; Voriconazole

Rhino-orbital-cerebral mucormycosis (ROCM) is a rare fulminant opportunistic fungal infection that despite relevant treatment has high mortality. We present a case of a 3-year-old girl with acute lymphoblastic leukemia and ROCM, who was treated successfully with excessive surgery, systemic antifungal treatment with amphotericin B (AmB), posaconazole, and terbinafine as well as hyperbaric oxygen. Surgery included, beside extracranial and intracranial removal of infected areas, endoscopic sinus and skull base surgery with local AmB installation and in addition placement of an Ommaya reservoir for 114 intrathecal administrations of AmB. In addition, we review the literature of ROCM in pediatric patients with hematological diseases.

Topics: Amphotericin B; Antifungal Agents; Brain; Child, Preschool; Female; Humans; Hyperbaric Oxygenation; Mucormycosis; Naphthalenes; Nose; Opportunistic Infections; Orbit; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Terbinafine; Triazoles

We present the case of a 51-year-old man with acute myeloid leukemia who developed fevers with a skin lesion following the first cycle of induction chemotherapy. Skin biopsy showed evidence of invasive fungal infection. Cultures remained negative, but polymerase chain reaction on tissue detected Rhizopus oryzae complex. The patient was started on liposomal amphotericin B and underwent surgical debridement. He was switched to posaconazole, with plans for allogeneic hematopoetic stem cell transplant in the future.

Topics: Amphotericin B; Antibiotic Prophylaxis; Antifungal Agents; Biopsy; Debridement; Dermatomycoses; Febrile Neutropenia; Forearm; Humans; Immunocompromised Host; Induction Chemotherapy; Invasive Fungal Infections; Leukemia, Myeloid, Acute; Male; Middle Aged; Mucormycosis; Polymerase Chain Reaction; Rhizopus; RNA, Fungal; Triazoles

Phaeosphaeriaceae is a family in the order Pleosporales containing numerous plant pathogens, endophytes, lichenised fungi, and environmental saprobes. A novel genus, Tintelnotia is introduced containing two species, one of which caused an eye infection and several nail infections in humans. All species of Tintelnotia produce conidia in soft pycnidia with a wide ostiole. The generic type species is T. opuntiae causing necrotic spots on cactus plants. The isolates of the human opportunist T. destructans showed variable susceptibility pattern to a panel of common antifungal agents. The MICs of amphotericin B, voriconazole, posaconazole and itraconazole were 1 μg/mL, complemented by an in vitro MEC of 16 μg/mL against caspofungin; the MIC of terbinafine was 0.125 μg/mL. The latter compound contributed to the successful therapy in the ocular mycosis refractory to standard antifungal therapy, the benefit of terbinafine should be highlighted as a therapeutic option especially in difficult-to-treat fungal keratitis.

Topics: Amphotericin B; Antifungal Agents; Ascomycota; Caspofungin; Cornea; Echinocandins; Eye Infections, Fungal; Female; Humans; Itraconazole; Keratitis; Lipopeptides; Microbial Sensitivity Tests; Middle Aged; Nails; Naphthalenes; Phylogeny; Terbinafine; Triazoles; Voriconazole

Feline sporotrichosis is common in Malaysia. Thermosensitivity and effects of azole treatment on fungal susceptibility are unknown.. To evaluate thermotolerance and antifungal susceptibility of feline Malaysian Sporothrix isolates, compare microdilution (MD) and E-test results, and investigate changes in susceptibility during azole therapy.. Sporothrix schenckii sensu stricto was isolated from 44 cats. Thermotolerance was determined via culture at 37°C for 7 days. Susceptibility to itraconazole (ITZ), ketoconazole (KTZ) and terbinafine (TRB) was assessed in 40 isolates by MD; to amphotericin B (AMB), KTZ, ITZ, fluconazole (FLC) and posaconazole (POS) by E-test. Results were statistically compared by Pearson's Product Moment. In eight ketoconazole treated cats, susceptibility testing to itraconazole and ketoconazole was repeated every two months for six months.. Thermotolerance was observed in 36 of 44 (82%) isolates. Assuming that isolates growing at antifungal concentrations ≥4 mg/mL were resistant, all were resistant on E-test to FLC and AMB, 11 (28%) to POS, 6 (15%) to ITZ and 1 (3%) to KTZ. On MD, 27 of 40 (68%) were resistant to TRB, 2 (5%) to ITZ and 3 (8%) to KTZ. There was no correlation between E-test and MD results (KTZ r = 0.10, P = 0.54, and ITZ r = 0.11, P = 0.48). MD values for ITZ and KTZ did not exceed 4 mg/L during KTZ therapy.. The majority of feline isolates in Malaysia are thermosensitive. Lack of correlation between E-test and MD suggests that the E-test is unreliable to test antifungal susceptibility for Sporothrix spp. compared to MD. KTZ was the antifungal drug with the lowest MIC. Prolonged KTZ administration may not induce changes in antifungal susceptibility.

Topics: Amphotericin B; Animals; Antifungal Agents; Cat Diseases; Cats; In Vitro Techniques; Itraconazole; Ketoconazole; Malaysia; Microbial Sensitivity Tests; Naphthalenes; Sporothrix; Sporotrichosis; Terbinafine; Triazoles

Topics: Amphotericin B; Animals; Antiprotozoal Agents; Cell Line; Cell Survival; Drug Evaluation, Preclinical; Female; Firefly Luciferin; Fluconazole; Genes, Reporter; High-Throughput Screening Assays; Leishmania major; Leishmaniasis, Cutaneous; Luciferases; Luminescent Measurements; Macrophages; Meglumine; Meglumine Antimoniate; Mesocricetus; Mice; Mice, Inbred BALB C; Ofloxacin; Optical Imaging; Organisms, Genetically Modified; Organometallic Compounds; Triazoles

Small bowel transplantation (SBT) can be a life-saving medical procedure. However, these recipients experience high risk of bloodstream infections caused by Candida. This research aims to characterise the SBT recipient gut microbiota over time following transplantation and investigate the epidemiology of candidaemia in seven paediatric patients. Candida species from the recipients' ileum and bloodstream were identified by internal transcribed spacer sequence and distinguished to strain by multilocus sequence typing and randomly amplified polymorphic DNA. Antifungal susceptibility of bloodstream isolates was determined against nine antifungals. Twenty-two ileostomy samples harboured at least one Candida species. Fungaemia were caused by Candida parapsilosis, Candida albicans, Candida glabrata, Candida orthopsilosis and Candida pelliculosa. All but three bloodstream isolates showed susceptibility to all the antifungals tested. One C. glabrata isolate showed multidrug resistance to itraconazole, amphotericin B and posaconazole and intermediate resistance to caspofungin. Results are congruent with both endogenous (C. albicans, C. glabrata) and exogenous (C. parapsilosis) infections; results also suggest two patients were infected by the same strain of C. parapsilosis. Continuing to work towards a better understanding of sources of infection-particularly the exogenous sources-would lead to targeted prevention strategies.

Topics: Adolescent; Adult; Amphotericin B; Antifungal Agents; Candida; Candidemia; Caspofungin; DNA, Fungal; Drug Resistance, Fungal; Echinocandins; Female; Humans; Intestine, Small; Itraconazole; Lipopeptides; Male; Multilocus Sequence Typing; Sequence Analysis, DNA; Transplant Recipients; Triazoles; Young Adult

Mucormycosis is a fungal infection associated with high mortality. Until recently, the only licensed treatments were amphotericin B (AMB) formulations. Isavuconazole (ISAV) is a new mucormycosis treatment. A UK-based economic model explored treatment costs with ISAV versus liposomal AMB followed by posaconazole.. As a matched case-control analysis showed similar efficacy for ISAV and AMB, a cost-minimization approach was taken. Direct costs - drug acquisition, monitoring and administration, and hospitalization costs - were estimated from the National Health Service perspective.. Per-patient costs for ISAV and liposomal AMB + posaconazole were UK£26,810 and UK£41,855, respectively, with savings primarily driven by drug acquisition and hospitalization costs.. ISAV may reduce costs compared with standard mucormycosis therapy.

Topics: Amphotericin B; Antifungal Agents; Case-Control Studies; Drug Costs; Hospitalization; Humans; Invasive Fungal Infections; Models, Economic; Mucormycosis; Nitriles; Pyridines; Triazoles; United Kingdom

Three months after a kidney transplant, a man experienced an internuclear ophthalmoplegia. Magnetic resonance imaging found a punctuate hyperintensity of the brainstem. Afterwards, the patient presented with peripheral facial paralysis. A complete morphologic assessment showed an increase of the brainstem lesion, together with an excavated pulmonary nodule. Combination therapy with high-dose liposomal amphotericin B and voriconazole was begun for the putative aspergillosis. Owing to its atypical clinical presentation and negative detection of Aspergillus galactomannan antigen on sera, a biopsy specimen of the lung lesion was obtained. Histopathological and mycological investigations allowed the diagnosis of mucormycosis owing to Rhizopus microsporus. Accordingly, voriconazole was replaced with posaconazole. After 5 months, regression of the cerebral lesion was noted. Disseminated mucormycosis in solid-organ recipients is uncommon and mycological diagnosis is challenging. Mortality is high and is increased by diagnostic delay. Treating mucormycosis requires surgical debridement and appropriate antifungal therapy (usually intravenous liposomal amphotericin B). This report suggests that a combination of liposomal amphotericin B and posaconazole can be a therapeutic option in patients with a poor prognosis.

Topics: Amphotericin B; Antifungal Agents; Central Nervous System Fungal Infections; Diagnosis, Differential; Drug Therapy, Combination; Fatal Outcome; Humans; Kidney Transplantation; Magnetic Resonance Imaging; Male; Middle Aged; Mucormycosis; Predictive Value of Tests; Rhizopus; Tomography, X-Ray Computed; Treatment Outcome; Triazoles

Aspergillus fumigatus is the main mold causing invasive fungal infection that shows high mortality rates. Therapeutic failure and the increase in drug resistance make it necessary to explore alternative treatments for this infection. We have evaluated the efficacy of amphotericin B at 0.8 mg/kg or 0.3 mg/kg of body weight combined with 40 mg/kg of posaconazole against three A. fumigatus isolates in a murine model of disseminated infection. The combination of the polyene and the azole led to a greater increase in survival and a significantly greater reduction in tissue burden than monotherapies.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Drug Administration Schedule; Drug Resistance, Fungal; Drug Synergism; Gene Expression; Isoenzymes; Kidney; Lung; Male; Mice; Microbial Sensitivity Tests; Sterol 14-Demethylase; Survival Analysis; Triazoles

ASP2397 is a new compound with a novel and as-yet-unknown target different from that of licensed antifungal agents. It has activity against Aspergillus and Candida glabrata. We compared its in vitro activity against wild-type and azole-resistant A. fumigatus and A. terreus isolates with that of amphotericin B, itraconazole, posaconazole, and voriconazole. Thirty-four isolates, including 4 wild-type A. fumigatus isolates, 24 A. fumigatus isolates with alterations in CYP51A TR/L98H (5 isolates), M220 (9 isolates), G54 (9 isolates), and HapE (1 isolate), and A. terreus isolates (2 wild-type isolates and 1 isolate with an M217I CYP51A alteration), were analyzed. EUCAST E.Def 9.2 and CLSI M38-A2 MIC susceptibility testing was performed. ASP2397 MIC50 values (in milligrams per liter, with MIC ranges in parentheses) determined by EUCAST and CLSI were 0.5 (0.25 to 1) and 0.25 (0.06 to 0.25) against A. fumigatus CYP51A wild-type isolates and were similarly 0.5 (0.125 to >4) and 0.125 (0.06 to >4) against azole-resistant A. fumigatus isolates, respectively. These values were comparable to those for amphotericin B, which were 0.25 (0.125 to 0.5) and 0.25 (0.125 to 0.25) against wild-type isolates and 0.25 (0.125 to 1) and 0.25 (0.125 to 1) against isolates with azole resistance mechanisms, respectively. In contrast, MICs for the azole compounds were elevated and highest for itraconazole: >4 (1 to >4) and 4 (0.5 to >4) against isolates with azole resistance mechanisms compared to 0.125 (0.125 to 0.25) and 0.125 (0.06 to 0.25) against wild-type isolates, respectively. ASP2397 was active against A. terreus CYP51A wild-type isolates (MIC 0.5 to 1), whereas MICs of both azole and ASP2397 were elevated for the mutant isolate. ASP2397 displayed in vitro activity against A. fumigatus and A. terreus isolates which was independent of the presence or absence of azole target gene resistance mutations in A. fumigatus. The findings are promising at a time when azole-resistant A. fumigatus is emerging globally.

Topics: Amino Acid Substitution; Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus; Aspergillus fumigatus; Azoles; Coordination Complexes; Cytochrome P-450 Enzyme System; Drug Resistance, Fungal; Fungal Proteins; Gene Expression; Humans; Itraconazole; Microbial Sensitivity Tests; Mutation; Peptides, Cyclic; Triazoles; Voriconazole

Aspergillus species can cause ocular morbidity and blindness, and thus, appropriate antifungal therapy is needed. We investigated the in vitro activity of itraconazole, voriconazole, posaconazole, caspofungin, anidulafungin, and amphotericin B against 14 Aspergillus isolates obtained from patients with ocular mycoses, using the CLSI reference broth microdilution methodology. In addition, time-kill assays were performed, exposing each isolate separately to 1-, 4-, and 16-fold concentrations above the minimum inhibitory concentration (MIC) of each antifungal agent. A sigmoid maximum-effect (E max) model was used to fit the time-kill curve data. The drug effect was further evaluated by measuring an increase/decrease in the killing rate of the tested isolates. The MICs of amphotericin B, itraconazole, voriconazole, and posaconazole were 0.5-1.0, 1.0, 0.5-1.0, and 0.25 µg/ml for A. brasiliensis, A. niger, and A. tubingensis isolates, respectively, and 2.0-4.0, 0.5, 1.0 for A. flavus, and 0.12-0.25 µg/ml for A. nomius isolates, respectively. A. calidoustus had the highest MIC range for the azoles (4.0-16.0 µg/ml) among all isolates tested. The minimum effective concentrations of caspofungin and anidulafungin were ≤0.03-0.5 µg/ml and ≤0.03 µg/ml for all isolates, respectively. Posaconazole demonstrated maximal killing rates (E(max) = 0.63 h(-1), r(2) = 0.71) against 14 ocular Aspergillus isolates, followed by amphotericin B (E(max) = 0.39 h(-1), r(2) = 0.87), voriconazole (E(max) = 0.35 h(-1), r(2) = 0.098), and itraconazole (E(max) = 0.01 h(-1), r(2) = 0.98). Overall, the antifungal susceptibility of the non-fumigatus Aspergillus isolates tested was species and antifungal agent dependent. Analysis of the kinetic growth assays, along with consideration of the killing rates, revealed that posaconazole was the most effective antifungal against all of the isolates.

Topics: Amphotericin B; Anidulafungin; Antifungal Agents; Aspergillosis; Aspergillus; Caspofungin; Echinocandins; Eye; Eye Infections, Fungal; Humans; Itraconazole; Lipopeptides; Microbial Sensitivity Tests; Triazoles; Voriconazole

Black aspergilli, particularly Aspergillus niger and A. tubingensis, are the most common etiological agents of otomycosis followed by onychomycosis, pulmonary aspergillosis and aspergilloma. However, so far there is no systematic study on their antifungal susceptibility profiles. A collection of 124 clinical and environmental species of black aspergilli consisted of A. niger, A. tubingensis, A. uvarum. A. acidus and A. sydowii were verified by DNA sequencing of the partial β-tubulin gene. MICs of amphotericin B, itraconazole, voriconazole, posaconazole, and MECs of caspofungin were performed based on CLSI M38-A2. Posaconazole and caspofungin had the lowest MIC range (0.016-0.125 µg/ml and 0.008-0.031 µg/ml, respectively), followed by amphotericin B (0.25-4 µg/ml), voriconazole (0.125-16 µg/ml) and itraconazole (0.25 to >16) in an increasing order. Some strains of A. niger showed high MIC value for itraconazole and voriconazole (>16 µg/ml), in contrast only environmental isolates of A. tubingensis had high itraconazole MICs (>16 µg/ml). These results confirm that posaconazole and caspofungin are potential drugs for treatment of aspergillosis due to opportunistic agents of Aspergillus Nigri complex. However, in vivo efficacy remains to be determined.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus; Caspofungin; Echinocandins; Humans; Itraconazole; Lipopeptides; Microbial Sensitivity Tests; Triazoles; Voriconazole

Topics: Abscess; Adult; Amphotericin B; Antifungal Agents; Drainage; Humans; Immunocompetence; Leg; Male; Methicillin-Resistant Staphylococcus aureus; Mucormycosis; Postoperative Complications; Skin Diseases; Staphylococcal Infections; Triazoles

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

Epidemiological cut-off values (ECVs) based on minimal inhibitory concentration (MIC) distribution have been recently proposed for some antifungal drug/Cryptococcus neoformans combinations. However, these ECVs vary according to the species studied, being serotypes and the geographical origin of strains, variables to be considered. The aims were to define the wild-type (WT) population of the C. neoformans species complex (C. neoformans) isolated from patients living in Argentina, and to propose ECVs for six antifungal drugs. A total of 707 unique C. neoformans isolates obtained from HIV patients suffering cryptococcal meningitis were studied. The MIC of amphotericin B, flucytosine, fluconazole, itraconazole, voriconazole and posaconazole was determined according to the EDef 7.2 (EUCAST) reference document. The MIC distribution, MIC50 , MIC90 and ECV for each of these drugs were calculated. The highest ECV, which included ≥95% of the WT population modelled, was observed for flucytosine and fluconazole (32 μg ml(-1) each). For amphotericin B, itraconazole, voriconazole and posaconazole, the ECVs were: 0.5, 0.5, 0.5 and 0.06 μg ml(-1) respectively. The ECVs determined in this study may aid in identifying the C. neoformans strains circulating in Argentina with decreased susceptibility to the antifungal drugs tested.

Topics: AIDS-Related Opportunistic Infections; Amphotericin B; Antifungal Agents; Argentina; Cryptococcosis; Cryptococcus neoformans; Drug Resistance, Fungal; Epidemiologic Methods; Fluconazole; Flucytosine; HIV Infections; Humans; Itraconazole; Meningitis, Cryptococcal; Microbial Sensitivity Tests; Triazoles; Voriconazole

Aspergillus flavus is the second leading cause of invasive and non-invasive aspergillosis, as well as the most common cause of fungal sinusitis, cutaneous infections, and endophthalmitis in tropical countries. Since resistance to antifungal agents has been observed in patients, susceptibility testing is helpful in defining the activity spectrum of antifungals and determining the appropriate drug for treatment. A collection of 199 clinical and environmental strains of Aspergillus flavus consisted of clinical (n=171) and environmental (n=28) were verified by DNA sequencing of the partial b-tubulin gene. MICs of amphotericin B, itraconazole, voriconazole, posaconazole, and MEC of caspofungin were determined in accordance with the Clinical and Laboratory Standards Institute M38-A2 document. Caspofungin, followed by posaconazole, exhibited the lowest minimum inhibitory concentrations (MIC). All isolates had caspofungin MEC90 (0.063μg/ml) lower than the epidemiologic cutoff values, and 3.5% of the isolates had amphotericin B MIC higher than the epidemiologic cutoff values. However, their clinical effectiveness in the treatment of A. flavus infection remains to be determined.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus flavus; Caspofungin; Dose-Response Relationship, Drug; Drug Resistance, Fungal; Echinocandins; Environmental Microbiology; Humans; Iran; Itraconazole; Lipopeptides; Microbial Sensitivity Tests; Opportunistic Infections; Triazoles; Voriconazole

In vitro interactions of INK128, a target of rapamycin (TOR) kinase inhibitor, and antifungals, including itraconazole, voriconazole, posaconazole, amphotericin B, and caspofungin, against Aspergillus spp. were assessed with the broth microdilution checkerboard technique. Our results suggested synergistic effects between INK128 and all azoles tested, against multiple Aspergillus fumigatus and Aspergillus flavus isolates. However, no synergistic effects were observed when INK128 was combined with amphotericin B or caspofungin. No antagonism was observed for any combination.

Topics: Amphotericin B; Antifungal Agents; Aspergillus flavus; Aspergillus fumigatus; Benzoxazoles; Caspofungin; Drug Combinations; Drug Synergism; Echinocandins; Fungal Proteins; Gene Expression; Itraconazole; Lipopeptides; Microbial Sensitivity Tests; Pyrimidines; TOR Serine-Threonine Kinases; Triazoles; Voriconazole

Inhibition of ABC transporters is a common mechanism underlying drug-drug interactions (DDIs). We determined the inhibitory potential of antifungal drugs currently used for invasive fungal infections on ABC transporters P-glycoprotein (P-gp), MRP1 to MRP5, BCRP, and BSEP in vitro Membrane vesicles isolated from transporter-overexpressing HEK 293 cells were used to investigate the inhibitory potential of antifungal drugs (250 μM) on transport of model substrates. Concentration-inhibition curves were determined if transport inhibition was >60%. Fifty percent inhibitory concentrations (IC50s) for P-gp and BCRP were both 2 μM for itraconazole, 5 and 12 μM for hydroxyitraconazole, 3 and 6 μM for posaconazole, and 3 and 11 μM for isavuconazole, respectively. BSEP was strongly inhibited by itraconazole and hydroxyitraconazole (3 and 17 μM, respectively). Fluconazole and voriconazole did not inhibit any transport for >60%. Micafungin uniquely inhibited all transporters, with strong inhibition of MRP4 (4 μM). Anidulafungin and caspofungin showed strong inhibition of BCRP (7 and 6 μM, respectively). Amphotericin B only weakly inhibited BCRP-mediated transport (127 μM). Despite their wide range of DDIs, azole antifungals exhibit selective inhibition on efflux transporters. Although echinocandins display low potential for clinically relevant DDIs, they demonstrate potent in vitro inhibitory activity. This suggests that inhibition of ABC transporters plays a crucial role in the inexplicable (non-cytochrome P450-mediated) DDIs with antifungal drugs.

Topics: Amphotericin B; Antifungal Agents; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Biological Transport; Echinocandins; Fluconazole; HEK293 Cells; Humans; Itraconazole; Lipopeptides; Micafungin; Multidrug Resistance-Associated Proteins; Neoplasm Proteins; Triazoles; Voriconazole

In Asian countries, Trichosporon infection is a well-known disease in Japan. In India, the infection is increasingly recognised. The study was conducted to characterise the clinical Trichosporon isolates from India by phenotypic and molecular techniques. A total of 31 Trichosporon clinical isolates, recovered from patients of 14 hospitals across India were sequenced (ITS and IGS1 regions of rDNA). In vitro drug susceptibility testing of the isolates was performed against amphotericin-B, fluconazole, itraconazole, voriconazole and posaconazole. IGS1, rather than ITS sequences, correctly identified the isolates: Trichosporon asahii, 20; Trichosporon ovoides, 3; Trichosporon inkin, 2; Trichosporon asteroides, 1; Trichosporon mucoides, 1; Trichosporon loubieri, 1; Trichosporon debeurmannianum, 1; and Trichosporon dermatis, 1. Trichosporon asahii genotype III was the most common type, followed by genotype I and VII. Both these targets did not help to identify one Trichosporon to the species level. Trichosporon debeurmannianum, T. dermatis and T. asteroides were isolated for the first time from a human disease in India. The minimum inhibitory concentrations for voriconazole and posaconazole were within effective range. The study highlights the presence of wide range of Trichosporon species causing infection in India. Voriconazole or posaconazole may be the better drugs to treat such patients.

Topics: Amphotericin B; Antifungal Agents; Female; Fluconazole; Genotype; Humans; India; Itraconazole; Male; Microbial Sensitivity Tests; Mycological Typing Techniques; Phenotype; Sequence Analysis, DNA; Triazoles; Trichosporon; Trichosporonosis; Voriconazole

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

In this study, our aim was to identify Candida species isolated from bloodstream infections and to determine their susceptibilities to various antifungal agents to demonstrate the local resistance profiles and to guide empirical treatment for clinicians.. Two hundred Candida isolates (95 Candida albicans, 105 non-albicans Candida strains) were included in the study. Candida species were identified by conventional, biochemical and molecular methods. Antifungal susceptibility tests for amphotericin B, fluconazole, voriconazole, posaconazole, caspofungin and anidulafungin were performed with broth microdilution method according to the Clinical and Laboratory Standards Institute M27-A3 document.. Of the 200 Candida strains, the most prevalent species were C. albicans (47.5 %), Candida glabrata (18.0 %) and Candida parapsilosis complex (14.0 %). All Candida species except for three (1.5 %) Candida kefyr strains were susceptible to amphotericin B. Only one (2.8 %) C. glabrata was resistant to fluconazole (MIC ≥ 64 μg/ml), and the others (97.2 %) exhibited dose-dependent susceptibility. All species, but C. glabrata strains, were susceptible to fluconazole. Resistance to voriconazole, posaconazole, caspofungin and anidulafungin was not detected in any strain.. Candida albicans were susceptible to all antifungal drugs. Three C. kefyr strains were resistant to amphotericin B. Only one C. glabrata was resistant to fluconazole. All the strains were susceptible to voriconazole, posaconazole, caspofungin and anidulafungin. In vitro antifungal susceptibility tests should be performed to select of appropriate and effective antifungal therapy, and monitor the development of resistance.

Topics: Amphotericin B; Anidulafungin; Antifungal Agents; Candida; Candida albicans; Candidiasis; Caspofungin; Echinocandins; Fluconazole; Humans; Lipopeptides; Microbial Sensitivity Tests; Species Specificity; Triazoles; Voriconazole

Invasive fungal infections are on the rise due to an increased population of critically ill patients as a result of HIV infections, chemotherapies, and organ transplantations. Current antifungal drugs are helpful, but are insufficient in addressing the problem of drug-resistant fungal infections. Thus, there is a growing need for novel antimycotics that are safe and effective. The ebselen scaffold has been evaluated in clinical trials and has been shown to be safe in humans. This makes ebselen an attractive scaffold for facile translation from bench to bedside. We recently reported a library of ebselen-inspired ebsulfur analogues with antibacterial properties, but their antifungal activity has not been characterized. In this study, we repurposed ebselen, ebsulfur, and 32 additional ebsulfur analogues as antifungal agents by evaluating their antifungal activity against a panel of 13 clinically relevant fungal strains. The effect of induction of reactive oxygen species (ROS) by three of these compounds was evaluated. Their hemolytic and cytotoxicity activities were also determined using mouse erythrocytes and mammalian cells. The MIC values of these compounds were found to be in the range of 0.02-12.5 μg mL(-1) against the fungal strains tested. Notably, yeast cells treated with our compounds showed an accumulation of ROS, which may further contribute to the growth-inhibitory effect against fungi. This study provides new lead compounds for the development of antimycotic agents.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillus; Candida; Fluconazole; HEK293 Cells; Hemolysis; Heterocyclic Compounds, 2-Ring; Humans; Itraconazole; Mice; Microbial Sensitivity Tests; Reactive Oxygen Species; Structure-Activity Relationship; Thiazoles; Triazoles; Voriconazole

Topics: Aged; Amphotericin B; Antifungal Agents; Drug Therapy, Combination; Gastrointestinal Diseases; Humans; Male; Mucormycosis; Treatment Outcome; Triazoles

Mucormycosis is serious emerging infection, caused by saprophytic fungi of the order Mucorales, which mainly affects immunocompromised patients. Presentation forms can be rinosinusal, pulmonary, gastrointestinal, disseminated and localized wounds and burns. The cutaneous presentation is caused by inoculation of spores into the dermis with the subsequent development compatible with gangrenous ecthyma. Our patient was treated with surgical lesion and antifungal cleaning. Presenting hemodynamic complication secondary to the administration of posaconazole.

Topics: Aged; Amphotericin B; Antifungal Agents; Debridement; Fatal Outcome; Humans; Male; Mucormycosis; Risk Factors; Triazoles

Mould-active antifungal prophylaxis is increasingly used in patients at risk for invasive fungal disease. Between June 2011 and June 2012, one hundred patients with various haematological malignancies at risk for invasive fungal disease received primary antifungal prophylaxis with intravenous micafungin at a daily dosage of 50 mg during neutropenia. The median number of days on micafungin prophylaxis was 14 (range, 6-48 d). The incidence of proven and probable breakthrough invasive fungal diseases (bIFDs) was 6% and 3%, respectively. There were two bloodstream infections caused by yeasts or yeast-like fungi (Candida krusei, Trichosporon asahii) in two patients during the neutropenic phase after allogeneic haematopoietic stem cell transplantation. Four proven bIFDs caused by non-Aspergillus moulds and three cases of probable pulmonary bIFDs were documented during the neutropenic phase after induction/consolidation chemotherapy for acute leukaemia. Colonisation with Candida spp. was documented in 51% of the patients with none of the isolates being in vitro micafungin resistant. Compared to a historical control, receiving primary prophylaxis with posaconazole micafungin is at least as effective in preventing IFD. In both cohorts, bIFDs were exclusively caused by emerging pathogens with a highly preserved in vitro sensitivity to amphotericin B.

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; Candida; Candidiasis; Drug Administration Schedule; Echinocandins; Female; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Injections, Intravenous; Lipopeptides; Male; Micafungin; Middle Aged; Retrospective Studies; Transplantation, Homologous; Triazoles; Trichosporon; Trichosporonosis

Case Report A healthy 55-years-old male went to emergency due to a white infiltrate in the left eye without corneal trauma which partially responds to antibiotic treatment. The infiltrate worsened by the use of topical steroids. Direct microscopic evaluation and Gram stain are a valuable diagnostic tool for the detection of Absidia filaments. There is a successful treatment with anphotericin and posaconazole. Discussion Keratitis caused by Zygomicetes are unusual. This is a rare condition in healthy patients with no corneal trauma. The treatment with amphotericin and posaconazole are synergistic against filamentous fungi.

Topics: Absidia; Administration, Ophthalmic; Adrenal Cortex Hormones; Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Combined Modality Therapy; Corneal Transplantation; Corneal Ulcer; Drug Therapy, Combination; Humans; Immunocompetence; Male; Middle Aged; Mucormycosis; Ophthalmic Solutions; Staining and Labeling; Triazoles; Voriconazole

The effect of hypoxic conditions on the in vitro efficacy of amphotericin B and posaconazole against Mucorales was evaluated by defining MICs with Etest and broth microdilution and identifying minimal fungicidal concentrations (MFCs). With Etest, oxygen-dependent changes were detected, while the MIC and the MFC determined with broth microdilution remained unaltered with reduced oxygen levels. The observed differences depended on the method used.

Topics: Amphotericin B; Antifungal Agents; Cell Hypoxia; Microbial Sensitivity Tests; Mucorales; Triazoles

Clinical breakpoints (CBPs) have not been established for the Mucorales and any antifungal agent. In lieu of CBPs, epidemiologic cutoff values (ECVs) are proposed for amphotericin B, posaconazole, and itraconazole and four Mucorales species. Wild-type (WT) MIC distributions (organisms in a species-drug combination with no detectable acquired resistance mechanisms) were defined with available pooled CLSI MICs from 14 laboratories (Argentina, Australia, Canada, Europe, India, Mexico, and the United States) as follows: 10 Apophysomyces variabilis, 32 Cunninghamella bertholletiae, 136 Lichtheimia corymbifera, 10 Mucor indicus, 123 M. circinelloides, 19 M. ramosissimus, 349 Rhizopus arrhizus, 146 R. microsporus, 33 Rhizomucor pusillus, and 36 Syncephalastrum racemosum isolates. CLSI broth microdilution MICs were aggregated for the analyses. ECVs comprising ≥95% and ≥97.5% of the modeled populations were as follows: amphotericin B ECVs for L. corymbifera were 1 and 2 μg/ml, those for M. circinelloides were 1 and 2 μg/ml, those for R. arrhizus were 2 and 4 μg/ml, and those for R. microsporus were 2 and 2 μg/ml, respectively; posaconazole ECVs for L. corymbifera were 1 and 2, those for M. circinelloides were 4 and 4, those for R. arrhizus were 1 and 2, and those for R. microsporus were 1 and 2, respectively; both itraconazole ECVs for R. arrhizus were 2 μg/ml. ECVs may aid in detecting emerging resistance or isolates with reduced susceptibility (non-WT MICs) to the agents evaluated.

Topics: Amphotericin B; Antifungal Agents; Drug Resistance, Multiple, Fungal; Humans; Itraconazole; Microbial Sensitivity Tests; Mucorales; Mucormycosis; Triazoles

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Cardiomyopathies; Electrocardiography; Heart Block; Humans; Male; Middle Aged; Opportunistic Infections; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Triazoles

We report the in vitro activity of nine systemically active antifungal agents against 237 contemporary clinical isolates of yeast and moulds obtained from 13 laboratories in China during 2010 through 2012. Susceptibility testing was performed using CLSI methods. Sequencing of fks hot spots was performed for echinocandin non-wild-type (WT) strains. Isolates included 220 from eight species of Candida, 15 from four species of Aspergillus and one isolate each of Rhodotorula mucilaginosa and Trichosporon asahii. Resistance to amphotericin B (0.0%), flucytosine (0.0-1.7%) and the echinocandins (0.0-3.4%) was distinctly uncommon among C. albicans, C. parapsilosis, C. tropicalis, C. glabrata and C. pelliculosa. Three C. albicans isolates showed resistance to echinocandins and one harboured a mutation in HS1 of fks1. Resistance to the azoles was much more common with resistance to fluconazole, voriconazole and posaconazole detected among isolates of C. glabrata and C. tropicalis. Both C. parapsilosis and C. pelliculosa exhibited decreased susceptibility to fluconazole. Amphotericin B, the mould-active azoles and the echinocandins were all quite active against isolates of A. fumigatus and A. flavus. Consistent with previous studies from China, resistance to fluconazole is prominent among Candida spp. isolates in this country.

Topics: Amphotericin B; Antifungal Agents; Aspergillus; Azoles; Candida; China; Drug Resistance, Fungal; Drug Resistance, Multiple, Fungal; Echinocandins; Fluconazole; Flucytosine; Humans; Microbial Sensitivity Tests; Mutation; Rhodotorula; Sequence Analysis, DNA; Triazoles; Trichosporon; Voriconazole

Despite the common, worldwide, occurrence of dermatophytes, little information is available regarding susceptibility profiles against currently available and novel antifungal agents. A collection of sixty-eight clinical Trichophyton species and Epidermophyton floccosum were previously identified and verified to the species level by sequencing the internal transcribed spacer (ITS) regions of rDNA. MICs of amphotericin B, fluconazole, itraconazole, voriconazole, posaconazole, isavuconazole, terbinafine and MECs of caspofungin and anidulafungin were performed based on CLSI M38-A2. The resulting MIC90 s of all strains were, in increasing order, as follows: terbinafine (0.063 mg l(-1) ); posaconazole (1 mg l(-1) ); isavuconazole and anidulafungin (2 mg l(-1) ); itraconazole, voriconazole, amphotericin B, and caspofungin (4 mg l(-1) ) and fluconazole (>64 mg l(-1) ). These results confirm that terbinafine is an excellent agent for treatment of dermatophytosis due to T. rubrum, T. mentagrophytes, T. verrucosum, T. schoenleinii and E. floccosum. In addition, the new azoles POS and ISA are potentially useful antifungals to treat dermatophytosis. However, the clinical effectiveness of these novel antifungals remains to be determined.

Topics: Amphotericin B; Anidulafungin; Antifungal Agents; Caspofungin; Echinocandins; Epidermophyton; Fluconazole; Humans; Itraconazole; Lipopeptides; Microbial Sensitivity Tests; Naphthalenes; Nitriles; Pyridines; Terbinafine; Tinea; Triazoles; Trichophyton; Voriconazole

Topics: Amphotericin B; Antifungal Agents; Burns; Critical Illness; Diffusion; Humans; Liposomes; Mucormycosis; Muscles; Renal Dialysis; Triazoles

We evaluated the combination of posaconazole with amphotericin B in vitro and in a murine model of systemic infections caused by Sporothrix brasiliensis and Sporothrix schenckii sensu stricto. In vitro data demonstrated a synergistic effect, and although posaconazole alone was effective against sporotrichosis, efficacy in terms of survival and burden reduction was increased with the combination. This combination might be an option against disseminated sporotrichosis, especially when itraconazole or amphotericin B at optimal doses are contraindicated.

Topics: Amphotericin B; Animals; Antifungal Agents; Drug Resistance, Multiple, Fungal; Drug Therapy, Combination; Mice; Microbial Sensitivity Tests; Sporothrix; Sporotrichosis; Triazoles

Aspergillus fumigatus is the most important etiological agent of invasive aspergillosis. Recently, an increasing number of azole-resistant A. fumigatus isolates have been described in various countries. The prevalence of azole resistance was investigated in this study using our culture collection of A. fumigatus isolates collected between 1999 and 2012 from clinical specimens. Seven hundred and forty-six A. fumigatus isolates, collected from 419 patients, were investigated. First, all isolates were screened for resistance to itraconazole by subculturing on Sabouraud dextrose agar that contained 4 mg/L itraconazole. For isolates that grew on the itraconazole containing agar, the in vitro activities of amphotericin B, itraconazole, voriconazole and posaconazole were determined using the Clinical and Laboratory Standards Institute (CLSI) M38-A reference method. After PCR amplification, the full sequence of the cyp51A gene and its promoter region was determined for all in vitro azole-resistant isolates. Itraconazole resistance was found in 10.2% of the A. fumigatus isolates. From 2000 onwards, patients were observed annually with an itraconazole-resistant isolate. According to in vitro susceptibility tests, amphotericin B exhibited good activity against all isolates whereas the azoles were resistant. Sequence analysis of the promoter region and CYP51A gene indicated the presence of TR34/L98H in 86.8% (n = 66) of isolates. This initial analysis of the resistance mechanism of A. fumigatus from Turkey revealed a common TR34/L98H mutation in the cyp51A gene.

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Cytochrome P-450 Enzyme System; DNA Mutational Analysis; Drug Resistance, Fungal; Female; Fungal Proteins; Humans; Itraconazole; Male; Microbial Sensitivity Tests; Middle Aged; Mutation; Promoter Regions, Genetic; Triazoles; Turkey; Voriconazole; Young Adult

The in vitro activities of 11 antifungal drugs against 68 Scopulariopsis and Microascus strains were investigated. Amphotericin B, 5-fluorocytosine, fluconazole, itraconazole, ketoconazole, miconazole, posaconazole, voriconazole, and ciclopirox showed no or poor antifungal effect. The best activities were exhibited by terbinafine and caspofungin, where the MIC and MEC (minimal effective concentration) ranges were 0.0313 to >16 μg/ml and 0.125 to 16 μg/ml, respectively. The MIC and MEC modes were both 1 µg/ml for terbinafine and caspofungin; the MIC50 and MEC50 were 1 µg/ml for both drugs, whereas the MIC90 and MEC90 were 4 µg/ml and 16 µg/ml, respectively.

Topics: Amphotericin B; Antifungal Agents; Ascomycota; Caspofungin; Drug Resistance, Fungal; Echinocandins; Fluconazole; Flucytosine; Itraconazole; Ketoconazole; Lipopeptides; Microbial Sensitivity Tests; Scopulariopsis; Triazoles; Voriconazole

The in vitro susceptibilities of 24 worldwide Exserohilum isolates belonging to 10 species from human and environmental sources were determined for eight antifungal drugs. The strains were characterized by internal transcribed spacer (ITS) sequencing and amplified fragment length polymorphism fingerprinting. Posaconazole had the lowest geometric mean MIC (0.16 μg/ml), followed by micafungin (0.21 μg/ml), amphotericin B (0.24 μg/ml), itraconazole (0.33 μg/ml), voriconazole (0.8 μg/ml), caspofungin (1.05 μg/ml), isavuconazole (1.38 μg/ml), and fluconazole (15.6 μg/ml).

Topics: Amphotericin B; Amplified Fragment Length Polymorphism Analysis; Antifungal Agents; Ascomycota; Caspofungin; Echinocandins; Fluconazole; Genotype; Itraconazole; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Molecular Sequence Data; Nitriles; Pyridines; Triazoles; Voriconazole

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

We compared EUCAST and CLSI antifungal susceptibility testing (AFST) methods for triazoles and amphotericin B against 124 clinical Mucorales isolates. The EUCAST method yielded MIC values 1- to 3-fold dilutions higher than those of the CLSI method for amphotericin B. The essential agreements between the two methods for triazoles were high, i.e., 99.1% (voriconazole), 98.3% (isavuconazole), and 87% (posaconazole), whereas it was significantly lower for amphotericin B (66.1%). Strategies for harmonization of the two methods for Mucorales AFST are warranted.

Topics: Amphotericin B; Antifungal Agents; Humans; Microbial Sensitivity Tests; Mucorales; Mucormycosis; Nitriles; Pyridines; Species Specificity; Triazoles; Voriconazole

A 55-year-old woman was admitted for orthotopic heart transplantation. Her medical history was notable for multiple cardiovascular problems, including ischemic cardiomyopathy that necessitated circulatory support with a left ventricular assist device. Five weeks after undergoing orthotopic heart transplantation, she developed Aspergillus calidoustus mediastinitis, for which she underwent a prolonged course of antifungal treatment that comprised (in sequence) posaconazole for 11 days, voriconazole for 10 days, and amphotericin B for 42 days. During this period, she also underwent repeated mediastinal drainage and sternal débridement, followed by sternal wiring and coverage with bilateral pectoralis advancement flaps. Four months postoperatively, she was discharged from the hospital with a successfully controlled infection and a healed sternum. To our knowledge, only 3 previous cases of Aspergillus mediastinitis after orthotopic heart transplantation have been reported in the literature, none of which was Aspergillus calidoustus.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus; Combined Modality Therapy; Debridement; Drainage; Drug Administration Schedule; Drug Therapy, Combination; Female; Heart Transplantation; Humans; Mediastinitis; Middle Aged; Reoperation; Surgical Flaps; Surgical Wound Infection; Time Factors; Treatment Outcome; Triazoles; Voriconazole

Topics: Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Drug Resistance, Fungal; Fatal Outcome; Female; Fever; Fusariosis; Fusarium; Humans; Idarubicin; Leukemia, Myeloid, Acute; Triazoles; Young Adult

Topics: Acremonium; Amphotericin B; Anidulafungin; Antifungal Agents; Drug Combinations; Drug Interactions; Drug Resistance, Fungal; Echinocandins; Humans; Microbial Sensitivity Tests; Naphthalenes; Pyrimidines; Terbinafine; Triazoles; Voriconazole

To study the effect of the initiation time of posaconazole treatment from 1 to 3 days after systemic infection by Trichosporon asahii in mice.. BALB/c mice, 4-5 weeks old, were intravenously infected with 1 × 10(7) cfu/mouse of T. asahii. The onset of treatment varied from 1 to 3 days after infection. Orally administered posaconazole at 0.5, 1, 2, 5 or 10 mg/kg body weight/day was compared with orally administered fluconazole (at 10 mg/kg/day) and intraperitoneally administered amphotericin B (at 1 mg/kg) on alternating days. Livers, kidneys and spleens of mice that died or survived to day 25 were removed to determine fungal tissue burdens.. When therapy began 1 day after challenge, posaconazole at ≥ 1 mg/kg significantly prolonged survival of mice compared with that of the control group and considerably reduced the fungal tissue burden over the control group. On the other hand, when treatment was started 3 days after infection, regimens of 5 and 10 mg/kg posaconazole significantly prolonged mice survival over that of the control group and appreciably diminished the fungal load compared with untreated mice. In this model, as the severity of trichosporonosis increased, higher doses of posaconazole were required to achieve equivalent activity levels. Fluconazole and amphotericin B were ineffective in preventing mice death and in significantly reducing fungal tissue burden. Posaconazole displayed potent in vivo activity against the strain tested.. Posaconazole may be a suitable option in the treatment of disseminated T. asahii infection.

Topics: Administration, Oral; Amphotericin B; Animals; Antifungal Agents; Colony Count, Microbial; Fluconazole; Injections, Intraperitoneal; Kidney; Liver; Male; Mice; Mice, Inbred BALB C; Spleen; Treatment Outcome; Triazoles; Trichosporon; Trichosporonosis

Topics: Amphotericin B; Antifungal Agents; Biopsy, Fine-Needle; Humans; Image-Guided Biopsy; Immunocompromised Host; Leukemia, Myeloid, Acute; Male; Middle Aged; Mucormycosis; Multiple Pulmonary Nodules; Tomography, X-Ray Computed; Treatment Outcome; Triazoles

We describe a case of a 62-year-old diabetic woman with hepatocellular carcinoma due to chronic hepatitis B virus infection. Two weeks after orthotopic liver transplantation, endoscopy for massive upper gastrointestinal bleeding revealed a large necrotic area in the gastric fundus. The patient underwent emergency resection. Histopathologically, angioinvasive mold infection compatible with mucormycosis was diagnosed in a large area of necrosis, mimicking an atypically localized gastric ulcer. Foreign bodies originating from transarterial chemoembolization (TACE) performed 7 and 8 months earlier and 40 days before transplantation were identified in the submucosal tissue. The patient was treated with liposomal amphotericin B (LAB) for 5 weeks, followed by 7 weeks of posaconazole. Follow-up biopsies after 1 and 5 months confirmed successful treatment. Review of the radiological images of the TACE procedure showed that some of the TACE material had been diverted to the stomach via an accessory gastric branch originating from the left hepatic artery. TACE agents may be associated with chronic, refractory gastroduodenal ulcers. We hypothesize that the ischemic lesion was first colonized with presumed Mucorales mold and invasive growth was promoted by the posttransplantation immunosuppression. Careful exploration of extrahepatic collaterals during TACE may prevent this complication.

Topics: Amphotericin B; Antifungal Agents; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Diabetes Complications; Female; Hepatitis B, Chronic; Histocytochemistry; Humans; Immunocompromised Host; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Microscopy; Middle Aged; Mucorales; Mucormycosis; Stomach Diseases; Triazoles

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: Abdominal Wall; Acute Kidney Injury; Adult; Amphotericin B; Anti-Infective Agents; Antibiotic Prophylaxis; Antifungal Agents; Clostridium Infections; Cytomegalovirus Infections; Debridement; Dermatomycoses; Hepatitis; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Mucormycosis; Opportunistic Infections; Postoperative Complications; Primary Graft Dysfunction; Reoperation; Triazoles

We used two established neutropenic murine models of pulmonary aspergillosis and mucormycosis to explore the association between the posaconazole area under the concentration-time curve (AUC)-to-MIC ratio (AUC/MIC) and treatment outcome. Posaconazole serum pharmacokinetics were verified in infected mice to ensure that the studied doses reflected human exposures with the oral suspension, delayed-release tablet, and intravenous formulations of posaconazole. Sinopulmonary infections were then induced in groups of neutropenic mice with Aspergillus fumigatus strain 293 (posaconazole MIC, 0.5 mg/liter) or Rhizopus oryzae strain 969 (posaconazole MIC, 2 mg/liter) and treated with escalating daily dosages of oral posaconazole, which was designed to achieve AUCs ranging from 1.10 to 392 mg · h/liter. After 5 days of treatment, lung fungal burden was analyzed by quantitative real-time PCR. The relationships of the total drug AUC/MIC and the treatment response were similar in both models, with 90% effective concentrations (EC90s) corresponding to an AUC/MIC threshold of 76 (95% confidence interval [CI], 46 to 102) for strain 293 versus 87 (95% CI, 66 to 101) for strain 969. Using a provisional AUC/MIC target of >100, these exposures correlated with minimum serum posaconazole concentrations (Cmins) of 1.25 mg/liter for strain 293 and 4.0 mg/liter for strain 969. The addition of deferasirox, but not liposomal amphotericin or caspofungin, improved the activity of a suboptimal posaconazole regimen (AUC/MIC, 33) in animals with pulmonary mucormycosis. However, no combination was as effective as the high-dose posaconazole monotherapy regimen (AUC/MIC, 184). Our analysis suggests that posaconazole pharmacodynamics are similar for A. fumigatus and R. oryzae when indexed to pathogen MICs.

Topics: Amphotericin B; Animals; Antifungal Agents; Area Under Curve; Aspergillosis; Aspergillus fumigatus; Benzoates; Caspofungin; Deferasirox; Disease Models, Animal; Drug Therapy, Combination; Echinocandins; Female; Invasive Pulmonary Aspergillosis; Lipopeptides; Lung; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Mucormycosis; Neutropenia; Rhizopus; Treatment Outcome; Triazoles

Mucormycosis is an invasive mycotic disease caused by fungi in the zygomycetes class. Although ubiquitous in the environment, zygomycetes are rarely known to cause invasive disease in immunocompromised hosts with a high mortality even under aggressive antifungal and surgical therapy. Clinically, mucormycosis frequently affects the sinus occasionally showing pulmonary or cerebral involvement. However skeletal manifestation with Rhizopus microsporus (RM) osteomyelitis leading to emergency surgical proximal femoral resection with fatal outcome has not been described yet.. We report the case of a 73-year-old male suffering from myelodysplastic syndrome with precedent bone marrow transplantation. Six months after transplantation he consulted our internal medicine department in a septic condition with a four week history of painful swelling of the right hip. Radiography, computed tomography and magnetic resonance imaging revealed multiple bone infarcts in both femurs. In the right femoral head, neck and trochanteric region a recent infarct showed massive secondary osteomyelitis, breaking through the medial cortex. Emergency surgical proximal femoral resection was performed due to extensive bone and soft tissue destruction. Microbiological and basic local alignment search tool (BLAST) analysis revealed RM. Amphotericin B and posaconazole treatment with septic revision surgery was performed. However the disease ran a rapid course and was fatal two months after hospital admission.. This alarming result with extensive RM osteomyelitis in the proximal femur of an immunocompromised patient may hopefully warn medical staff to perform early imaging and aggressive surgical supported multimodal treatment in similar cases.

Topics: Aged; Amphotericin B; Antifungal Agents; Bone Marrow Transplantation; Combined Modality Therapy; Fatal Outcome; Humans; Male; Mucormycosis; Osteomyelitis; Rhizopus; Triazoles

Mucormycosis is a highly aggressive disease which is usually fatal in immunocompromised patients. The species of mucormycetes show significant differences in susceptibility to amphotericin B, azoles and terbinafine. The precise species level identification for this fungal group could be achieved by internal transcribed-spacer (ITS) region sequencing. Herein, we present the largest series of antifungal susceptibility data of molecularly characterised isolates of mucormycetes reported so far from India. Eighty isolates originating from 71 patients comprised 50 (62.5%) from pulmonary cases, 15 (19%) from rhino-orbital-cerebral, 13 (16.2%) from cutaneous and 2 (2.5%) from disseminated mucormycosis. ITS and D1/D2 regions sequencing of the isolates identified, Rhizopus arrhizus var. delemar (n = 25), R. arrhizus var. arrhizus (n = 15), R. microsporus (n = 17), R. stolonifer (n = 3), Syncephalastrum racemosum (n = 11), Apophysomyces elegans (n = 2), A. variabilis (n = 2), Lichtheimia ramosa (n = 3) and Mucor circinelloides f. lusitanicus (n = 2). Amplified fragment length polymorphism analysis was done to genotype Rhizopus isolates and revealed 5 clusters of R. arrhizus, which were well separated from R. microsporus. Amphotericin B was the most potent antifungal followed by posaconazole, itraconazole and isavuconazole. Etest and CLSI MICs of amphotericin B showed 87% agreement. Overall, the commonest underlying condition was uncontrolled diabetes mellitus. Records of 54 patients revealed fatalities in 28 cases.

Topics: Amphotericin B; Amplified Fragment Length Polymorphism Analysis; Antifungal Agents; DNA, Fungal; Drug Resistance, Fungal; Humans; India; Itraconazole; Microbial Sensitivity Tests; Mucor; Mucorales; Mucormycosis; Mycological Typing Techniques; Nitriles; Pyridines; Rhizopus; Sequence Analysis, DNA; Specimen Handling; Triazoles

Mucormycosis is a rare but aggressive fungal infection that predominantly affects immunocompromised patients. We report a case that highlights the importance of knowledge to enable prompt diagnosis and management of an otherwise fatal phenomenon.

Topics: Aged, 80 and over; Amphotericin B; Anemia, Aplastic; Antifungal Agents; Escherichia coli Infections; Fatal Outcome; Female; Humans; Immunocompromised Host; Mucormycosis; Necrosis; Rhizopus; Tongue; Triazoles

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

Mucormycosis are the fungal infections caused by emerging ubiquitous filamentous fungi classified as zygometes and order as mucorales. They occur mainly in immunosuppressed patients and diabetics. The onset of hemoptysis, in this context, may rapidly become life-threatening.. We report the case of a man of 83 years, Caribbean with a history of non-insulindependent diabetes and HTLV1 seropositive. At admission he presented with fever, cough and cachexia. Chest X-ray revealed a snapshot of excavation within alveolar consolidation. Endoscopy showed a mucopurulent plug obstructing lingula. The histological appearance of bronchial biopsies was in favor of mucormycosis. A combined treatment with liposomal amphotericin B and posaconasole was implemented, but the occurrence of abundant hemoptysis led us to make a left upper lobectomy. Finally, the outcome was favorable and the patient was discharged after hospitalization of 56 days.. A medicosurgical treatment during mucormycosis complicating bronchopulmonary hemoptysis not controlled by medical treatment alone seems to offer an effective therapeutic strategy.

Topics: Aged, 80 and over; Amphotericin B; Combined Modality Therapy; Diabetes Mellitus, Type 2; Hemoptysis; Humans; Lung Diseases, Fungal; Male; Mucormycosis; Opportunistic Infections; Pneumonectomy; Triazoles

Mucormycosis is a rare, but invasive infection caused by ubiquitous molds. Amphotericin B and surgery have been known to help improve the outcome. Sporadic case reports support the use of posaconazole in adults. We report a toddler with acute lymphoblastic leukemia who acquired rhino-orbital mucormycosis caused by Rhizopus species at the end of induction chemotherapy. She was successfully treated with multiple surgical debridements, amphotericin B, posaconazole and hyperbaric oxygen therapy. In conclusion, mucormycosis is a serious infection that requires aggressive surgical and medical therapy. To the best of our knowledge the use of posaconazole combined with hyperbaric oxygen therapy has not been reported in a toddler with leukemia and invasive Rhizopus sp. infection. This approach was found to be safe and effective in our patient.

Topics: Adult; Amphotericin B; Antifungal Agents; Child, Preschool; Combined Modality Therapy; Female; Humans; Hyperbaric Oxygenation; Mucormycosis; Orbital Diseases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Remission Induction; Rhizopus; Tomography, X-Ray Computed; Triazoles

Candida nivariensis is a cryptic species, phenotypically indistinguishable from Candida glabrata and identified by molecular methods. Aside its isolation from broncho-alveolar lavage, we report for the first time the etiologic role of C. nivariensis in 4 patients with vulvovaginal candidiasis. Of 100 phenotypically identified C. glabrata isolates originating from vaginal swabs, 4 were identified as C. nivariensis by polymerase chain reaction and confirmed by sequencing. All of the C. nivariensis isolates exhibited white colonies on CHROMagar. Phylogenetic analysis revealed genotypic diversity in the C. nivariensis isolates originating from within or outside of India. Barring a solitary C. nivariensis isolate with MIC, 16 μg/mL of fluconazole, the rest were susceptible to voriconazole, itraconazole, posaconazole, isavuconazole, amphotericin B, and echinocandins. The patient with high fluconazole MIC did not respond to fluconazole therapy. It is suggested that the prevalence of this species is likely to be much higher than apparent from the sporadic published reports.

Topics: Adult; Amphotericin B; Antifungal Agents; Candida; Candidiasis, Vulvovaginal; DNA, Fungal; Drug Resistance, Fungal; Echinocandins; Female; Fluconazole; Genotype; Humans; India; Itraconazole; Microbial Sensitivity Tests; Nitriles; Phenotype; Phylogeny; Polymerase Chain Reaction; Pyridines; Pyrimidines; Sequence Analysis, DNA; Tertiary Care Centers; Triazoles; Voriconazole; Young Adult

The in vitro antifungal susceptibility of a set of 99 clinical isolates of Curvularia was tested against 9 drugs using a reference microdilution method. The isolates had been identified previously to species level by comparing their ITS rDNA and glyceraldehyde-3-phosphate dehydrogenase gene sequences with those of reference strains. We were able to reliably identify 73.2% of the isolates, the most frequent species being Curvularia aeria, Curvularia geniculata/Curvularia senegalensis, Curvularia lunata, Curvularia inaequalis, Curvularia verruculosa, and Curvularia borreriae. Most of these isolates had been recovered from nasal sinus, which is generally considered one of the most frequent sites of infection by these fungi. In addition, at least 3 phylogenetic species that have not yet been formally described were detected. The most active drugs were the echinocandins, amphotericin B, and posaconazole, whereas voriconazole and itraconazole showed poor activity.

Topics: Amphotericin B; Antifungal Agents; Ascomycota; Drug Resistance, Multiple, Fungal; Echinocandins; Humans; Itraconazole; Microbial Sensitivity Tests; Phylogeny; Pyrimidines; Triazoles; Voriconazole

Combinations of terbinafine or caspofungin with amphotericin B, posaconazole, or itraconazole were studied as potential treatments against 18 isolates of Mucor irregularis in vitro. Synergism of the combinations of terbinafine with amphotericin B, posaconazole, and itraconazole against 38.9, 33.3, and 44.4% of the strains studied was observed. In contrast, synergism of the combinations of caspofungin with amphotericin B, posaconazole, and itraconazole against 99.4, 66.7, and 99.4% of the strains studied was observed. Furthermore, no antagonism was observed.

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Drug Combinations; Drug Synergism; Echinocandins; Itraconazole; Lipopeptides; Microbial Sensitivity Tests; Mucor; Mucormycosis; Naphthalenes; Terbinafine; Triazoles

Mucormycosis is a life-threatening fungal infection almost uniformly affecting diabetics in ketoacidosis or other forms of acidosis and/or immunocompromised patients. Inhalation of Mucorales spores provides the most common natural route of entry into the host. In this study, we developed an intratracheal instillation model of pulmonary mucormycosis that hematogenously disseminates into other organs using diabetic ketoacidotic (DKA) or cyclophosphamide-cortisone acetate-treated mice. Various degrees of lethality were achieved for the DKA or cyclophosphamide-cortisone acetate-treated mice when infected with different clinical isolates of Mucorales. In both DKA and cyclophosphamide-cortisone acetate models, liposomal amphotericin B (LAmB) or posaconazole (POS) treatments were effective in improving survival, reducing lungs and brain fungal burdens, and histologically resolving the infection compared with placebo. These models can be used to study mechanisms of infection, develop immunotherapeutic strategies, and evaluate drug efficacies against life-threatening Mucorales infections.

Topics: Amphotericin B; Animals; Antifungal Agents; Cortisone; Cyclophosphamide; Diabetic Ketoacidosis; Disease Models, Animal; Male; Mice; Mice, Inbred ICR; Mice, Inbred NOD; Microbial Sensitivity Tests; Mucorales; Mucormycosis; Triazoles

Topics: Amphotericin B; Antifungal Agents; Drug Therapy, Combination; Follow-Up Studies; Hematologic Diseases; Humans; Mucormycosis; Registries; Treatment Outcome; Triazoles

The high mortality rate of mucormycosis with currently available monotherapy has created interest in studying novel strategies for antifungal agents. With the exception of amphotericin B (AMB), the triazoles (posaconazole [PCZ] and itraconazole [ICZ]) are fungistatic in vitro against Rhizopus oryzae . We hypothesized that growth at a high temperature (42°C) results in fungicidal activity of PCZ and ICZ that is mediated through apoptosis. R. oryzae had high MIC values for PCZ and ICZ (16 to 64 μg/ml) at 25°C; in contrast, the MICs for PCZ and ICZ were significantly lower at 37°C (8 to 16 μg/ml) and 42°C (0.25 to 1 μg/ml). Furthermore, PCZ and ICZ dose-dependent inhibition of germination was more pronounced at 42°C than at 37°C. In addition, intracellular reactive oxygen species (ROS) increased significantly when fungi were exposed to antifungals at 42°C. Characteristic cellular changes of apoptosis in R. oryzae were induced by the accumulation of intracellular reactive oxygen species. Cells treated with PCZ or ICZ in combination with hyperthermia (42°C) exhibited characteristic markers of early apoptosis: phosphatidylserine externalization visualized by annexin V staining, membrane depolarization visualized by bis-[1,3-dibutylbarbituric acid] trimethine oxonol (DiBAC) staining, and increased metacaspase activity. Moreover, terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) assay and DAPI (4',6-diamidino-2-phenylindole) staining demonstrated DNA fragmentation and condensation, respectively. The addition of N-acetylcysteine increased fungal survival, prevented apoptosis, reduced ROS accumulation, and decreased metacaspase activation. We concluded that hyperthermia, either alone or in the presence of PCZ or ICZ, induces apoptosis in R. oryzae. Local thermal delivery could be a therapeutically useful adjunct strategy for these refractory infections.

Topics: Acetylcysteine; Amphotericin B; Antifungal Agents; Apoptosis; Caspases; Free Radical Scavengers; Hot Temperature; Humans; Itraconazole; Membrane Potentials; Microbial Sensitivity Tests; Phosphatidylserines; Reactive Oxygen Species; Rhizopus; Triazoles

Topics: Amphotericin B; Animals; Cryptococcus neoformans; Drug Resistance, Bacterial; Drug Therapy, Combination; Male; Meningitis, Cryptococcal; Mice; Survival; Treatment Outcome; Triazoles

A recent large outbreak of fungal infections by Exserohilum rostratum from contaminated compounding solutions has highlighted the need to rapidly screen available pharmaceuticals that could be useful in therapy. The present study utilized two newly-developed high throughput assays to screen approved drugs and pharmaceutically active compounds for identification of potential antifungal agents. Several known drugs were found that have potent effects against E. rostratum including the triazole antifungal posaconazole. Posaconazole is likely to be effective against infections involving septic joints and may provide an alternative for refractory central nervous system infections. The anti-E. rostratum activities of several other drugs including bithionol (an anti-parasitic drug), tacrolimus (an immunosuppressive agent) and floxuridine (an antimetabolite) were also identified from the drug repurposing screens. In addition, activities of other potential antifungal agents against E. rostratum were excluded, which may avoid unnecessary therapeutic trials and reveals the limited therapeutic alternatives for this outbreak. In summary, this study has demonstrated that drug repurposing screens can be quickly conducted within a useful time-frame. This would allow clinical implementation of identified alternative therapeutics and should be considered as part of the initial public health response to new outbreaks or rapidly-emerging microbial pathogens.

Topics: Adenosine Triphosphate; Amphotericin B; Antifungal Agents; Ascomycota; Bithionol; Cell Line, Tumor; Drug Evaluation, Preclinical; Drug Repositioning; Floxuridine; Humans; Hyphae; Sepsis; Spores, Fungal; Tacrolimus; Triazoles

Triazoles are first-line agents for treating aspergillosis. The prevalence of azole resistance in Aspergillus fumigatus is increasing, and cross-resistance is a growing concern. In this study, the susceptibilities of 40 A. fumigatus clinical isolates were tested by using the CLSI method with amphotericin B, itraconazole, voriconazole, posaconazole, and the new triazole isavuconazole. Isavuconazole MICs were higher in strains with reduced susceptibilities to other triazoles, mirroring changes in voriconazole susceptibility. Isavuconazole MICs differed depending on the Cyp51A substitution.

Topics: Amino Acid Substitution; Amphotericin B; Antifungal Agents; Aspergillus fumigatus; Cytochrome P-450 Enzyme System; Drug Resistance, Fungal; Fungal Proteins; Humans; Itraconazole; Microbial Sensitivity Tests; Mutation; Nitriles; Pyridines; Pyrimidines; Triazoles; Voriconazole

Topics: Adolescent; Amphotericin B; Antifungal Agents; Female; Fungi; Humans; Liposomes; Mucormycosis; Neutropenia; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Remission Induction; Stem Cell Transplantation; Tomography, X-Ray Computed; Triazoles

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

The in vitro activities of eight antifungal drugs against 106 clinical and environmental isolates of waterborne and cutaneous Exophiala species were tested. The MICs and minimum effective concentrations for 90% of the strains tested (n = 106) were, in increasing order, as follows: posaconazole, 0.063 μg/ml; itraconazole, 0.25 μg/ml; micafungin, 1 μg/ml; voriconazole, 2 μg/ml; isavuconazole, 4 μg/ml; caspofungin, 8 μg/ml; amphotericin B, 16 μg/ml; fluconazole, 64 μg/ml.

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Echinocandins; Exophiala; Fluconazole; Itraconazole; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Nitriles; Pyridines; Pyrimidines; Triazoles; Voriconazole

Aggressive chemotherapy and immunosuppressive treatment may prolong patients' life, but influence the risk of severe, life-threatening infections. Here, we report the case of a 21-year-old caucasian female who developed a disseminated infection of Scedosporium prolificans after allogenic stem cell transplantation performed for treatment of relapsed acute lymphoblastic leukaemia. The pathogen was isolated from the blood and identified on the basis of its macroscopic and microscopic morphological features. The empirical treatment with amphotericin B provided no improvement. However, introduction of intravenous voriconazole resulted in amelioration of fever. Unfortunately, the patient died due to progression of underlying disease and multiorgan failure. However, this case report indicates a possible relevance of voriconazole-based treatment regimens in invasive S. prolificans infections.

Topics: Allografts; Amphotericin B; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Drug Substitution; Fatal Outcome; Female; Fluconazole; Fungemia; Graft vs Host Disease; Humans; Immunocompromised Host; Immunosuppressive Agents; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Scedosporium; Triazoles; Voriconazole; Young Adult

To describe the clinical manifestations and diagnosis of pulmonary mucormycosis.. We presented 5 proven diagnosed cases of pulmonary mucormycosis in our hospital and reviewed all proven cases of pulmonary mucormycosis previously reported in mainland China. Publications in the form of case reports and articles between January 1982 and December 2011 were searched from Wan Fang Data and China Hospital Knowledge Database.. Of the 5 patients in our hospital, the main symptoms included cough, fever, and hemoptysis. Two cases were diagnosed by transbronchial lung biopsy (TBLB), 1 by surgery, 1 by CT-guided percutaneous lung biopsy, and 1 by blood culture. Three patients were cured by antifungal chemotherapy alone, 1 was cured by surgery, and 1 died. Forty-six proven diagnosed cases of pulmonary mucormycosis were retrieved from Wan Fang Data and China Hospital Knowledge Database using key word (pulmonary mucormycosis). Of the 51 patients in total, there were 31 males and 20 females, with a mean age of (47 ± 13)years. The most common risk factors for pulmonary mucormycosis were poorly controlled diabetes mellitus (18 cases), administration of immunosuppressants (7 cases), malignancy (5 cases) and kidney diseases (5 cases). Chest CT showed nodules (27 cases), infiltrates (21 cases), and cavities (18 cases). White blood cell count and neutrophil percentage were elevated in 26 patients. Eighteen cases were diagnosed by histological study of transbronchial biopsy or TBLB specimen. The diagnosis was proven with surgical specimen in 15 patients, CT-guided percutaneous lung biopsy specimen in 7 patients, autopsy in 4 patients, skin biopsy in 1 patient, and renal biopsy in one patient. Three cases were diagnosed by pleural effusion cultures and 2 were diagnosed by blood cultures. Administration of low-dose liposomal amphotericin B (AMB) alone or combined with posaconazole in 12 patients were effective and safe. Fourteen patients who had received surgical resection were cured.. There were no specific clinical features of pulmonary mucormycosis. Transbronchial biopsy and CT-guided percutaneous lung biopsy are useful diagnostic tools for pulmonary mucormycosis. Surgical resection and administration of low-dose liposomal AMB alone or combined with posaconazole were all effective and safe.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Biopsy, Needle; Bronchoscopy; Drug Therapy, Combination; Female; Humans; Lung; Lung Diseases, Fungal; Male; Middle Aged; Mucormycosis; Risk Factors; Tomography, X-Ray Computed; Triazoles; Young Adult

Zygomycosis can manifest as severe infections, particularly in immunocompromised patients, which can be nosocomial in nature resulting from complications of invasive procedures. We report the case of a 65-year-old woman with a medical history of unclassified inflammatory rheumatism who underwent arteriovenous extracorporeal membrane oxygenation because of a myocardial failure following the drainage of a tuberculous tamponade. This procedure was complicated by a superinfection of the scarpa which revealed a disseminated zygomycosis with renal involvement. A favorable outcome was achieved after 15 months of antifungal therapy involving the use of liposomal amphotericin B followed with posaconazole which involved the close monitoring of the concentrations of this antifungal. Extracorporeal membrane oxygenation is a frequent procedure which could be complicated with severe fungal nosocomial infections such as zygomycosis. The outcome of such complication can be favorable with the utilization of new antifungal therapies.

Topics: Acute Kidney Injury; Aged; Amphotericin B; Antifungal Agents; Cross Infection; Extracorporeal Membrane Oxygenation; Female; France; Heart Failure; Humans; Immunocompromised Host; Kidney; Mucormycosis; Rheumatic Fever; Rhizopus; Treatment Outcome; Triazoles; Tuberculosis, Pulmonary

Rhinocerebral mucormycosis is a rare, rapidly progressive life threatening opportunistic fungal disease that usually occurs in immunocompromised patients.. The aim of the study is to present a case series of six immunocompromised patients who were diagnosed with rhinocerebral mucormycosis, review the diagnostic criteria and treatment approach.. Six patients were treated in our department between the years 2005-2010. Their diagnostic criteria, surgical treatment and mortality rate are analyzed and discussed.. All six immunocompromised patients suffered from a primary hematological malignancy and received chemotherapy to treat their primary disease. Symptoms such as pain mimicking sinusitis, facial swelling, oral or dental pain, and fever were found in most patients. The diagnosis was based on both clinical signs and a biopsy for microbiological culture and histological examination. All patients underwent aggressive surgical resection and were treated simultaneously with anti fungal therapy. Four patients died from their primary illness. One patient died due to uncontrolled spreading of mucormycosis and one patient, the youngest and with the most extensive form of the disease (brain invasion) survived and clinically recovered with no evidence of recurrent disease following the surgical management.. Rhinocerebral mucormycosis is a rapidly progressing disease with a high mortality rate, which requires immediate surgical and medical intervention. It seems from the data presented that the presence of mucormycosis is an ominous sign in immunocompromised patients. The extent of the disease is of less prognostic value, since the only patients in our series who survived had the most extensive disease, yet his primary haemato-oncological disease was under control. Controlling the underlying disease with early diagnosis and aggressive surgical intervention appears to be the most important factor for survival.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Brain Diseases; Cause of Death; Combined Modality Therapy; Diagnosis, Differential; Fatal Outcome; Female; Hematologic Neoplasms; Humans; Immunocompromised Host; Male; Maxillary Sinusitis; Middle Aged; Mucormycosis; Nose Diseases; Paranasal Sinus Diseases; Pyrimidines; Triazoles; Voriconazole; Young Adult

Topics: Acute Kidney Injury; Adult; Amphotericin B; Antifungal Agents; Debridement; Echinocandins; Humans; Lipopeptides; Lung Diseases, Fungal; Male; Micafungin; Mucormycosis; Pneumonectomy; Triazoles

Pulmonary zygomycosis, also referred to as mucormycosis, is a fungal infection of lungs caused by fungi of the order Mucorales in the class of Zygomycetes. It is usually associated with high morbidity and mortality. Here, we report the case of a 14-year-old girl with pediatric acute promyelocytic leukemia (APL) on antifungal prophylaxis with posaconazole, who developed pulmonary Lichtheimia corymbifera (formerly Absidia corymbifera) zygomycosis. She was successfully treated by means of liposomal amphotericin B (L-AmB) and surgery. To our knowledge, this is the first published report on pediatric APL and pulmonary zygomycosis in the English language literature. At present, the patient is in complete remission of her APL and without any signs of recurrence of zygomycosis. This report suggests that efficient diagnostics, increased physician awareness, and reliance on adjunctive surgical therapy can result in a favorable outcome of pulmonary zygomycosis in immunocompromised children with hematological malignancies.

Topics: Absidia; Adolescent; Amphotericin B; Antifungal Agents; Female; Humans; Immunocompromised Host; Leukemia, Promyelocytic, Acute; Lung Diseases, Fungal; Mucormycosis; Pneumonectomy; Triazoles

The in vitro antifungal susceptibility of 77 isolates belonging to different clinically relevant species of Aspergillus section Flavi, including those of different phylogenetic clades of A. flavus, was tested for nine antifungal agents using a microdilution reference method (CLSI, M38-A2). Terbinafine and the echinocandins demonstrated lower MICs/MECs for all species evaluated, followed by posaconazole. Amphotericin B showed MICs ≥ 2 μg/ml for 38 (49.4%) of the 77 isolates tested.

Topics: Amphotericin B; Antifungal Agents; Aspergillus; Echinocandins; Microbial Sensitivity Tests; Naphthalenes; Phylogeny; Terbinafine; Triazoles

A global collection of Cladophialophora carrionii strains (n = 81) was tested against nine antifungal drugs. MIC90s of all strains were as follows in increasing order: itraconazole and posaconazole, 0.063 μg/ml; terbinafine, 0.125 μg/ml; isavuconazole and voriconazole, 0.25 μg/ml; caspofungin, 2 μg/ml; micafungin, 4 μg/ml; amphotericin B, 8 μg/ml; and fluconazole, 64 μg/ml.

Topics: Amphotericin B; Antifungal Agents; Ascomycota; Caspofungin; Chromoblastomycosis; Echinocandins; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Nitriles; Pyridines; Pyrimidines; Triazoles; Voriconazole

We describe a case of disseminated Sporothrix schenckii infection in a man with underlying hairy cell leukemia. The immunological defects associated with this malignancy, as well as the management of refractory sporotrichosis are reviewed.

Topics: Adult; Amphotericin B; Antifungal Agents; Humans; Leg; Leukemia, Hairy Cell; Male; Skin; Sporothrix; Sporotrichosis; Triazoles

A 59-year-old male with acute lymphoblastic leukemia developed sinus, tracheobroncheal, pulmonary, and intracerebral aspergillosis. All lesions except the intracerebral aspergillosis healed after combination antifungal treatment. Long-term voriconazole--but not posaconazole--therapy induced partial regression of the cerebral manifestations. At the time of writing, 3.5 years after the initial diagnosis, the patient is working half-time and suffers from a possible voriconazole-induced polyneuropathy.

Topics: Amphotericin B; Antifungal Agents; Aspergillus fumigatus; Brain; Caspofungin; Cerebrum; Echinocandins; Humans; Larynx; Lipopeptides; Lung; Magnetic Resonance Imaging; Male; Middle Aged; Neuroaspergillosis; Paranasal Sinuses; Peripheral Nervous System Diseases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pulmonary Aspergillosis; Pyrimidines; Sweden; Tomography, X-Ray Computed; Triazoles; Voriconazole

Many case reports suggest that the use of hyperbaric oxygen therapy associated with surgical and medical approaches may contribute to restricting the growth of zygomycetes in patient tissue. The primary aim of this study was to obtain data concerning the in vitro susceptibility of 22 zygomycetes to antifungals such as amphotericin B and posaconazole, and to compare the in vitro development of these fungi in aerobic normobaric versus hyperoxic normobaric and hyperbaric atmosphere. None of the zygomycetes grew after 24-hour and 72-hour incubation in a hyperoxic hyperbaric (2 or 3 ATA) atmosphere. However, when plates were maintained at room temperature in aerobic conditions, colonies were observed from 36-96 h after inoculation, while minimum inhibitory concentration (MIC) values remained the same. This preliminary in vitro study focuses on the in vitro examination of combination therapies to potentiate antifungal activity. Both hyperoxic hyperbaric conditions and a single antifungal agent, as well as combinations of different antifungal drugs were used. Results suggest an impressive in vitro fungistatic activity of the hyperoxic hyperbaric atmosphere, even if the antifungal effect is strictly time-dependent using these incubation conditions.

Topics: Aerobiosis; Amphotericin B; Antifungal Agents; Atmospheric Pressure; Fungi; Humans; Microbial Sensitivity Tests; Triazoles; Zygomycosis

We investigated the triazole, amphotericin B, and micafungin susceptibilities of 196 A. fumigatus clinical isolates in Nagasaki, Japan. The percentages of non-wild-type (non-WT) isolates for which MICs of itraconazole, posaconazole, and voriconazole were above the ECV were 7.1%, 2.6%, and 4.1%, respectively. A G54 mutation in cyp51A was detected in 64.2% (9/14 isolates) and 100% (5/5 isolates) of non-WT isolates for itraconazole and posaconazole, respectively. Amphotericin B MICs of ≥2 μg/ml and micafungin minimum effective concentrations (MECs) of ≥16 μg/ml were recorded for two and one isolates, respectively.

Topics: Amino Acid Substitution; Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Cytochrome P-450 Enzyme System; Drug Resistance, Fungal; Echinocandins; Female; Fungal Proteins; Humans; Itraconazole; Japan; Lipopeptides; Male; Micafungin; Microbial Sensitivity Tests; Mutation; Pyrimidines; Sequence Analysis, DNA; Triazoles; Voriconazole

The purpose of this study was to investigate the performance of non-invasive diagnostic tests such as galactomannan enzyme immunoassay and quantitative PCR in the early diagnosis of invasive aspergillosis (IA), and how these tests are impacted upon by the use of different classes of antifungal agents in an in-vivo model of IA.. A standardised rat inhalation model of IA was used to examine the effects of an azole, posaconazole, a polyene, amphotericin B and an echinocandin caspofungin. Daily blood samples were collected for subsequent analysis using a commercially available galactomannan assay and an inhouse qPCR assay.. No significant differences were observed in the CE/g of Aspergillus fumigatus in the lungs of each group. qPCR was statistically more sensitive than galactomannan for both the early detection of infected controls (p=0.045) and for overall detection (p=0.018). However, antifungal treatment significantly reduced the overall sensitivity of qPCR (p=0.020); these effects were due to posaconazole and caspofungin. In the latter stages of infection (days 4 and 5) there were no significant differences in the numbers of infections detected by galactomannan and qPCR; however, the antifungal class used caused significant qualitative differences (p=0.041). Galactomannan showed improved detection in posaconazole-treated animals.. Previous exposure to antifungal therapy must be considered when interpreting either qPCR or galactomannan-based IA diagnostics as this study has shown that individual classes of antifungal agents impact upon the dynamics of antigen and DNA release into the circulation.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillus fumigatus; Biomarkers; Caspofungin; Disease Models, Animal; DNA, Fungal; Early Diagnosis; Echinocandins; Galactose; Immunoenzyme Techniques; Invasive Pulmonary Aspergillosis; Lipopeptides; Mannans; Microbiological Techniques; Mycological Typing Techniques; Predictive Value of Tests; Rats; Real-Time Polymerase Chain Reaction; Time Factors; Triazoles

Fusarium (n = 67) and Scedosporium (n = 63) clinical isolates were tested by two reference broth microdilution (BMD) methods against a novel broad-spectrum (active against both yeasts and molds) antifungal, E1210, and comparator agents. E1210 inhibits the inositol acylation step in glycophosphatidylinositol (GPI) biosynthesis, resulting in defects in fungal cell wall biosynthesis. Five species complex organisms/species of Fusarium (4 isolates unspeciated) and 28 Scedosporium apiospermum, 7 Scedosporium aurantiacum, and 28 Scedosporium prolificans species were identified by molecular techniques. Comparator antifungal agents included anidulafungin, caspofungin, itraconazole, posaconazole, voriconazole, and amphotericin B. E1210 was highly active against all of the tested isolates, with minimum effective concentration (MEC)/MIC(90) values (μg/ml) for E1210, anidulafungin, caspofungin, itraconazole, posaconazole, voriconazole, and amphotericin B, respectively, for Fusarium of 0.12, >16, >16, >8, >8, 8, and 4 μg/ml. E1210 was very potent against the Scedosporium spp. tested. The E1210 MEC(90) was 0.12 μg/ml for S. apiospermum, but 1 to >8 μg/ml for other tested agents. Against S. aurantiacum, the MEC(50) for E1210 was 0.06 μg/ml versus 0.5 to >8 μg/ml for the comparators. Against S. prolificans, the MEC(90) for E1210 was only 0.12 μg/ml, compared to >4 μg/ml for amphotericin B and >8 μg/ml for itraconazole, posaconazole, and voriconazole. Both CLSI and EUCAST methods were highly concordant for E1210 and all comparator agents. The essential agreement (EA; ±2 doubling dilutions) was >93% for all comparisons, with the exception of posaconazole and F. oxysporum species complex (SC) (60%), posaconazole and S. aurantiacum (85.7%), and voriconazole and S. aurantiacum (85.7%). In conclusion, E1210 exhibited very potent and broad-spectrum antifungal activity against azole- and amphotericin B-resistant strains of Fusarium spp. and Scedosporium spp. Furthermore, in vitro susceptibility testing of E1210 against isolates of Fusarium and Scedosporium may be accomplished using either of the CLSI or EUCAST BMD methods, each producing very similar results.

Topics: Acylation; Aminopyridines; Amphotericin B; Anidulafungin; Antifungal Agents; Caspofungin; Echinocandins; Fusarium; Glycosylphosphatidylinositols; Humans; Inositol; Isoxazoles; Itraconazole; Lipopeptides; Microbial Sensitivity Tests; Pyrimidines; Scedosporium; Triazoles; Voriconazole

The in vitro susceptibility of 17 strains of Mucor circinelloides to amphotericin B and posaconazole was ascertained by using broth microdilution and disk diffusion methods and by determining the minimal fungicidal concentration (MFC). We evaluated the efficacy of posaconazole at 40 mg/kg of body weight/day and amphotericin B at 0.8 mg/kg/day in a neutropenic murine model of disseminated infection by M. circinelloides by using 6 different strains tested previously in vitro. In general, most of the posaconazole MICs were within the range of susceptibility or intermediate susceptibility, while the small inhibition zone diameters (IZDs) were indicative of nonsusceptibility for all isolates tested. The MFCs were ≥ 3 dilutions higher than the corresponding MICs. In contrast, amphotericin B showed good activity against all of the strains tested regardless of the method used. The in vivo studies demonstrated that amphotericin B was effective in prolonging survival and reducing the fungal load. Posaconazole showed poor in vivo efficacy with no correlation with the MIC values. The results suggested that posaconazole should be used with caution in the treatment of infections caused by Mucor circinelloides or by strains of Mucor not identified to the species level.

Topics: Amphotericin B; Animals; Antifungal Agents; Brain; Disease Models, Animal; Drug Resistance, Fungal; Kidney; Male; Mice; Microbial Sensitivity Tests; Mucor; Mucormycosis; Neutropenia; Species Specificity; Survival Rate; Treatment Failure; Triazoles

We developed a murine model of systemic sporotrichosis by using three strains of each of the two commonest species causing sporotrichosis, i.e., Sporothrix schenckii sensu stricto and Sporothrix brasiliensis, in order to evaluate the efficacy of posaconazole (PSC). The drug was administered at a dose of 2.5 or 5 mg/kg of body weight twice a day by gavage, and one group was treated with amphotericin B (AMB) as a control treatment. Posaconazole, especially at 5 mg/kg, showed good efficacy against all the strains tested, regardless of their MICs, as measured by prolonged survival, tissue burden reduction, and histopathology.

Topics: Administration, Oral; Amphotericin B; Animals; Antifungal Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Histocytochemistry; Liver; Male; Mice; Microbial Sensitivity Tests; Species Specificity; Sporothrix; Sporotrichosis; Survival Rate; Treatment Outcome; Triazoles

We evaluated the in vitro activity of posaconazole and amphotericin B against several clinical strains of the mucoralean fungus Apophysomyces variabilis, and their efficacy in a murine model of disseminated infection caused by that fungus.. The in vitro susceptibility of seven strains of A. variabilis to posaconazole and amphotericin B was determined by using a broth microdilution method. The in vivo efficacy of both drugs, posaconazole at 20 mg/kg twice daily orally by gavage and amphotericin B at 0.8 mg/kg once daily intravenously, was evaluated against six of the strains previously tested in vitro using immunocompetent mice.. In general, MICs of both drugs were within the range of susceptibility or intermediate susceptibility. Posaconazole and amphotericin B were able to significantly reduce the percentages of positive cultures in the affected tissues. However, in general, posaconazole significantly improved survival (median, 23 days; range, 7-30 days) compared with untreated controls (median, 6 days; range, 4-7 days) and, in some cases, with respect to the animals treated with amphotericin B (median, 15 days; range, 5-30 days).. Our results demonstrate the efficacy of posaconazole in the treatment of a disseminated murine infection caused by A. variabilis. However, further clinical studies are required to ascertain the potential use in human infections caused by this fungus.

Topics: Amphotericin B; Animals; Antifungal Agents; Disease Models, Animal; Humans; Injections, Intravenous; Male; Mice; Microbial Sensitivity Tests; Mucorales; Mucormycosis; Treatment Outcome; Triazoles

We have determined the in vitro activity of amphotericin B (AMB) and posaconazole (PSC) against Saksenaea vasiformis using broth microdilution and disk diffusion methods and determined the minimal fungicidal concentration (MFC). PSC was found to have the greatest in vitro activity in all cases and was the most efficacious in prolonging survival and reducing the fungal load in an immunocompetent murine model of disseminated infection caused by four strains of the fungus.

Topics: Amphotericin B; Animals; Antifungal Agents; Disease Models, Animal; Male; Mice; Microbial Sensitivity Tests; Mucorales; Mucormycosis; Treatment Outcome; Triazoles

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

The European Committee on Antimicrobial Susceptibility Testing Subcommittee on Antifungal Susceptibility Testing (EUCAST-AFST) has determined breakpoints for amphotericin B, itraconazole and posaconazole for Aspergillus species. This Technical Note is based on the EUCAST amphotericin B, itraconazole and posaconazole rationale documents (available on the EUCAST website: http://www.eucast.org/antifungal_susceptibility_testing_afst/rationale_documents_for_antifungals/). The amphotericin B and itraconazole breakpoints are based on epidemiological cut-off values and clinical experience. The posaconazole breakpoints are also based on pharmacokinetic and pharmacodynamic data. Breakpoints will be reviewed regularly or when new data emerge.

Topics: Amphotericin B; Antifungal Agents; Aspergillus; Europe; Humans; Itraconazole; Microbial Sensitivity Tests; Triazoles

Aspergillosis and zygomycosis are life-threatening fungal infections in immunocompromised patients. We report a heart transplant recipient with an early pulmonary invasive aspergillosis successfully treated with association of voriconazole and caspofungin. Zygomycosis sinusitis, which was diagnosed while he still was on voriconazole therapy, was successfully treated with the use of combination antifungal therapy including liposomal amphotericin plus posaconazole and conservative surgical debridement.

Topics: Amphotericin B; Antifungal Agents; Debridement; Drug Therapy, Combination; Heart Transplantation; Humans; Immunocompromised Host; Invasive Pulmonary Aspergillosis; Male; Middle Aged; Pyrimidines; Sinusitis; Treatment Outcome; Triazoles; Voriconazole; Zygomycosis

Central nervous system infections caused by Cryptococcus neoformans remain to be opportunistic infections with high mortality in severely immunocompromised patients such as patients with AIDS. Amphotericin B deoxycholate and fluconazole remain to be the drugs of choice; however, in consideration of the intolerance to amphotericin B deoxycholate and the possible resistance to fluconazole, it is necessary to evaluate other azoles, such as posaconazole, that have demonstrated lower adverse events. The objective of this study was to describe the characteristics and clinical and microbiological response of the use of posaconazole in patients with CNS infections caused by C. neoformans.. We designed a case study that included eight patients diagnosed with AIDS and cryptococcal meningitis. Seven patients were treated with 800 mg of posaconazole orally for 28 days.. During the second week of treatment, a cerebrospinal fluid (CSF) culture was performed and was negative for the development of C. neoformans. The patients showed an improvement in signs and symptoms of impairment of the CNS such as reduction of cephalea, fever, visual disturbances such as double vision, meningism and papilledema, and improved alertness and environmental awareness.. CNS fungal infections usually occur in immunocompromised patients. The use of systemic antifungal agents contributes to the development of fungal resistance. The results of this study suggest that posaconazole is a good alternative in the treatment of fungal CNS infection due to C. neoformans.

Topics: Administration, Oral; Adult; AIDS-Related Opportunistic Infections; Amphotericin B; Antifungal Agents; Cryptococcus neoformans; Humans; Male; Meningitis, Cryptococcal; Mexico; Microbial Sensitivity Tests; Treatment Outcome; Triazoles

Cyphellophora guyanensis (n = 15), other Cyphellophora species (n = 11), Phialophora europaea (n = 43), and other Phialophora species (n = 12) were tested in vitro against nine antifungal drugs. The MIC(90)s across all of the strains (n = 81) were, in increasing order, as follows: posaconazole, 0.063 μg/ml; itraconazole, 0.5 μg/ml; voriconazole, 1 μg/ml; micafungin, 1 μg/ml; terbinafine, 2 μg/ml; isavuconazole, 4 μg/ml; caspofungin, 4 μg/ml; fluconazole, 8 μg/ml; amphotericin B, 16 μg/ml.

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Echinocandins; Fluconazole; Itraconazole; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Mitosporic Fungi; Naphthalenes; Nitriles; Phialophora; Pyridines; Pyrimidines; Terbinafine; Triazoles; Voriconazole

Mucormycosis is a rare but emerging fungal infection complicating solid organ transplantation (SOT), with a cumulative incidence of around 2% during the first year after SOT. The associated mortality rate is high, and surgical debridement is frequently required as part of the treatment along with antifungal therapy based mostly on amphotericin B formulations, We describe here an unusual case of hepatic mucormycosis in a liver transplant recipient that was successfully treated with clinical therapy based on liposomal amphotericin B followed by posaconazole, without surgical resection.

Topics: Amphotericin B; Antifungal Agents; Drug Administration Schedule; Female; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Mucormycosis; Time Factors; Treatment Outcome; Triazoles; Young Adult

The present work aimed to investigate the curative effect of benznidazole (BZL) in combination with other patented drugs [nifurtimox (NFX), posaconazole (POS) or AmBisome(®) (AMB)] in mice acutely or chronically infected with either a BZL-susceptible (Tulahuen) or a BZL-partially-resistant (Y) strain of Trypanosoma cruzi. To appreciate the eventual advantage of such combinations, infected mice were treated for short durations (non-curative) of each individual treatment. Cure rates were determined by investigating blood parasites (microscopic examination) and parasite DNA (quantitative PCR) after submitting treated mice to immune suppression with cyclophosphamide. The results mainly suggest that shorter durations of treatment combining BZL and POS or NFX might cure mice acutely or chronically infected with the Tulahuen strain, whereas the combination of BZL with AMB does not have such an effect. Moreover, the association BZL+POS does not improve the curative effect of POS (all used for shorter durations) in infection with the Y strain. Shortening the duration of treatment whilst keeping a complete curative effect deserves interest in limiting adverse reactions due to dose-cumulative toxic effects of long treatment. Genotyping of the T. cruzi strain(s) infecting patients might also allow a better adaptation of individual therapeutic schedules, improving both the efficiency and safety of trypanocidal treatment. This preliminary experimental study should encourage further investigations to find the best combination of adequate drug concentrations and timing of treatment.

Topics: Amphotericin B; Animals; Chagas Disease; Disease Models, Animal; DNA, Protozoan; Drug Therapy, Combination; Female; Mice; Mice, Inbred BALB C; Nifurtimox; Nitroimidazoles; Parasite Load; Parasitemia; Real-Time Polymerase Chain Reaction; Treatment Outcome; Triazoles; Trypanocidal Agents; Trypanosoma cruzi

A retrospective study of 35 case reports of Aspergillus endocarditis published between 2003 and 2009 was carried out. Fifteen percent of cases presented with a new cardiac murmur, 38% with an embolus. Eighty percent of cases involved the aortic or mitral valves. Seventy-four percent of cases involved patients with a history of prior surgery, 48% of these involved a heart valve, 20% had other cardiac surgery and 32% had non-cardiac surgery. Galactomannan testing was helpful diagnostically in four out of nine cases, but PCR testing was positive in six out of six cases. Overall mortality was 68%, all eight survivors had heart valve surgery apart from one - an 8-month-old child. Seven out of eight survivors received liposomal amphotericin B, three of these in combination with other antifungals. We need to think more about the possibility of Aspergillus endocarditis, particularly in immunocompromised patients with recent surgery. Galactomannan and PCR testing may be used more vigorously. Valve replacement, or at least vegetectomy, should be carried out in all patients. Liposomal amphotericin B, 3-5mg/kg/day, for at least 4 weeks is the treatment of choice. Oral voriconazole should be used for at least 2 years. Posaconazole may be an alternative, however there have been no prior cases reported to suggest its efficacy. The value of combination antifungal therapy is uncertain, but consideration should be given to the use of a second agent in addition to liposomal amphotericin. While further case reports on this condition will be helpful, more definitive management guidelines will depend on a prospective study.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus; Child; Child, Preschool; Endocarditis; Humans; Immunocompromised Host; Infant; Male; Middle Aged; Pyrimidines; Retrospective Studies; Surgical Procedures, Operative; Triazoles; Voriconazole; Young Adult

Two new species in the order Mucorales, Mucor velutinosus and Mucor ellipsoideus, isolated from human clinical specimens in the USA, are described and illustrated. The former species is similar to Mucor ramosissimus, from which it can be differentiated by its ability to grow at 37°C and produce verrucose sporangiospores. Mucor ellipsoideus is also able to grow and sporulate at 37°C like M. indicus, the nearest phylogenetic species in this study, however, the former has narrow ellipsoidal sporangiospores in contrast to the subglobose to ellipsoidal sporangiospores of M. indicus. Analysis of the sequences of the ITS and the D1-D2 regions of the rRNA genes confirmed the novelty of these species. The in vitro antifungal susceptibility of the new species showed that amphotericin B was active against all isolates and posaconazole and itraconazole showed low activity.

Topics: Amphotericin B; Antifungal Agents; DNA, Fungal; DNA, Ribosomal; DNA, Ribosomal Spacer; Humans; Itraconazole; Microbial Sensitivity Tests; Molecular Sequence Data; Mucorales; Mucormycosis; Mycological Typing Techniques; Phylogeny; Sequence Analysis, DNA; Temperature; Triazoles; United States

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

There are few multilaboratory studies of antifungal combination testing to suggest a format for use in clinical laboratories. In the present study, eight laboratories tested quality control (QC) strain Candida parapsilosis ATCC 22019 and clinical isolates Candida albicans 20533.043, C. albicans 20464.007, Candida glabrata 20205.075, and C. parapsilosis 20580.070. The clinical isolates had relatively high azole and echinocandin MICs. A modified CLSI M27-A3 protocol was used, with 96-well custom-made plates containing checkerboard pairwise combinations of amphotericin B (AMB), anidulafungin (AND), caspofungin (CSP), micafungin (MCF), posaconazole (PSC), and voriconazole (VRC). The endpoints were scored visually and on a spectrophotometer or enzyme-linked immunosorbent assay (ELISA) reader for 50% growth reduction (50% inhibitory concentration [IC(50)]). Combination IC(50)s were used to calculate summation fractional inhibitory concentration indices (FICIs) (ΣFIC) based on the Lowe additivity formula. The results revealed that the IC(50)s of all drug combinations were lower or equal to the IC(50) of individual drugs in the combination. A majority of the ΣFIC values were indifferent (ΣFIC = 0.51 to 2.0), but no antagonism was observed (ΣFIC ≥ 4). Synergistic combinations (ΣFIC ≤ 0.5) were found for AMB-PSC against C. glabrata and for AMB-AND and AMB-CSP against C. parapsilosis by both visual and spectrophotometric readings. Additional synergistic interactions were revealed by either of the two endpoints for AMB-AND, AMB-CSP, AMB-MCF, AMB-PSC, AMB-VRC, AND-PSC, CSP-MCF, and CSP-PSC. The percent agreements among participating laboratories ranged from 37.5% (lowest) for AND-CSP and POS-VOR to 87.5% (highest) for AMB-MCF and AND-CSP. Median ΣFIC values showed a wide dispersion, and interlaboratory agreements were less than 85% in most instances. Additional studies are needed to improve the interlaboratory reproducibility of antifungal combination testing.

Topics: Amphotericin B; Anidulafungin; Antifungal Agents; Candida; Candida glabrata; Caspofungin; Drug Combinations; Echinocandins; Enzyme-Linked Immunosorbent Assay; Inhibitory Concentration 50; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Pyrimidines; Triazoles; Voriconazole

Immunosuppressive agents increase the vulnerability of solid organ transplant patients to opportunistic infections. An atypical clinical presentation of a bacterial and fungal co-infection makes diagnosis and treatment even more challenging in this population. A 54-year-old hypertensive woman underwent a cadaveric kidney transplant after years on hemodialysis. Her treatment included mycophenolate, tacrolimus, and prednisone. By post-transplant week 8, she had pneumonia followed by progressive visual changes and seizures. Diagnostic work-up, consisting of magnetic resonance imaging of the brain and chest x-ray, showed several cerebral ring-enhancing lesions, and a pulmonary cavitary lesion. Disseminated nocardiosis was suspected and therapy was started. Skin biopsy was taken from a nodular lesion and culture confirmed Nocardia species infection. During hospitalization, neurological deficit persisted with worsening of brain lesions. She underwent excision of a brain abscess and the final pathologic report showed mucormycosis, revealing the patient's co-infection by 2 different pathogens. After therapy with liposomal amphotericin B and posaconazole, she has remained stable for more than 1 year. Disseminated nocardiosis masked and delayed the diagnosis and treatment of a more aggressive and worrisome organism. Mucormycosis, as a non-fatal isolated brain abscess without rhinal involvement, is an atypical presentation, and only a few cases have been reported.

Topics: Amphotericin B; Antifungal Agents; Brain Abscess; Coinfection; Female; Humans; Kidney Transplantation; Middle Aged; Nocardia; Nocardia Infections; Opportunistic Infections; Pneumonia, Bacterial; Radiography; Triazoles; Zygomycosis

The occurrence of infections due to previously rare opportunistic pathogens is increasing despite the use of novel treatment strategies for immunocompromised patients. Here, we report the case of a patient presenting with fever, muscle pain, and bilateral endophthalmitis after allogeneic hematopoietic stem cell transplantation. Fusarium solani was isolated from peripheral blood samples and identified as the cause of gradual bilateral vision loss, despite appropriate antifungal prophylaxis, and therapy including vitrectomy and intraocular instillation of antifungal agents. The patient became comatose; basal meningitis involving both optic nerves was suspected based on magnetic resonance tomography. The patient died 8 days later due to septic multi-organ failure. Autopsy revealed that both kidneys, but no other organs, were infiltrated by Fusarium. No fungus was found in cerebral tissues or cerebrospinal fluid. Our case demonstrates some of the typical clinical features of systemic fusariosis and its potentially fatal outcome. The clinical observations reported here may help clinicians caring for immunocompromised patients to accelerate diagnosis and initiate treatment early at the onset of this fatal complication, and highlight the urgent need for interdisciplinary management of invasive fusariosis.

Topics: Aged; Amphotericin B; Antifungal Agents; Endophthalmitis; Eye Infections, Fungal; Fatal Outcome; Fusariosis; Fusarium; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Male; Transplantation, Homologous; Triazoles

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

A three-month laboratory-based prospective survey was conducted at four major university hospitals covering one-third of the Danish population in order to determine the prevalence, significance, and susceptibility pattern of aspergilli in airway samples. Samples received in January-March 2007 for routine microbiologic investigation were examined for Aspergillus following routine procedures and with extended incubation (5 days). Identification was done by morphologic criteria and susceptibility testing using EUCAST method for azoles and amphotericin B E-test. Invasive aspergillosis (IA) was evaluated using modified EORTC/MSG criteria. A total of 11,368 airway samples were received. Growth of Aspergillus spp. was found in 129 and 151 patients using routine and extended incubation, respectively. Three patients had proven IA (2%), 11 probable (7%), four had allergic bronchopulmonary aspergillosis (ABPA) (3%), but the majority was colonised (88%). Underlying conditions were cystic fibrosis in 82 patients (55%), chronic obstructive pulmonary disease in 19 (13%) and haematological disorder in 11 (7%). Twenty-six patients (18%) were at intensive care unit and 69 (47%) received steroid treatment. Azole MICs were elevated for five isolates as follows (itraconazole, posaconazole, voriconazole MICs [mg/L]): two A. fumigatus isolates (>4; >4; 2 and >4; 0.125; 1), one A. lentulus isolate (2; 2; 0.5) and two A. terreus isolates (2; 2; 2 and 2; 0.125; 1). For four isolates the amphotericin B MIC was >1 μg/ml (3/112 A. fumigatus, 1/2 A. terreus). In conclusion, Aspergillus appears to be an important pathogen in Denmark. Elevated itraconazole MICs were detected in 4% of the isolates including a multi-azole resistant isolate.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus; Child; Child, Preschool; Denmark; Drug Resistance, Fungal; Female; Hospitals; Humans; Itraconazole; Male; Microbial Sensitivity Tests; Middle Aged; Prevalence; Prospective Studies; Pyrimidines; Respiratory System; Respiratory Tract Infections; Treatment Outcome; Triazoles; Voriconazole

Topics: Amphotericin B; Antifungal Agents; Humans; Kidney Transplantation; Lung Diseases, Fungal; Male; Middle Aged; Mucormycosis; Radiography, Thoracic; Rhizopus; Triazoles

Cerebral mucormycosis without systemic foci of involvement is a rare life-threatening fungal infection that is reported to be more common in intravenous drug abusers. We present a case of isolated cerebral mucormycosis in a diabetic patient diagnosed through excision and biopsy and treated with combination of surgery and amphotericin with posaconazole.

Topics: Amphotericin B; Antifungal Agents; Biopsy; Brain Diseases; Combined Modality Therapy; Diabetes Mellitus, Type 2; Diagnosis, Differential; Drug Therapy, Combination; Endoscopy; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Mucormycosis; Tomography, X-Ray Computed; Triazoles

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

The objective of this paper is to review a recent case of rhino-orbital-cerebral mucormycosis that involved the successful treatment of an immunocompromised male patient that took place in a deployed military setting. In this interventional case review, a comprehensive evaluation of predisposing factors, presenting signs and symptoms, diagnostic evaluation, and treatment will be discussed in detail. The patient was a 38-yr-old noncompliant insulin-dependent diabetes mellitus Iraqi man whose initial presentation encompassed nonspecific signs and symptoms consistent with sinusitis. Symptoms progressed rapidly including the development of acute visual loss, unilateral facial edema, fixed dilated right pupil, loss of extraocular movements, and oropharyngeal eschar formation. With this progressive clinical picture, a diagnosis of mucormycosis was made in the absence of histological confirmation due to the nature of the deployed environment. Treatment included hospitalization for combined intervention with intravenous antifungal therapy and a series of surgeries which ultimately resulted in orbital exenteration and preservation of life. Successful treatment was attributed to having a high index of suspicion in the clinical presentation of nonspecific otorhinolaryngological and ophthalmological symptoms superimposed with underlying predisposing immunocompromised host conditions.

Topics: Adult; Amphotericin B; Antifungal Agents; Brain Diseases; Debridement; Diabetes Insipidus, Nephrogenic; Diabetes Mellitus, Type 1; Disease Progression; Eye Infections, Fungal; Humans; Immunocompromised Host; Magnetic Resonance Imaging; Male; Mucormycosis; Nose Diseases; Orbital Diseases; Tomography, X-Ray Computed; Triazoles

Topics: Aged; Amphotericin B; Antifungal Agents; British Columbia; Bromhexine; Cryptococcosis; Cryptococcus gattii; Flucytosine; Humans; Lung Diseases, Fungal; Male; Microbial Sensitivity Tests; Radiography; Triazoles

Topics: Amphotericin B; Antifungal Agents; Biopsy; Debridement; Fatal Outcome; Female; Hemochromatosis; Hepatic Encephalopathy; Humans; Intubation, Gastrointestinal; Liver; Liver Failure, Acute; Middle Aged; Mucormycosis; Necrosis; Nose; Nose Diseases; Opportunistic Infections; Triazoles

The in vivo efficacy of posaconazole against 4 clinical Aspergillus fumigatus isolates with posaconazole MICs ranging from 0.03 to 16 mg/liter, as determined by CLSI method M38A, was assessed in a nonneutropenic murine model of disseminated aspergillosis. The underlying resistance mechanisms of the isolates included substitutions in the cyp51A gene at codon 220 (M220I), codon 54 (G54W), and codon 98 (L98H). The latter was combined with a 34-bp tandem repeat in the gene promoter region (TR L98H). The control isolate exhibited a wild-type phenotype without any known resistance mechanism. Oral posaconazole therapy was started 24 h after infection and was given once daily for 14 consecutive days. Mice were treated with four different doses (1 to 64 mg/kg of body weight), and survival was used as the end point. Survival was dependent both on the dose and on the MIC. The Hill equation with a variable slope fitted the relationship between the dose/MIC ratio and 14-day survival well (R2, 0.92), with a 50% effective dose (ED50) of 29.0 mg/kg (95% confidence interval [CI], 15.6 to 53.6 mg/kg). This also applied to the relationship between the area under the plasma concentration-time curve (AUC)/MIC ratio and 14-day survival (50% effective pharmacodynamic index [EI50], 321.3 [95% CI, 222.7 to 463.4]). Near-maximum survival was reached at an AUC/MIC ratio of nearly 1,000. These results indicate that treatment of infections with A. fumigatus strains for which MICs are 0.5 mg/liter requires doses exceeding the present licensed doses. Increasing the standard dosing regimen may have some effect and may be clinically useful if no alternatives are available.

Topics: Administration, Oral; Animals; Antifungal Agents; Area Under Curve; Aspergillosis; Aspergillus fumigatus; Cytochrome P-450 Enzyme System; Disease Models, Animal; Drug Administration Schedule; Female; Fungal Proteins; Mice; Microbial Sensitivity Tests; Mutation; Triazoles

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

The in vitro activities of eight antifungal drugs against clinical isolates of Fonsecaea pedrosoi (n = 21), Fonsecaea monophora (n = 25), and Fonsecaea nubica (n = 9) were tested. The resulting MIC(90)s for all strains (n = 55) were as follows, in increasing order: posaconazole, 0.063 microg/ml; itraconazole, 0.125 microg/ml; isavuconazole, 0.25 microg/ml; voriconazole, 0.5 microg/ml; amphotericin B, 2 microg/ml; caspofungin, 2 microg/ml; anidulafungin, 2 microg/ml; and fluconazole, 32 microg/ml.

Topics: Amphotericin B; Anidulafungin; Antifungal Agents; Ascomycota; Caspofungin; Chromoblastomycosis; Drug Resistance, Fungal; Echinocandins; Fluconazole; Humans; In Vitro Techniques; Itraconazole; Lipopeptides; Microbial Sensitivity Tests; Nitriles; Pyridines; Pyrimidines; Triazoles; Voriconazole

Forty-four isolates belonging to human pathogenic species of Lichtheimia were tested against nine antifungal agents by using the EUCAST methodology. No remarkable differences were found between the clinical species, although L. ramosa showed slightly higher MICs for all drugs. Amphotericin B was the most active drug. Among azole drugs, posaconazole had the best activity in vitro and voriconazole was inactive. Echinocandins showed activity for some isolates, suggesting a potential role in combination therapy.

Topics: Amphotericin B; Antifungal Agents; Humans; Microbial Sensitivity Tests; Mucorales; Pyrimidines; Triazoles; Voriconazole

The histopathology of clinical isolates of Scedosporium apiospermum, Scedosporium boydii, and Scedosporium aurantiacum in immunosuppressed mice was evaluated. The organs most affected were the brain, kidneys, and spleen. S. aurantiacum produced more tissue damage than the other two species. Amphotericin B (AMB) was ineffective in the treatment of murine infections caused by such isolates, and posaconazole and voriconazole showed efficacy that correlated with the in vitro susceptibility data.

Topics: Amphotericin B; Animals; Antifungal Agents; Azoles; Brain; Kidney; Mice; Mycetoma; Pyrimidines; Scedosporium; Spleen; Treatment Outcome; Triazoles; Voriconazole

We have determined the in vitro activities of amphotericin B (AMB), voriconazole, posaconazole (PSC), itraconazole (ITC), ravuconazole, terbinafine, and caspofungin against five strains of Cunninghamella bertholletiae and four of Cunninghamella echinulata. The best activity was shown by terbinafine against both species (MIC range = 0.3 to 0.6 μg/ml) and PSC against Cunninghamella bertholletiae (MIC = 0.5 μg/ml). We have also evaluated the efficacies of PSC, ITC, and AMB in neutropenic and diabetic murine models of disseminated infection by Cunninghamella bertholletiae. PSC at 40, 60, or 80 mg/kg of body weight/day was as effective as AMB at 0.8 mg/kg/day in prolonging survival and reducing the fungal tissue burden in neutropenic mice. PSC at 80 mg/kg/day was more effective than AMB at 0.8 mg/kg/day in reducing the fungal load in brain and lung of diabetic mice. Histological studies revealed an absence of fungal elements in organs of mice treated with either AMB at 0.8 mg/kg/day or PSC at 60 or 80 mg/kg/day in both models. ITC showed limited efficacy in both models. PSC could be a therapeutic option for the treatment of systemic infections caused by Cunninghamella bertholletiae.

Topics: Amphotericin B; Animals; Antifungal Agents; Caspofungin; Cunninghamella; Diabetes Mellitus, Experimental; Echinocandins; Itraconazole; Lipopeptides; Male; Mice; Microbial Sensitivity Tests; Mucormycosis; Pyrimidines; Thiazoles; Triazoles; Voriconazole

We report two cases of invasive zygomycoses occurring in severely immunocompromised patients with haematological malignancies that were successfully treated with liposomal amphotericin B and surgical debridement, followed by oral administration of posaconazole. These cases demonstrated that an early instituted, aggressive and combined therapeutic approach results in a recovery from invasive fungal infection, without any relapse of infection, thanks to secondary prophylaxis using posaconazole.

Topics: Aged; Amphotericin B; Antifungal Agents; Hematologic Neoplasms; Humans; Immunocompromised Host; Male; Middle Aged; Treatment Outcome; Triazoles; Zygomycosis

Topics: Adult; Amphotericin B; Antifungal Agents; Debridement; Histocytochemistry; Humans; Lung; Lung Diseases, Fungal; Male; Microscopy; Middle Aged; Radiography, Thoracic; Tomography; Transplantation; Treatment Outcome; Triazoles; Zygomycosis

The aim of this study was to examine the antifungal activity of amphotericin B, caspofungin and posaconazole on Candida albicans biofilms in the intermediate and mature development phases. Candida albicans biofilms, previously grown for either 24, 48 or 72 h in 96-well microtitre plates, were treated for 48 h with amphotericin B, caspofungin or posaconazole in increasing concentrations according to the respective minimal inhibitory concentration (MIC) determined for planktonic cells (1-128 x MIC). The biofilms were quantified using the mean optical density (OD) determined by XTT assay. Antifungal activities were expressed as percentage of reduction in OD of drug-treated biofilms compared to untreated biofilms. To test the fungicidal activity of antifungal agents, the unfixed biofilms were scraped off and seeded to Sabouraud agar. Caspofungin and amphotericin B showed higher activity against C. albicans biofilm grown for 24 h and 72 h (>or=50% reduction of OD) than biofilms grown for 48 h, whereas posaconazole showed similar, but reduced activity against all phases of C. albicans biofilm (

Topics: Amphotericin B; Antifungal Agents; Biofilms; Candida albicans; Caspofungin; Colony Count, Microbial; Echinocandins; Humans; Lipopeptides; Microbial Sensitivity Tests; Microbial Viability; Triazoles

Topics: Acute Disease; Amphotericin B; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Aspergillosis; Aspergillus; Caspofungin; Combined Modality Therapy; Echinocandins; Humans; Hyphae; Immunocompromised Host; Invasive Pulmonary Aspergillosis; Leukemia, B-Cell; Lipopeptides; Male; Middle Aged; Neutropenia; Spleen; Splenectomy; Splenic Diseases; Triazoles

Antifungal prophylaxis with posaconazole (POS) has been shown to decrease the mortality associated with invasive fungal infections in high-risk patients. We report on a patient, with severe graft-versus-host disease after allogeneic stem cell transplantation, who developed proven pneumonia due to Rhizopus microsporus after 40 days of POS prophylaxis (fasting serum levels: 691-904 ng/mL). Despite combination treatment with liposomal amphotericin B and POS for 39 days, the patient died from pulmonary hemorrhage. This case highlights the need for continued awareness of breakthrough zygomycosis in patients receiving POS.

Topics: Amphotericin B; Antifungal Agents; Chemoprevention; Drug Therapy, Combination; Fatal Outcome; Graft vs Host Disease; Humans; Lung Diseases, Fungal; Male; Middle Aged; Mucormycosis; Pneumonia; Rhizopus; Stem Cell Transplantation; Transplantation, Homologous; Triazoles

The aim of the present study was to evaluate the in vitro activity and synergism of the combinations of amphotericin B/caspofungin and amphotericin B/posaconazole against Candida albicans, grown either as planktonic cells or in biofilms.. Ten C. albicans bloodstream isolates used in this study were collected from intensive care patients admitted to the Vienna University Hospital between 2006 and 2007. Chequerboard tests were employed to determine the efficacy of the antifungal combinations amphotericin B/caspofungin and amphotericin B/posaconazole against both planktonic cells and biofilms. C. albicans biofilms were prepared using the static microtitre plate model. The activity of antifungal combination therapy was determined by visual reading for planktonic cells and using the XTT assay for biofilms.. For Candida biofilms the median MIC was 4 mg/L for amphotericin B and caspofungin, and >256 mg/L for posaconazole. The combination amphotericin B/posaconazole yielded synergism [fractional inhibitory concentration index (FICI) <0.26], whereas amphotericin B/caspofungin yielded indifferent interaction only (FICI 0.75-1.25) against all isolates when grown in biofilms. Under planktonic conditions, synergism was demonstrable for the combination amphotericin B/caspofungin against 4 of the 10 isolates, whereas the combination of caspofungin/posaconazole was indifferent against all tested isolates.. We showed that MICs for planktonic and biofilm forms of C. albicans were much lower when treated with an antifungal combination than when treated with single agents. The combination of amphotericin B/posaconazole yielded synergism against Candida biofilms, whereas amphotericin B/caspofungin yielded indifferent interaction.

Topics: Amphotericin B; Antifungal Agents; Austria; Biofilms; Candida albicans; Candidiasis; Caspofungin; Drug Synergism; Echinocandins; Fungemia; Humans; Intensive Care Units; Lipopeptides; Microbial Sensitivity Tests; Triazoles

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: Amphotericin B; Antifungal Agents; Cunninghamella; Drug Therapy, Combination; Humans; Lung Diseases, Fungal; Mucormycosis; Pyrimidines; Triazoles; Voriconazole

Mucormycosis are opportunistic infections mostly observed in immunocompromised patients. We report the case of a 13-year-old girl who suffered a systemic mucormycosis without presenting the usual risk factors. She was undergoing antineoplastic chemotherapy for advanced osteosarcoma of the femur with an uncommunicative pathologic fracture and pulmonary metastasis. Absidia corymbifera was isolated from skin lesions at the primary tumor site. She subsequently developed fungal pulmonary localizations and blood vessel thrombosis. Surgical treatment together with systemic, high doses of liposomal amphotericin B, posaconazole, and caspofungin cured the local infection and controlled systemic lesions. Unfortunately, the break in chemotherapy led to pulmonary metastasis progression.

Topics: Absidia; Adolescent; Amphotericin B; Antineoplastic Agents; Caspofungin; Drug Therapy, Combination; Echinocandins; Female; Femoral Neoplasms; Humans; Lipopeptides; Mucormycosis; Opportunistic Infections; Osteosarcoma; Triazoles

Zygomycosis is an emerging, opportunistic fungal infection particularly affecting immunocomprised patients. We report the case of a 10-year-old girl who developed pulmonary zygomycosis because of Cunninghamella bertholletiae 1 year after undergoing bone marrow transplantation complicated with severe cutaneous and digestive graft-versus-host disease. Treatment with surgery and liposomal amphotericin B followed by posaconazole successfully treated the infection.

Topics: Amphotericin B; Bone Marrow Transplantation; Child; Cunninghamella; Drug Therapy, Combination; Female; Graft vs Host Disease; Humans; Lung Diseases, Fungal; Mucormycosis; Triazoles

Invasive Zygomycetes infection complicating prolonged neutropenia is associated with high mortality in the absence of immune recovery. We report a patient who developed disseminated zygomycosis due to Rhizopus microsporus during induction chemotherapy for acute myeloid leukemia. Rescue allogeneic hematopoietic stem cell transplantation (allo-HSCT) was performed as her only chance of cure of this infection and to treat refractory leukemia. Posaconazole combined with liposomal amphotericin B contained the zygomycosis during prolonged neutropenia due to allo-HSCT followed by intense immunosuppression for grade IV acute graft-versus-host disease. Surgical removal of all infected sites after immune recovery, with prolonged posaconazole treatment, ultimately cured the infection. New combination antifungal therapies might sufficiently control disseminated zygomycosis to allow allo-HSCT to be performed, assuring life-saving immune recovery. Surgery appears to be necessary for definite cure of these infections.

Topics: Amphotericin B; Antifungal Agents; Drug Therapy, Combination; Female; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Middle Aged; Mucormycosis; Rhizopus; Salvage Therapy; Transplantation, Homologous; Treatment Outcome; Triazoles

We describe the first reported case of renal zygomycosis presenting as an isolated fungus ball (bezoar) without renal parenchymal invasion. Since all previous descriptions of renal involvement have discussed tissue invasion, our case is unique in that the infection was confined solely in the renal pelvis and extended to the distal ureter without signs of contiguous renal infection. Our patient later developed renal insufficiency while receiving amphotericin B Lipid Complex (ABLC). The therapy was changed to posaconazole with subsequent clinical, mycologic, and radiographic improvement and the patient has remained free of recurrence 5 years after diagnosis.

Topics: Adult; Amphotericin B; Antifungal Agents; Humans; Kidney Diseases; Kidney Pelvis; Male; Mucormycosis; Renal Insufficiency; Rhizopus; Triazoles; Ureter

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

Topics: Adult; Amphotericin B; Antifungal Agents; Diagnosis, Differential; Drug Therapy, Combination; Granulomatosis with Polyangiitis; Humans; Immunocompromised Host; Male; Mucormycosis; Radiography, Thoracic; Recurrence; Treatment Outcome; Triazoles

We have evaluated the efficacy of posaconazole (PSC), voriconazole (VRC), and amphotericin B (AMB) in a murine model of systemic infection by Cryptococcus gattii using immunocompromised animals and three clinical strains of the fungus. AMB was the most effective drug in prolonging the survival of mice and also in reducing tissue burden in all organs tested. To a lesser degree, VRC at 60 mg/kg of body weight in lung tissue and PSC at 40 mg/kg also in spleen demonstrated good efficacy in reducing the fungal load. The PSC and VRC levels in serum and brain tissue, determined by an agar diffusion bioassay method at 4 h after the last dose of the therapy, were above the corresponding MIC values. However, these drugs were not able to reduce the fungal load in brain tissue. Our results demonstrated that PSC and, to a lesser degree, VRC, have fungistatic activity and potential for the treatment of human pulmonary cryptococcosis.

Topics: Amphotericin B; Animals; Antifungal Agents; Cryptococcosis; Cryptococcus gattii; Male; Mice; Pyrimidines; Triazoles; Voriconazole

We analysed the in vitro and in vivo effects of posaconazole and amphotericin B against three clinical isolates of zygomycetes: Lichtheimia corymbifera, F1; and Rhizopus oryzae, F5 and F6.. In vitro activities of both drugs were assessed by determining MICs, minimum fungicidal concentrations (MFCs) and fungal damage measured by the XTT assay against either the spores or the hyphal forms. Additionally, the survival curves of neutropenic mice systemically infected with the zygomycete isolates were used as the marker of antifungal response to amphotericin B (1 mg/kg/day) or posaconazole (2.5, 10 and 50 mg/kg/day).. In terms of MICs, posaconazole proved to be active against the three isolates (MICs ranging from 0.125 to 1.0 mg/L). The median posaconazole MFCs were 0.25, 0.5 and >16 mg/L for F1, F5 and F6, respectively. The XTT assay showed that posaconazole was active against spores of all three isolates, but only partially effective against the hyphae. The survival studies showed that amphotericin B at 1 mg/kg/day and posaconazole at 10 mg/kg/day prolonged the survival of the animals infected with L. corymbifera F1. In mice infected with R. oryzae F5, only posaconazole at 50 mg/kg/day significantly prolonged survival, whereas amphotericin B at 1 mg/kg/day was the only regimen active against R. oryzae F6.. Our findings showed that posaconazole could be useful in the treatment of zygomycosis. Also, we report that an isolate of R. oryzae with low MFC responded to posaconazole, while another isolate with high MFC did not.

Topics: Amphotericin B; Animals; Antifungal Agents; Child; Disease Models, Animal; Humans; Male; Mice; Microbial Sensitivity Tests; Microbial Viability; Mucorales; Rhizopus; Survival Analysis; Tetrazolium Salts; Treatment Outcome; Triazoles; Zygomycosis

To present and discuss the case of a diabetic patient admitted with acidoketotic coma, with inner canthus tumefaction due to mucormycosis.. A 38-year-old diabetic man was admitted with acidoketotic coma and poor general health status. Clinical examination found right inner canthus tumefaction and mucopurulent rhinorrhea. Endoscopy of the nasal fossae found medial meatus sphaceluses. Sinus CT scan found a bilateral ethmoid infiltrating and osteolytic infectious process. Emergency endoscopic bilateral ethmoidectomy was performed. Mucormycosis was diagnosed, and liposomal amphotericin B was administered intravenously for 1 month then replaced by posaconazole. The patient was followed up monthly; the antifungal treatment was terminated after 8 months, the disease appearing to have resolved.. Mucormycosis is one of the most rapidly fatal fungal infections. Facial and cerebral CT scan is essential and is systematically abnormal in case of sinonasal mucormycosis. Emergency multidisciplinary treatment should address the diabetes and include rapid surgical debridement and effective antifungal medication. The reference antifungal is amphotericin B, to be administered at maximal dose (3 to 5 mg/kg per day). Posaconazole, available in Europe since July 2005, proved successful in the present case.

Topics: Administration, Oral; Adult; Amphotericin B; Antifungal Agents; Combined Modality Therapy; Diabetes Complications; Diabetic Ketoacidosis; Endoscopy; Ethmoid Sinusitis; Humans; Infusions, Intravenous; Male; Mucormycosis; Opportunistic Infections; Rhinitis; Tomography, X-Ray Computed; Triazoles

The in vitro susceptibilities of a worldwide collection of 350 Cryptococcus gattii isolates to seven antifungal drugs, including the new triazole isavuconazole, were tested. With amplified fragment length polymorphism (AFLP) fingerprinting, human, veterinary, and environmental C. gattii isolates were subdivided into seven AFLP genotypes, including the interspecies hybrids AFLP8 and AFLP9. The majority of clinical isolates (n = 215) comprised genotypes AFLP4 (n = 76) and AFLP6 (n = 103). The clinical AFLP6 isolates had significantly higher geometric mean MICs for flucytosine and fluconazole than the clinical AFLP4 isolates. Of the seven antifungal compounds examined in this study, isavuconazole had the lowest MIC(90) (0.125 μg/ml) for all C. gattii isolates, followed by a 1 log(2) dilution step increase (MIC(90), 0.25 μg/ml) for itraconazole, voriconazole, and posaconazole. Amphotericin B had an acceptable MIC(90) of 0.5 μg/ml, but fluconazole and flucytosine had relatively high MIC(90)s of 8 μg/ml.

Topics: Amphotericin B; Amplified Fragment Length Polymorphism Analysis; Animals; Antifungal Agents; Cryptococcus gattii; Environmental Microbiology; Fluconazole; Flucytosine; Genotype; Humans; Microbial Sensitivity Tests; Nitriles; Pyridines; Pyrimidines; Triazoles; Voriconazole

During recent years, the incidence of serious infections caused by opportunistic fungi has increased dramatically due to alterations of the immune status of patients with hematological diseases, malignant tumors, transplantations and so forth. Unfortunately, the wide use of triazole antifungal agents to treat these infections has lead to the emergence of Aspergillus spp. resistant to triazoles. The present study was to assess the in vitro activities of five antifungal agents (voriconazole, itraconazole, posaconazole, amphotericin B and caspofungin) against different kinds of Aspergillus spp. that are commonly encountered in the clinical setting.. The agar-based Etest MIC method was employed. One hundred and seven strains of Aspergillus spp. (5 species) were collected and prepared according to Etest Technique Manuel. Etest MICs were determined with RPMI agar containing 2% glucose and were read after incubation for 48 hours at 35°C. MIC(50), MIC(90) and MIC range were acquired by Whonet 5.4 software.. The MIC(90) of caspofungin against A. fumigatus, A. flavus and A. nidulans was 0.094 µg/ml whereas the MIC(90) against A. niger was 0.19 µg/ml. For these four species, the MIC(90) of caspofungin was the lowest among the five antifungal agents. For A. terrus, the MIC(90) of posaconazole was the lowest. For A. fumigatus and A. flavus, the MIC(90) in order of increasing was caspofungin, posaconazole, voriconazole, itraconazole, and amphotericin B. The MIC of amphotericin B against A. terrus was higher than 32 µg/ml in all 7 strains tested.. The in vitro antifungal susceptibility test shows the new drug caspofungin, which is a kind of echinocandins, has good activity against the five species of Aspergillus spp. and all the triazoles tested have better in vitro activity than traditional amphotericin B.

Topics: Amphotericin B; Antifungal Agents; Aspergillus; Caspofungin; Echinocandins; Itraconazole; Lipopeptides; Microbial Sensitivity Tests; Pyrimidines; Triazoles; Voriconazole

We measured antifungal activity against 128 cryptococcal isolates (86 of C. neoformans and 42 of C. gattii) to determine if differences in serotype susceptibility exist. Contrary to previous results, we found no serotype susceptibility differences. Isavuconazole, posaconazole, and voriconazole demonstrated excellent potency against each isolate and serotype, including isolates with reduced fluconazole susceptibilities.

Topics: Antifungal Agents; Cryptococcus; Cryptococcus neoformans; Fluconazole; Microbial Sensitivity Tests; Nitriles; Pyridines; Pyrimidines; Serotyping; Triazoles; Voriconazole

The antifungal susceptibility profiles of 77 clinical strains of Mucorales species, identified by internal transcribed spacer sequencing, were analyzed. MICs obtained at 24 and 48 h were compared. Amphotericin B was the most active agent against all isolates, except for Cunninghamella and Apophysomyces isolates. Posaconazole also showed good activity for all species but Cunninghamella bertholletiae. Voriconazole had no activity against any of the fungi tested. Terbinafine showed good activity, except for Rhizopus oryzae, Mucor circinelloides, and Rhizomucor variabilis isolates.

Topics: Amphotericin B; Antifungal Agents; DNA, Ribosomal Spacer; Microbial Sensitivity Tests; Mucorales; Triazoles

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

The in vitro interaction of antifungals with immunosuppressive drugs was evaluated against zygomycetes. The combination of amphotericin B with cyclosporine, rapamycin, or tacrolimus was synergistic for 90%, 70%, and 30% of the isolates, respectively. For posaconazole, itraconazole, and ravuconazole, synergy was more frequently observed with cyclosporine than with rapamycin or tacrolimus and antagonistic interactions were rarely noted. In summary, calcineurin inhibitors and rapamycin can be synergistic in vitro with amphotericin B and azoles against zygomycetes.

Topics: Amphotericin B; Antifungal Agents; Azoles; Cyclosporine; Drug Interactions; Immunosuppressive Agents; Itraconazole; Microbial Sensitivity Tests; Mucorales; Rhizopus; Sirolimus; Tacrolimus; Thiazoles; Triazoles

We evaluated the efficacies of posaconazole and voriconazole in comparison with that of amphotericin B in a systemic murine infection by Candida krusei. Posaconazole at 50 mg/kg/day and voriconazole at 40 and 60 mg/kg/day prolonged survival and reduced the fungal tissue burden in the kidneys of mice similarly to amphotericin B at 1.5 mg/kg/day and liposomal amphotericin B at 10 mg/kg/day. None of the treatments tested completely resolved the infection.

Topics: Amphotericin B; Animals; Antifungal Agents; Candida; Candidiasis; Kidney; Male; Mice; Pyrimidines; Random Allocation; Triazoles; Voriconazole

A broth microdilution method was used to evaluate the in vitro activities of seven antifungal agents against 15 clinical strains of Rhizopus microsporus. Amphotericin B (AMB) and posaconazole (POS) were the most active drugs. In a model of disseminated R. microsporus infection in immunosuppressed mice, we studied the efficacy of POS administered once or twice daily against four of the strains previously tested in vitro and compared it with that of liposomal AMB (LAMB). LAMB was the most effective treatment for the two strains with intermediate susceptibility to POS. For the two POS-susceptible strains, LAMB and POS at 20 mg/kg of body weight twice a day orally showed similar efficacies. The in vivo efficacy of POS administered twice a day orally correlated with the in vitro susceptibility data and the serum drug concentrations.

Topics: Amphotericin B; Animals; Antifungal Agents; Brain; Kidney; Male; Mice; Mucormycosis; Rhizopus; Triazoles

Invasive fungal infection negatively influences the morbidity and mortality in heavily immuno-incompetent patients. Diagnosis of non-Aspergillus mould infections remains challenging despite application of a wide spectrum of non-culture-based microbiological techniques. Invasive diagnostic procedures are often essential. In this article, we present the case of a 15-month-old boy diagnosed with Rhizopus microsporus var. rhizopodiformis liver mycetoma during induction chemotherapy for acute promyelocytic leukaemia. Following surgery, he was effectively treated with a combination of ABLC and posaconazole during ongoing intensive chemotherapy. Posaconazole was also used as long-term secondary prophylaxis.

Topics: Amphotericin B; Antifungal Agents; Drug Therapy, Combination; Humans; Infant; Leukemia, Myeloid, Acute; Liver; Liver Diseases; Male; Mycetoma; Rhizopus; Triazoles

Cryptococcus diffluens is a recently re-established species that shares several phenotypic features with Cryptococcus neoformans. We evaluated the application of the Clinical Laboratory Standards Institute (CLSI, formerly NCCLS) macro- and microbroth dilution methods and the E-test agar diffusion method to determine the in vitro susceptibilities of known strains of C. diffluens against amphotericin B (AMB), flucytosine (5-FC), fluconazole (FLC), itraconazole (ITC) and the novel triazoles, voriconazole (VRC) and posaconazole (PSC). Seven strains were found to be resistant in vitro to AMB (MICs >/=2 microg/ml), five were resistant to 5-FC (MICs of >/=32 microg/ml), four were resistant to FLC (MICs of FLC >/=32 microg/ml) and nine were resistant to ITC (MICs of ITC >1 microg/ml). In contrast, VRC and PSC showed good in vitro activity against C.diffluens strains, even those with elevated MICs to amphotericin B and/or established azoles. Most of the isolates were inhibited by 0.5 microg/ml of both VRC and PSC. A clinical isolate showing phenotypic switching exhibited elevated MICs to both agents, i.e., VRC (>16 microg/ml) and PSC (>8 microg/ml).

Topics: Amphotericin B; Antifungal Agents; Azoles; Cryptococcus; Culture Media; Drug Resistance, Fungal; Fluconazole; Flucytosine; Humans; Itraconazole; Microbial Sensitivity Tests; Pyrimidines; Triazoles; Voriconazole

We compared the efficacy of combination posaconazole-liposomal amphotericin B (LAmB) therapy to monotherapy with either drug in diabetic ketoacidotic or neutropenic mice with disseminated zygomycosis caused by Rhizopus oryzae. Combination therapy was no better than LAmB alone, and posaconazole monotherapy did not improve survival or reduce fungal burden versus placebo.

Topics: Amphotericin B; Animals; Antifungal Agents; Brain; Diabetic Ketoacidosis; Dose-Response Relationship, Drug; Drug Combinations; Kidney; Liposomes; Male; Mice; Mice, Inbred BALB C; Neutropenia; Rhizopus; Triazoles; Zygomycosis

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

Topics: Amphotericin B; Antifungal Agents; Candida; Cardiac Surgical Procedures; Child; Drug Resistance, Multiple, Fungal; Fungemia; Humans; Infant; Postoperative Complications; Pyrimidines; Triazoles; Voriconazole

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

A case of maxillofacial zygomycosis caused by Mucor circinelloides, identified by phenotypic and molecular methods and treated successfully with liposomal amphotericin B (AmBisome) and surgical debridement, is described. The isolate was resistant to posaconazole. This report underscores the importance of prior susceptibility testing of zygomycetes to guide therapy with the most effective antifungal agent for an improved prognosis.

Topics: Adult; Amphotericin B; Antifungal Agents; DNA, Fungal; Drug Resistance, Fungal; Humans; Male; Maxillary Diseases; Molecular Sequence Data; Mucor; Sequence Analysis, DNA; Triazoles; Zygomycosis

Cutaneous zygomycosis is a rare but serious infection in trauma patients. We report two cases of cutaneous zygomycosis caused by Mycocladus corymbifer (formerly Absidia corymbifera) which were probably the result of soil contamination of wounds of the patient's lower extremities. Both patients received appropriate antifungal therapy in combination with aggressive surgical debridement. While a cure was achieved with amphotericin B in one, the other patient was intolerant to this antifungal and cure was achieved with a new drug, posaconazole. Twenty seven cases (including the two cases in this study) of cutaneous M. corymbifer zygomycosis reported in the literature were reviewed. The data showed an increase in infections with 16 cases (59.2%) reported since 2002.

Topics: Absidia; Adult; Amphotericin B; Antifungal Agents; Debridement; Dermatomycoses; Foot; Humans; Leg; Male; Triazoles; Zygomycosis

Zygomycoses is a rapidly progressive infection associated with high mortality. Although amphotericin B (AMB) has been the only treatment option for years, recent studies have demonstrated that posaconazole (PCZ) has good activity against Zygomycetes. Because rapid onset of antifungal activity is crucial in the management and never studied before, we compared the time for maximum fungicidal activity of AMB versus PCZ using time-kill curves. The MIC of AMB and PCZ against clinical isolates of Mucor spp. and Rhizopus spp. was determined by the Clinical and Laboratory Standards Institute M38-A2 method, and the fungicidal activity was examined by time-kill studies. AMB was rapidly fungicidal, with 95% killing noted as early as 6 h and 99.9% killing at 24 h; PCZ showed <70% killing at 6 h and 99.9% killing at 48 h. In vivo animal studies using AMB in the early phase, followed by a switch to high-dose PCZ later, could provide data that may have clinical implications because there are only a few drugs currently available for the management of zygomycoses.

Topics: Amphotericin B; Animals; Antifungal Agents; Humans; Microbial Sensitivity Tests; Microbial Viability; Mucor; Rhizopus; Time Factors; Triazoles; Zygomycosis

Topics: Acinetobacter baumannii; Acinetobacter Infections; Adult; Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Arthritis, Rheumatoid; Colitis, Ulcerative; Combined Modality Therapy; Drainage; Fatal Outcome; Gastrointestinal Diseases; Humans; Ileal Diseases; Intestinal Perforation; Intraoperative Complications; Jejunal Diseases; Liposomes; Male; Mucormycosis; Peritonitis; Postoperative Complications; Shock, Septic; Triazoles

We describe a case of cutaneous zygomycosis caused by Saksenaea vasiformis in an immunocompetent 24-year-old woman. Diagnosis was based on histological and microbiological examination. The patient made a complete recovery with surgical debridement and antifungal therapy (liposomal amphotericin and posaconazole).

Topics: Amphotericin B; Antifungal Agents; Debridement; Dermatomycoses; Female; Histocytochemistry; Humans; Mucorales; Skin; Triazoles; Wound Infection; Young Adult; Zygomycosis

Mucormycosis is a rare fungal infection occurring most frequently in immunocompromised patients. The pathogens are filamentous fungi, order of Mucorales. Disseminated mucormycosis is a severe, life treating disease. Early diagnosis is a major determinant for prognosis, however, it remains difficult. The management consists in an early antifungal therapy using lipid formulation of amphotericin B associated with an extensive surgical debridement. Despite this therapeutic of choice, the mortality of disseminated mucormycosis remains high.. We report the case of disseminated mucormycosis in a 25 years old woman 9 months after a pulmonary transplantation. The clinical presentation included pulmonary and thyroid localization and the pathogen was Absidia corymbifera. The patient survived thanks to a large surgical debridement, and an early antifungal bitherapy by lipid formulation of amphotericin B and posaconazole.. The re-emergence and the high mortality of mucormycosis in solid organ transplant receiver show the necessity to find new therapeutic approaches. Posaconazole associated with liposomal amphotericin B could be an interesting option to treat disseminated mucormycosis and improve their outcome.

Topics: Absidia; Adult; Amphotericin B; Antifungal Agents; Combined Modality Therapy; Debridement; Female; Humans; Lung Diseases, Fungal; Lung Transplantation; Mucormycosis; Opportunistic Infections; Thyroid Diseases; Triazoles

We report a fatal case of a rhino-cerebral zygomycosis, caused by Rhizopus arrhizus (oryzae). The patient was suffering from idiopathic thrombopenic purpura, diagnosed 1 year earlier. He was already treated with methylprednisolone 5 months prior to his admission to the hospital for a loss of vision and pain in the left eye as well as left orbital cellulitis. After an initial empirical treatment with broad spectrum antibiotics and voriconazole (infection of unknown origin), the patient was treated with liposomal amphotericin as soon as a positive fungal culture revealed a zygomycete. Unfortunately, the mould was resistant to amphotericin B (MIC: 16 microg ml(-1)) and probably to posaconazole (MIC: 4 microg ml(-1)), which was co-administrated a few days later.

Topics: Aged; Amphotericin B; Anti-Inflammatory Agents; Antifungal Agents; Central Nervous System Diseases; Drug Resistance, Fungal; Fatal Outcome; Humans; Male; Methylprednisolone; Purpura, Thrombocytopenic, Idiopathic; Pyrimidines; Rhinitis; Rhizopus; Triazoles; Voriconazole; Zygomycosis

We evaluated the effects of sequential therapy with caspofungin (CAS) or amphotericin B (AMB) followed by posaconazole (POS) against Candida glabrata. The susceptibilities to POS of yeast cells pre-exposed to CAS or AMB were identical to those of untreated cells as shown by standard Clinical and Laboratory Standards Institute broth dilution, cell viability, and disk diffusion methods. We then investigated the activity of sequential regimens in an experimental model of disseminated candidiasis. CAS given at 1 mg/kg/day for 2 days followed by POS at either 15 or 30 mg/kg/day significantly reduced the counts compared to the controls, but this treatment was not superior to the use of CAS alone. Also, sequential regimens with AMB given at 1 mg/kg/day for 2 days followed by POS (AMB/POS) were effective at reducing the fungal burden against the controls. In addition, AMB/POS with both doses of the triazole were significantly more effective than AMB alone. Overall, our data showed that there is no therapeutic advantage in using CAS followed by POS, whereas an induction therapy with AMB followed by a maintenance regimen with POS might be a suitable strategy in managing C. glabrata infections.

Topics: Amphotericin B; Animals; Antifungal Agents; Candida glabrata; Candidiasis; Caspofungin; Colony Count, Microbial; Drug Administration Schedule; Echinocandins; Humans; Kidney; Lipopeptides; Male; Mice; Microbial Sensitivity Tests; Treatment Outcome; Triazoles

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

We investigated the in vitro activities of posaconazole (POS), fluconazole (FLC), amphotericin B (AMB), and caspofungin (CAS) against four clinical isolates of Candida glabrata with various susceptibilities to FLC (FLC MICs ranging from 1.0 to >64 microg/ml). POS MICs ranged from < or =0.03 to 0.5 microg/ml; AMB MICs ranged from 0.25 to 2.0 microg/ml, while CAS MICs ranged from 0.03 to 0.25 microg/ml. When FLC MICs increased, so did POS MICs, although we did not observe any isolate with a POS MIC greater than 0.5 mug/ml. Time-kill experiments showed that POS, FLC, and CAS were fungistatic against all isolates, while AMB at eight times the MIC was fungicidal against three out of four isolates of C. glabrata tested. Then, we investigated the activity of POS in an experimental model of disseminated candidiasis using three different isolates of C. glabrata: one susceptible to FLC (S; FLC MICs ranging from 1.0 to 4.0 microg/ml; POS MIC of < or =0.03 microg/ml), one susceptible in a dose-dependent manner (SDD; FLC MICs ranging from 32 to 64 microg/ml; POS MICs ranging from 0.125 to 0.25 microg/ml), and another one resistant to FLC (R; FLC MIC of >64 microg/ml; POS MIC of 0.5 microg/ml). FLC significantly reduced the kidney burden of mice infected with the S strain (P = 0.0070) but not of those infected with the S-DD and R strains. POS was significantly effective against all three isolates at reducing the kidney fungal burden with respect to the controls (P ranging from 0.0003 to 0.029). In conclusion, our data suggest that POS may be a useful option in the management of systemic infections caused by C. glabrata. Additionally, the new triazole may be a therapeutic option in those cases where an FLC-resistant isolate is found to retain a relatively low POS MIC.

Topics: Animals; Antifungal Agents; Candida glabrata; Candidiasis; Drug Resistance, Fungal; Fluconazole; Humans; Kidney; Male; Mice; Microbial Sensitivity Tests; Treatment Outcome; Triazoles

The in vitro activity of posaconazole plus amphotericin B against conidia and hyphae of 30 clinical zygomycetes was investigated. The combination of posaconazole with amphotericin B was found to be significantly more synergistic (40%) against hyphae (P < 0.05) than against conidia (10%). Antagonism was not observed.

Topics: Absidia; Amphotericin B; Antifungal Agents; Cunninghamella; Drug Synergism; Humans; Hyphae; Microbial Sensitivity Tests; Mucor; Mucorales; Mucormycosis; Rhizomucor; Rhizopus; Spores, Fungal; Triazoles

Voriconazole, posaconazole, caspofungin, micafungin, and anidulafungin demonstrated potent in vitro activities against 286 invasive Candida isolates. Analysis of the fluconazole susceptibilities of 204 bloodstream Candida glabrata isolates revealed a rapid shift from susceptible (64% in 1999 to 2001 to 19% in 2007) to susceptible-dose dependent (27% in 1999 to 2001 and 75% in 2007).

Topics: Anidulafungin; Antifungal Agents; Candida; Candida glabrata; Caspofungin; Echinocandins; Fluconazole; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Pyrimidines; Triazoles; Voriconazole

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

The data available in the literature concerning Cryptococcus gattii in vitro antifungal susceptibility are contradictory. We have analyzed the activity of eight antifungal agents against 23 C. gattii clinical isolates and compared the susceptibility profiles with those of C. neoformans. MIC analysis (mg/L) revealed that C. gattii isolates were more susceptible to amphotericin B and flucytosine than were C. neoformans isolates. Fluconazole and other azole compounds showed high MIC values for C. gattii. Posaconazole displayed good activity. Further studies are required to ascertain the predictive value of the in vitro data presented here.

Topics: Amphotericin B; Antifungal Agents; Cryptococcus; Cryptococcus neoformans; Drug Resistance, Fungal; Fluconazole; Flucytosine; Humans; Microbial Sensitivity Tests; Triazoles

During a 3-year surveillance program (2004 to 2007) in Monterrey, Mexico, 398 isolates of Candida spp. were collected from five hospitals. We established the species distribution and in vitro susceptibilities of these isolates. The species included 127 Candida albicans strains, 151 C. parapsilosis strains, 59 C. tropicalis strains, 32 C. glabrata strains, 11 C. krusei strains, 5 C. guilliermondii strains, 4 C. famata strains, 2 C. utilis strains, 2 C. zeylanoides strains, 2 C. rugosa strains, 2 C. lusitaniae strains, and 1 C. boidinii strain. The species distribution differed with the age of the patients. The proportion of candidemias caused by C. parapsilosis was higher among infants 45 years old). MICs were calculated following the criteria of the Clinical Laboratory Standards Institute reference broth macrodilution method. Overall, C. albicans, C. parapsilosis, and C. tropicalis isolates were susceptible to fluconazole and amphotericin B. However, 31.3% of C. glabrata isolates were resistant to fluconazole (MIC >or= 64 microg/ml), 43.3% were resistant to itraconazole (MIC >or= 1 microg/ml), and 12.5% displayed resistance to amphotericin B (MIC >or= 2 microg/ml). Newer triazoles, namely, voriconazole, posaconazole, and ravuconazole, had a notable in vitro activity against all Candida species tested. Also, caspofungin was active against Candida sp. isolates (MIC(90)

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Candida; Candida albicans; Candida glabrata; Candida tropicalis; Candidiasis; Caspofungin; Child; Child, Preschool; Echinocandins; Female; Fluconazole; Humans; Infant; Infant, Newborn; Itraconazole; Lipopeptides; Male; Mexico; Microbial Sensitivity Tests; Middle Aged; Pyrimidines; Thiazoles; Triazoles; Voriconazole; Young Adult

In a murine model of disseminated zygomycosis, low doses of amphotericin B (0.3 mg/kg body weight/day) combined with posaconazole (40 mg/kg/day) prolonged survival and reduced tissue burden with respect to that of controls and that of both drugs administered alone. Results were similar to those obtained with amphotericin B given alone at 0.8 mg/kg/day.

Topics: Amphotericin B; Animals; Antifungal Agents; Colony Count, Microbial; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Humans; Male; Mice; Mucormycosis; Rhizopus; Triazoles

Topics: Amphotericin B; Antifungal Agents; Child; Fungemia; Humans; Immunocompetence; Male; Mucorales; Mucormycosis; Plastic Surgery Procedures; Surgical Flaps; Triazoles

We compared the in vitro activities of posaconazole, voriconazole, itraconazole, and amphotericin B against clinical isolates of Aspergillus spp. and Rhizopus spp., and explored the in vitro interaction between posaconazole and amphotericin B against Rhizopus spp. Clinical strains of 82 Aspergillus spp. (43 Aspergillus fumigatus, 29 A. flavus, 7 A. niger, 2 A. terreus, 1 A. nidulans) and 11 Rhizopus oryzae isolates were tested in accordance with CLSI M38-A microdilution guidelines. In vitro activity of posaconazole against Aspergillus spp. was also investigated with the Etest. The combination of posaconazole and amphotericin B against R. oryzae isolates was investigated by the checkerboard methodology. Voriconazole was the most active drug in vitro against Aspergillus spp., followed by posaconazole, itraconazole, and amphotericin B, in order of decreasing activity. In studies with R. oryzae isolates, posaconazole was found to be the most potent drug followed by itraconazole and amphotericin B. Voriconazole had no meaningful activity against Rhizopus. Posaconazole Etest MICs (microg/ml) with Aspergillus spp. were found to be considerably lower than those obtained with the CLSI microdilution method (4-9 and 3-7 two-fold lower than CLSI MICs at 24 and 48 h, respectively). The interaction between posaconazole and amphotericin B was indifferent for all R. oryzae isolates tested; importantly no antagonism was observed.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus; Drug Synergism; Humans; Itraconazole; Microbial Sensitivity Tests; Mucormycosis; Pyrimidines; Rhizopus; Triazoles; Voriconazole

We report the case of a 67-year-old patient who presented with a myelodysplastic syndrome and who developed a pulmonary mucormycosis with a rare extension to the dorsal spine. A decompressive laminectomy was attempted after failure of broad-spectrum antifungal treatment (Cancidas, V-Fend). The diagnosis was obtained after surgical biopsy. The scheduled lobectomy could not be performed because of altered clinical condition. The patient eventually died despite adapted antifungal treatment (Abelcet, Posaconazole). Pulmonary mucormycosis is a rare cause of mycotic infection that reaches most of the time immunocompromised patients. The pathogenic agent is part of zygomyces that have angio-invasive ability. Perineural propagation was recently described. Immunodepression, late diagnosis and lack of response to new generation antifungal drugs (V-Fend, Cancidas) are responsible for therapeutic failure in this disease. This case emphasizes the risk inherent to empirical antifungal treatment and the need of early biopsy in cases that do not respond to treatment.

Topics: Aged; Amphotericin B; Antifungal Agents; Drug Therapy, Combination; Fatal Outcome; Humans; Immunocompromised Host; Laminectomy; Lung Diseases, Fungal; Male; Mucormycosis; Myelodysplastic Syndromes; Spinal Diseases; Thoracic Vertebrae; Triazoles

Topics: Amphotericin B; Drug Combinations; Drug Synergism; Humans; Rhizopus; Triazoles

Candida krusei ATCC 6258 was tested by eight laboratories using 96-well plates containing checkerboard pairwise combinations of amphotericin B (AMB), posaconazole (PSC), caspofungin (CSP), and voriconazole (VRC). The methodology led to reproducible results across the laboratories. All drug combinations yielded MICs lower than the MICs of any two drugs tested singly, and combinations of AMB, PSC, CSP, and VRC were indifferent (no antagonism) by summations of fractional inhibitory concentration.

Topics: Amphotericin B; Antifungal Agents; Candida; Caspofungin; Drug Therapy, Combination; Echinocandins; Humans; Laboratories; Lipopeptides; Microbial Sensitivity Tests; Pyrimidines; Quality Control; Triazoles; Voriconazole

The frequency of zygomycosis has increased considerably over recent years mainly in immunocompromised and diabetic patients. Little is known about the effects of host innate immunity against different Zygomycetes especially under the influence of antifungal agents. The antifungal activity of human polymorphonuclear leucocytes (PMN) in combination with liposomal amphotericin B (LAMB), amphotericin B lipid complex (ABLC), voriconazole (VRC) and posaconazole (PSC) against Rhizopus oryzae and Rhizopus microsporus, frequently isolated Zygomycetes, were studied and compared with Absidia corymbifera, a less pathogenic Zygomycete. Antifungal activity was evaluated as per cent of hyphal damage using the XTT metabolic assay. While A. corymbifera was more susceptible to PMN than the other two Zygomycetes, R. microsporus appeared to be the most susceptible to combined effects of amphotericin B formulations and VRC with PMN. LAMB exhibited synergistic activity with PMN in inducing hyphal damage to R. microsporus but not to the other fungi. In contrast, ABLC exhibited synergistic or additive activity with PMN against all three fungi. Among triazoles, only VRC exhibited additive effect with PMN against R. microsporus. Lipid formulations of amphotericin B and particularly ABLC interact with PMN predominantly in inducing augmented hyphal damage to three different species of Zygomycetes.

Topics: Absidia; Adult; Amphotericin B; Antifungal Agents; Drug Combinations; Drug Interactions; Humans; Hyphae; Liposomes; Microbial Sensitivity Tests; Neutrophils; Phosphatidylcholines; Phosphatidylglycerols; Pyrimidines; Rhizopus; Triazoles; Voriconazole

Three isolates of zygomycetes belonging to two different genera (Rhizopus oryzae and Absidia corymbifera) were used to produce a systemic infection in neutropenic mice. On days -2 and -1 and at 2 h prior to infection, the mice received either posaconazole (POS) at doses ranging from 20 to 80 mg/kg of body weight/day or amphotericin B (AMB) at 1 mg/kg/day. Antifungal drug efficacy was assessed by determination of the prolongation of survival, determination of the percentage of infected organs (brain, lung, spleen, and kidney), and histological examination for the number of infection foci and their sizes in brain and kidney tissues. AMB significantly prolonged the survival of mice infected with all isolates. POS significantly prolonged the survival of mice infected with zygomycetes. Cultured organs from mice infected with R. oryzae were all positive, while treated mice challenged with A. corymbifera generally showed lower percentages of infected organs compared with the percentages for the controls. Zygomycete isolates established an active infection (the presence of hyphae) in the brains and the kidneys of all controls. In mice challenged with R. oryzae, both antifungal drugs were effective at reducing the number and the size of infection foci in the kidneys. Only AMB reduced the numbers, but not the sizes, of infection foci in the brain. Finally, both drugs significantly reduced the numbers and the sizes of infection foci in both tissues of mice infected with A. corymbifera. Our data suggest that prophylaxis with POS has some potential to prevent zygomycosis.

Topics: Absidia; Amphotericin B; Animals; Antibiotic Prophylaxis; Antifungal Agents; Brain; Cells, Cultured; Disease Models, Animal; Kidney; Lung; Male; Mice; Microbial Sensitivity Tests; Mucormycosis; Rhizopus; Spleen; Time Factors; Triazoles

The MICs and fractional inhibitory concentrations of posaconazole (POS) and voriconazole (VRZ), alone and in combination with amphotericin B (AMB), for the conidia and hyphae of 100 Aspergillus isolates were evaluated. POS-AMB had more synergistic activity against hyphae (75% of isolates) than VRZ-AMB (37%) and significantly more synergistic activity against hyphae than against conidia (12%).

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus; Drug Synergism; Drug Therapy, Combination; Microbial Sensitivity Tests; Pyrimidines; Triazoles; Voriconazole

We evaluated the in vitro susceptibilities of 217 zygomycetes to amphotericin B, ketoconazole, fluconazole, itraconazole, voriconazole, posaconazole, caspofungin, and flucytosine. The significant in vitro activity of posaconazole against several species appears to support its reported clinical efficacy. Decreased susceptibility to amphotericin B was noted with Cunninghamella bertholletiae.

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Echinocandins; Fluconazole; Flucytosine; Humans; In Vitro Techniques; Itraconazole; Ketoconazole; Lipopeptides; Microbial Sensitivity Tests; Mucormycosis; Peptides, Cyclic; Pyrimidines; Triazoles; Voriconazole

A 21-year-old white male with relapsed acute lymphoblastic leukemia (ALL) developed an invasive Zygomycosis infection 3 weeks after beginning re-induction chemotherapy. Because of the high risk of fatal recurrence of the fungal infection, neither long-term maintenance chemotherapy nor allogeneic hematopoietic stem cell transplant (HSCT) was considered appropriate. Because his ALL blasts expressed CD34 but lacked CD133, he received a CD133 selected autologous graft following high-dose consolidation chemotherapy. The patient survives in remission 19 months after HSCT.

Topics: AC133 Antigen; Amphotericin B; Antifungal Agents; Antigens, CD; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Caspofungin; Child; Combined Modality Therapy; Contraindications; Dexamethasone; Drug Therapy, Combination; Echinocandins; Glycoproteins; Humans; Immunomagnetic Separation; Lipopeptides; Male; Mercaptopurine; Methotrexate; Peptides; Peptides, Cyclic; Peripheral Blood Stem Cell Transplantation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrimidines; Recurrence; Remission Induction; Salvage Therapy; Transplantation, Autologous; Transplantation, Homologous; Triazoles; Vincristine; Voriconazole; Zygomycosis

The purpose of this study was to correlate inhibition zone diameters, in millimeters (agar diffusion disk method), with the broth dilution MICs or minimum effective concentrations (MECs) (CLSI M38-A method) of five antifungal agents to identify optimal testing guidelines for disk mold testing. The following disk diffusion testing parameters were evaluated for 555 isolates of the molds Absidia corymbifera, Aspergillus sp. (five species), Alternaria sp., Bipolaris spicifera, Fusarium sp. (three species), Mucor sp. (two species), Paecilomyces lilacinus, Rhizopus sp. (two species), and Scedosporium sp. (two species): (i) two media (supplemented Mueller-Hinton agar [2% dextrose and 0.5 microg/ml methylene blue] and plain Mueller-Hinton [MH] agar), (ii) three incubation times (16 to 24, 48, and 72 h), and (iii) seven disks (amphotericin B and itraconazole 10-microg disks, voriconazole 1- and 10-microg disks, two sources of caspofungin 5-microg disks [BBL and Oxoid], and posaconazole 5-microg disks). MH agar supported better growth of all of the species tested (24 to 48 h). The reproducibility of zone diameters and their correlation with either MICs or MECs (caspofungin) were superior on MH agar (91 to 100% versus 82 to 100%; R, 0.71 to 0.93 versus 0.53 to 0.96 for four of the five agents). Based on these results, the optimal testing conditions for mold disk diffusion testing were (i) plain MH agar; (ii) incubation times of 16 to 24 h (zygomycetes), 24 h (Aspergillus fumigatus, A. flavus, and A. niger), and 48 h (other species); and (iii) the posaconazole 5-microg disk, voriconazole 1-microg disk, itraconazole 10-microg disk (for all except zygomycetes), BBL caspofungin 5-microg disk, and amphotericin B 10-microg (zygomycetes only).

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Culture Media; Disk Diffusion Antimicrobial Tests; Echinocandins; Fungi; Itraconazole; Lipopeptides; Microbial Sensitivity Tests; Peptides, Cyclic; Pyrimidines; Reproducibility of Results; Triazoles; Voriconazole

A case of sinus-orbital Rhizopus microsporus var. rhizopodiformis infection in a patient with graft versus host disease following allogeneic blood stem cell transplantation is reported. Commercially available pea straw compost used for gardening was suspected to be the source of the infection. After an initial relapse, treatment with surgical debridement, liposomal amphotericin B and posaconazole was successful.

Topics: Adult; Amphotericin B; Eye Infections, Fungal; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Male; Orbital Diseases; Paranasal Sinus Diseases; Rhizopus; Soil; Soil Microbiology; Transplantation, Homologous; Triazoles; Zygomycosis

This is a case of mucormycosis complicated by necrotizing fasciitis in a renal transplant recipient on immunosuppressive therapy treated with posaconazole. Mucormycosis occurs most commonly as an opportunistic infection in the immunocompromised host. This patient, with predisposing risk factors for infection, including diabetes mellitus status post cadaveric renal transplantation on immunosuppressive therapy, is the first reported case of successful treatment of Mucor involving an extremity which was neither fatal nor required extremity amputation.

Topics: Alcaligenes; Amphotericin B; Amputation, Surgical; Antifungal Agents; Cefazolin; Combined Modality Therapy; Debridement; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Combinations; Drug Resistance, Multiple, Fungal; Escherichia coli Infections; Fatal Outcome; Fluconazole; Gangrene; Graft Rejection; Gram-Negative Bacterial Infections; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Leg; Leg Ulcer; Male; Middle Aged; Mucor; Mucormycosis; Penicillanic Acid; Phosphatidylcholines; Phosphatidylglycerols; Piperacillin; Postoperative Complications; Pyrimidines; Renal Dialysis; Reoperation; Sepsis; Skin Transplantation; Tazobactam; Triazoles; Voriconazole

To characterize the susceptibility of filamentous fungi isolated from keratitis to amphotericin B, natamycin, caspofungin acetate, itraconazole, voriconazole, and posaconazole.. Ninety isolates from fungal keratitis cases at Aravind Eye Hospital in South India were tested using macrobroth dilution for susceptibility to amphotericin B, natamycin, caspofungin, itraconazole, voriconazole, and posaconazole. The minimum inhibitory concentration (MIC) median and 90th percentile were determined.. The 90 isolates included 41 Aspergillus species, 38 Fusarium species, and 11 others. The triazoles and caspofungin had the lowest MICs against Aspergillus species; voriconazole, amphotericin B, and posaconazole had the lowest MICs against Fusarium species, and none of the Fusarium species were inhibited by itraconazole or caspofungin. Amphotericin B had significantly lower MICs compared with natamycin, but after correcting for the typical prescription dose, natamycin was superior.. No single agent was universally most effective, but voriconazole and other triazoles demonstrated the broadest spectrum. Itraconazole and caspofungin were not effective against Fusarium species.. Fungal ulcers are commonly treated empirically; drugs are typically selected without regard to susceptibility data. The nonocular infectious disease literature suggests modern fungal susceptibility methods are clinically relevant, but ocular studies are limited. Our results suggest antifungal therapy might be tailored to individual organisms.

Topics: Amphotericin B; Antifungal Agents; Aspergillus; Caspofungin; Corneal Ulcer; Echinocandins; Eye Infections, Fungal; Fusarium; Humans; Itraconazole; Lipopeptides; Microbial Sensitivity Tests; Natamycin; Peptides, Cyclic; Prospective Studies; Pyrimidines; 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

Invasive pulmonary aspergillosis is associated with high mortality. To assess new antifungal therapy options, animal models have to be developed to assess, in an appropriate setting, the activity of new drugs.. Male albino CD rats (125-150 g) were fed with a protein-free diet and received dexamethasone thrice weekly subcutaneously during the whole experiment. After 2 weeks, an inoculum of 10(6) conidia of Aspergillus fumigatus (H11-20) was injected intratracheally. Antifungal treatment was initiated and continued for a total of 7 days. Animals were grouped in numbers of 10. One group of animals served as untreated control, whereas the others were treated with amphotericin B intraperitoneally (2 and 4 mg/kg) and posaconazole via gavage (2, 4, 10 and 20 mg/kg). Survival and log(10) cfu/g of the lungs were the endpoints. The strain H11-20 was tested for susceptibility in vitro to amphotericin B and posaconazole, respectively. Fungal burden of the lungs was expressed as log(10) cfu/g. Survival analysis was performed by the Kaplan-Meier method. Differences in fungal burden were assessed by the Mann-Whitney test.. All untreated animals died within a week. Amphotericin B and posaconazole at 2 mg/kg demonstrated survival benefits over control (P = 0.01 and P = 0.04). Dosages of 4 mg/kg were superior to 2 mg/kg for amphotericin B (P = 0.02) and posaconazole (P < 0.05), respectively. No further survival benefits were demonstrated beyond dosages of 10 mg/kg. Rats treated with 20 mg/kg posaconazole, however, had a lower fungal burden than all the other treatment groups (P = 0.0002).. Posaconazole and amphotericin B are effective in a dosage-dependent manner in this pulmonary aspergillosis model in immunocompromised rats.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis, Allergic Bronchopulmonary; Aspergillus fumigatus; Dexamethasone; Dose-Response Relationship, Drug; Drug Resistance, Fungal; Drug Therapy, Combination; Immunocompromised Host; Male; Microbial Sensitivity Tests; Rats; Rats, Sprague-Dawley; Triazoles

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

A 52-year-old man underwent haematopoietic stem-cell transplant for myelodysplastic syndrome; after treatment with voriconazole for invasive aspergillosis, he was diagnosed with invasive zygomycosis caused by Rhizopus microsporus. He died despite treatment with intravenous liposomal amphotericin B and posaconazole. A 5-year-old boy with acute lymphatic leukaemia was diagnosed with invasive zygomycosis at autopsy. In a third case, a 16-year-old boy with acute myeloid leukaemia received repeated courses of empiric antifungal therapy, although the presence of an invasive fungal infection was not demonstrated. The patient died, and disseminated invasive zygomycosis caused by Rhizomucor pusillus was found at autopsy. Invasive infections by Zygomycetes are difficult to diagnose and are associated with a high mortality rate. The incidence of invasive zygomycosis appears to be increasing. Therefore, awareness of this type of invasive fungal infection is warranted. Lipid formulations ofamphotericin B remain the first choice for therapy.

Topics: Adolescent; Amphotericin B; Antifungal Agents; Child, Preschool; Fatal Outcome; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Male; Middle Aged; Mucormycosis; Organ Transplantation; Rhizopus; Transplantation Immunology; Triazoles; Zygomycosis

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

The in vitro activity of the novel triazole antifungal agent posaconazole (Noxafil; SCH 56592) was assessed in 45 laboratories against approximately 19,000 clinically important strains of yeasts and molds. The activity of posaconazole was compared with those of itraconazole, fluconazole, voriconazole, and amphotericin B against subsets of the isolates. Strains were tested utilizing Clinical and Laboratory Standards Institute broth microdilution methods using RPMI 1640 medium (except for amphotericin B, which was frequently tested in antibiotic medium 3). MICs were determined at the recommended endpoints and time intervals. Against all fungi in the database (22,850 MICs), the MIC(50) and MIC(90) values for posaconazole were 0.063 microg/ml and 1 mug/ml, respectively. MIC(90) values against all yeasts (18,351 MICs) and molds (4,499 MICs) were both 1 mug/ml. In comparative studies against subsets of the isolates, posaconazole was more active than, or within 1 dilution of, the comparator drugs itraconazole, fluconazole, voriconazole, and amphotericin B against approximately 7,000 isolates of Candida and Cryptococcus spp. Against all molds (1,702 MICs, including 1,423 MICs for Aspergillus isolates), posaconazole was more active than or equal to the comparator drugs in almost every category. Posaconazole was active against isolates of Candida and Aspergillus spp. that exhibit resistance to fluconazole, voriconazole, and amphotericin B and was much more active than the other triazoles against zygomycetes. Posaconazole exhibited potent antifungal activity against a wide variety of clinically important fungal pathogens and was frequently more active than other azoles and amphotericin B.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus; Candida; Candidiasis; Cryptococcosis; Cryptococcus; Drug Resistance, Fungal; Fluconazole; Fungi; Humans; In Vitro Techniques; Itraconazole; Microbial Sensitivity Tests; Mycoses; Pyrimidines; Triazoles; Voriconazole

The activities of 10 combinations of antifungal agents against 25 clinical isolates of Scopulariopsis brevicaulis were tested by the checkerboard technique. An average indifferent effect was detected for all combinations. Synergy was observed for some isolates and combinations, particularly with posaconazole-terbinafine (68% of strains), amphotericin B-caspofungin (60%), and posaconazole-caspofungin (48%).

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Drug Resistance, Multiple, Fungal; Drug Synergism; Echinocandins; Humans; In Vitro Techniques; Itraconazole; Lipopeptides; Microbial Sensitivity Tests; Mitosporic Fungi; Naphthalenes; Peptides, Cyclic; Pyrimidines; Terbinafine; Triazoles; Voriconazole

Topics: Amphotericin B; Antifungal Agents; Gastrointestinal Diseases; Humans; Kidney Transplantation; Triazoles; Zygomycosis

We describe a 57-year-old woman with acute lymphoblastic leukemia who had a cavitary lesion develop in the right upper lobe caused by Cunninghamella bertholletiae, a zygomycete. The infection was resistant to both high-dose liposomal amphotericin B and voriconazole. The current report demonstrates successful treatment, even in the setting of subsequent bone marrow transplantation and immunosuppression, using a combination of surgical resection and posaconazole therapy.

Topics: Amphotericin B; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Benzamides; Bone Marrow Transplantation; Cefepime; Cephalosporins; Combined Modality Therapy; Cunninghamella; Daunorubicin; Drug Resistance, Multiple, Fungal; Female; Humans; Imatinib Mesylate; Immunocompromised Host; Lung Diseases, Fungal; Middle Aged; Neutropenia; Piperazines; Pneumonectomy; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Pyrimidines; Transplantation Conditioning; Triazoles; Vancomycin; Vincristine; Voriconazole; Zygomycosis

To report a pediatric case of posttraumatic fungal fasciitis treated successfully with a combination including posaconazole.. Case report.. Pediatric critical care unit at Antwerp University Hospital.. A 12-yr-old female polytrauma patient, suffering from extensive skin and muscle injuries, developed fasciitis. Two fungi (Mucor and Trichosporon species) were isolated. The necrotic tissues were aggressively excised, hyperbaric oxygen therapy was applied, and oral posaconazole was added to the initial amphotericin B treatment. The patient made an excellent recovery.. A combination of a high index of suspicion, early aggressive surgery, hyperbaric oxygen, and the association of amphotericin B and posaconazole led to a successful outcome in a case of fungal necrotizing fasciitis. After decades of disappointing amphotericin B treatment in spite of acceptable in vitro activity, the combination with the new triazole posaconazole seems promising.

Topics: Amphotericin B; Antifungal Agents; Child; Drug Therapy, Combination; Fasciitis, Necrotizing; Female; Humans; Mucormycosis; Mycoses; Triazoles; Trichosporon

We compared posaconazole M27-A2 and M38-A MICs to Etest and YeastOne MICs for 92 zygomycetes, 126 Aspergillus isolates, 110 Candida isolates, and Cryptococcus neoformans. Reference MICs were also correlated with inhibition zone diameters in millimeters (modified M44-A disk and Neo-Sensitabs tablet methods). Etest MICs were obtained on solidified (1.5% agar) RPMI 1640 (2% dextrose), and zone diameters were obtained on supplemented (2% glucose and 0.5 microg/ml methylene blue [for all isolates]) and nonsupplemented Mueller-Hinton (MH; molds only) agar. MICs and zone diameters were obtained between 16 and 72 h. The overall agreement (% MIC pairs within a three-dilution range) between reference posaconazole and YeastOne MICs was 98 to 100% at 16 to 24 h for zygomycetes and yeasts and 99% at 24 to 48 h for Aspergillus. The overall agreement was lower between reference posaconazole and Etest MICs (94 to 97%) and by both methods with amphotericin B for all species (95 to 99.3%). For yeasts, the correlation coefficient was similar between reference posaconazole MICs and either disk (R, 0.810) or tablet (R, 0.769) zone diameter at 24 h and was superior on MH agar for molds at 16 to 48 h (R, 0.804 and 0.799 for disk and tablet, respectively). For amphotericin B, the best correlation between reference MICs and zone diameters was observed at 16 to 48 h for molds on MH agar (R, 0.736 to 0.812 and 0.765 to 0.749 for disk and tablet, respectively) and at 48 h for yeasts (R, 0.681 and 0.503 for disk and tablet, respectively). These data suggest the potential value of these alternative broth dilution and agar diffusion methods for testing posaconazole and amphotericin B in the clinical laboratory against the species evaluated.

Topics: Amphotericin B; Antifungal Agents; Aspergillus; Candida; Cryptococcus neoformans; Drug Resistance, Fungal; Microbial Sensitivity Tests; Mycological Typing Techniques; Triazoles

The combination of resection of infected tissue and antifungal therapy is the treatment of choice in mucormycosis. In disseminated mucormycosis, where surgery is impossible, the mortality is almost 90%. We report the first case of disseminated mucormycosis that was cured with a combination therapy of liposomal amphotericin B and posaconazole without surgical intervention.

Topics: Amphotericin B; Antifungal Agents; Drug Therapy, Combination; Female; Humans; Leukemia, Myeloid, Acute; Liposomes; Middle Aged; Mucormycosis; Rhizomucor; Treatment Outcome; Triazoles

We report on a 10-year-old girl with severe aplastic anaemia who developed rhinocerebral infection caused by Absidia corymbifera and a possible co-infection caused by Alternaria alternata. Despite prolonged neutropenia, therapy with liposomal amphotericin B and posaconazole improved the clinical condition. Subsequently, the girl underwent allogeneic haematopoietic stem cell transplantation (HSCT) for the underlying disease, but the fungal infection remained under control with the antifungal treatment. No severe side effect of the antifungal drugs was noted. Unfortunately, the girl died 5 months after HSCT due to disseminated adenovirus infection.

Topics: Absidia; Alternaria; Amphotericin B; Anemia, Aplastic; Antifungal Agents; Central Nervous System Fungal Infections; Child; Female; Humans; Radiography; Sinusitis; Stem Cell Transplantation; Telencephalon; Transplantation, Homologous; Triazoles; Zygomycosis

Eighty-four isolates belonging to eight species that constitute the Pseudallescheria boydii complex were tested against 11 antifungal agents by using the microdilution method. There were significant differences among the species, with Scedosporium aurantiacum being the most resistant. In general, voriconazole was the most active drug, followed by posaconazole.

Topics: Amphotericin B; Antifungal Agents; Candida; Drug Resistance, Fungal; Echinocandins; Fluconazole; Flucytosine; Humans; Itraconazole; Ketoconazole; Lipopeptides; Lipoproteins; Micafungin; Microbial Sensitivity Tests; Naphthalenes; Peptides, Cyclic; Pseudallescheria; Pyrimidines; Quality Control; Quinazolines; Scedosporium; Terbinafine; Thiazoles; Triazoles; Voriconazole

Topics: Adolescent; Adult; Alternaria; Amphotericin B; Antifungal Agents; Chronic Disease; Deoxycholic Acid; Drug Combinations; Female; Humans; Mouth Diseases; Mycoses; Treatment Outcome; Triazoles

Azole resistance in Aspergillus spp. is unusual. We report a patient who received long-term treatment with itraconazole and voriconazole for bilateral chronic cavitary aspergillosis with aspergillomas whose isolates of Aspergillus fumigatus developed simultaneous resistance to itraconazole and voriconazole. A novel mutation (G138C) in the target gene (cyp51A) encoding 14alpha-demethylase was detected. The patient had some response to intravenous caspofungin, which he received six times weekly, without the development of resistance over 9 months.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Caspofungin; Cytochrome P-450 Enzyme System; Drug Resistance, Multiple, Fungal; Echinocandins; Fungal Proteins; Humans; Itraconazole; Lipopeptides; Lung Diseases, Fungal; Male; Microbial Sensitivity Tests; Middle Aged; Mutation, Missense; Peptides, Cyclic; Pyrimidines; Thiazoles; Triazoles; Voriconazole

The interaction of posaconazole and amphotericin B was evaluated in concomitant treatment of Candida albicans systemic infections in immunocompetent mice by using four strains of C. albicans with different susceptibilities to fluconazole. Posaconazole and amphotericin B were each tested at four dose levels alone and in all possible combinations against each C. albicans strain. Survival curves of mice treated with combinations of posaconazole and amphotericin B were statistically compared with those of mice treated with the component monotherapies. Of the 64 total combinations evaluated against the C. albicans strains (16 combinations per strain), 20.3% were more effective in prolonging mouse survival than both of the monotherapies, 45.3% were more effective than one of the monotherapies, and 32.8% were similar to both monotherapies. No evidence of antagonism was observed between posaconazole and amphotericin B in this mouse model, consistent with in vitro results against the same strains.

Topics: Amphotericin B; Animals; Antifungal Agents; Candida albicans; Candidiasis; Drug Interactions; Male; Mice; Survival Analysis; Triazoles

The in vitro antifungal activity of posaconazole was compared with that of fluconazole and amphotericin B.. A microdilution method (M27-A2) was used with 331 clinical yeast isolates.. The geometric mean MICs of posaconazole, fluconazole and amphotericin B were 0.16, 0.91 and 0.15 mg/L, respectively. Posaconazole was markedly more active than fluconazole and was active against 9/11 fluconazole-resistant Candida albicans, and five Candida glabrata had an MIC of posaconazole of 16 mg/L.. These data indicate that posaconazole is a potentially effective antifungal agent for the treatment of mycoses caused by yeasts.

Topics: Amphotericin B; Antifungal Agents; Candida; Candidiasis, Oral; Fluconazole; Humans; Microbial Sensitivity Tests; Triazoles

We report the first case of Phialemonium obovatum fungemia with subsequent caseating granulomatas in the lung and Crohn disease-like involvement of the gastrointestinal tract in a bone marrow transplant recipient. This phaeoid fungus has been rarely described as an opportunistic infection in immunosuppressed patients. The patient was diagnosed with chronic myelogenous leukemia and underwent subsequent peripheral bone marrow transplant. After 6 months, he developed graft-versus-host disease of the skin and liver with fever and severe diarrhea. Fecal bacterial cultures and cytomegalovirus serologies were negative. Computed tomographic scan showed a peripheral pulmonary mass. A lung wedge biopsy of the lesion showed septate branching hyphae (4-5 microm in diameter) with terminal globular structures (10 microm in diameter). The hyphae were similar in width to that of an Aspergillus species but had a more moniliform appearance. Blood cultures grew a pure culture of P. obovatum. He was treated with amphotericin B and itraconazole for 6 months without remission of the diarrhea. Biopsies of the stomach, colon, and rectum showed granulomatous inflammation with marked crypt distortion simulating Crohn disease. In retrospect, the fungus was found to be resistant to both of the aforementioned drugs and susceptible to voriconazole and posaconazole. The gastrointestinal findings raise the possibility of further dissemination of a partially treated Phialemonium infection.

Topics: Amphotericin B; Antifungal Agents; Ascomycota; Bone Marrow Transplantation; Drug Resistance, Fungal; Fungemia; Gastrointestinal Diseases; Graft vs Host Disease; Granuloma; Humans; Immunocompromised Host; Itraconazole; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Lung Diseases, Fungal; Male; Middle Aged; Opportunistic Infections; Pyrimidines; Triazoles; Voriconazole

Although standard conditions are available for testing the susceptibilities of filamentous fungi to antifungal agents by the Clinical and Laboratory Standards Institute (CLSI; formerly National Committee for Clinical Laboratory Standards) broth microdilution assay, quality control (QC) MIC limits have not been established for any mold-agent combination. This multicenter (eight-center) study documented the reproducibility of tests for one isolate of Paecilomyces variotii ATCC MYA-3630 and 11 other mold isolates (three isolates of Aspergillus fumigatus; two isolates of A. terreus; one isolate each of A. flavus, A. nidulans, Fusarium moniliforme, and F. solani; and two isolates of Scedosporium apiospermum) by the CLSI reference broth microdilution method (M 38-A document). Control limits (amphotericin B, 1 to 4 microg/ml; itraconazole, 0.06 to 0.5 microg/ml; posaconazole, 0.03 to 0.25 microg/ml; voriconazole, 0.015 to 0.12 microg/ml) for the selected QC P. variotii ATCC MYA-3630 were established by the analysis of replicate MIC results. Reference isolates and corresponding MIC ranges were also established for 6 of the 12 molds evaluated. MIC limits were not proposed for the other five molds tested due to low testing reproducibility for these isolates.

Topics: Amphotericin B; Antifungal Agents; Drug Resistance, Fungal; Fungi; Humans; Itraconazole; Microbial Sensitivity Tests; Paecilomyces; Pyrimidines; Quality Control; Triazoles; Voriconazole

Topics: Amphotericin B; Antifungal Agents; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Rhizopus; Triazoles; Zygomycosis

Mucormycoses are seen with an increasing incidence in immunocompromised patients. Most common presentations are rhinocerebral and pulmonary. We here report the experience of a single center with mucormycoses in patients with hematologic malignancies.. Mucormycoses were diagnosed in six patients, (median age of 52 years; range, 26-74) treated between 2001-2004. Diagnoses included acute myeloid leukemia (AML) (n=3), acute lymphoblastic leukemia (n=1), chronic lymphocytic leukemia (n=1) and multiple myeloma (n=1). Mucormycosis was diagnosed in the neutropenic state following allogeneic hematopoietic cell transplantation (n=3) or intense chemotherapy (n=3). Sites of infections were rhinocerebral, facial and pulmonary involvement in one patient each and disseminated mucormycosis in three patients. The diagnosis was established by computed tomography followed by surgical interventions and histological diagnosis in 4 patients and post-mortem in two patients. Species identified were Rhizopus (n=3), Rhizomucor (n=2) and Absidia (n=1). Treatment responses were best if surgical resection was followed by aggressive antifungal chemotherapy. Five of six 6 patients died, all of complications of mucormycosis or their underlying disease. Only one patient with facial mucormycosis is still alive.. This experience demonstrates that patient with mucormycoses have a high mortality rate and early recognition followed by aggressive surgical debridement, high dose antifungal therapy and attempts to correct the underlying immunocompromised state are crucial in the treatment of this fatal infection.

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; Antineoplastic Agents; Communicable Diseases, Emerging; Dermatomycoses; Disease Susceptibility; Female; Fluconazole; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Itraconazole; Lung Diseases, Fungal; Male; Middle Aged; Mucormycosis; Neutropenia; Pyrimidines; Sinusitis; Transplantation Conditioning; Triazoles; Viscera; Voriconazole

Posaconazole and/or amphotericin B was given to mice pretreated with a steroid and then infected by inhalation of Aspergillus flavus conidia. Two laboratories conducted studies using almost identical protocols to evaluate both survival and lung tissue burdens 8 days after infection. The results of the in vivo studies performed at both laboratories were consistent. We found that (i). up to 5 mg of amphotericin B per kg of body weight was poorly effective in treating invasive aspergillosis; (ii). posaconazole at 2 or 10 mg/kg/dose prolonged survival and reduced lung tissue CFU; and (iii). there was generally no antagonistic interaction of the drugs in combination, even when the experiments were designed to maximize the likelihood of antagonism. These studies do not confirm the antagonistic interaction of triazoles and polyenes reported by others.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Aspergillus flavus; Colony Count, Microbial; Lung; Mice; Survival Analysis; Triazoles

Topics: Adult; Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Ethmoid Sinusitis; Humans; Immunocompromised Host; Magnetic Resonance Imaging; Male; Mucor; Mucormycosis; Triazoles

Amphotericin B failure is frequently seen in patients with candidaemia caused by Candida rugosa. We evaluated amphotericin B, fluconazole, posaconazole and voriconazole as alternative treatments against infection in mice with two isolates of C. rugosa.. Neutropenic mice were inoculated intravenously with C. rugosa. Amphotericin B, fluconazole, posaconazole and voriconazole were administered for 7 days after infection. Efficacy of the antifungal treatment was assessed by survival and tissue burden of C. rugosa.. All of the four drugs significantly prolonged survival over controls. With both isolates, kidney counts were reduced significantly below controls for amphotericin B, fluconazole and posaconazole. However, voriconazole was less effective than the other antifungals.. Despite poor clinical response to amphotericin B, in vivo data indicate that amphotericin B increases organ clearance and survival over untreated controls. However, although voriconazole improved survival over controls, increased tissue clearance was not seen. This discrepancy may be caused by rapid clearance of voriconazole in mice. These studies suggest fluconazole, posaconazole or voriconazole may be useful alternatives to amphotericin B in therapy of C. rugosa infection.

Topics: Amphotericin B; Animals; Antifungal Agents; Candidiasis; Colony Count, Microbial; Fluconazole; Kidney; Male; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Neutropenia; Organ Size; Pyrimidines; Spleen; Survival Analysis; Triazoles; Voriconazole

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Polyenes; Research Design; Triazoles

To investigate the effects of posaconazole (POS) and amphotericin B (AMB) combination therapy in cryptococcal infection, we established an experimental model of systemic cryptococcosis in CD1 mice by intravenous injection of three distinct clinical isolates of Cryptococcus neoformans. Therapy was started 24 h after the infection and continued for 10 consecutive days. POS was given at 3 and 10 mg/kg of body weight/day, while AMB was given at 0.3 mg/kg/day. Combination therapy consisted of POS given at a low (combo 3) or at a high (combo 10) dose plus AMB. Survival studies showed that combo 3 was significantly more effective than POS at 3 mg/kg for two isolates tested (P value, < or = 0.001), while combo 10 was significantly more effective than POS at 10 mg/kg for all three isolates (P values ranging from <0.001 to 0.005). However, neither combination regimen was more effective than AMB alone. For two isolates, combination therapy was significantly more effective than each single drug at reducing the fungal burden in the brain (P values ranging from 0.001 to 0.015) but not in the lungs. This study demonstrates that the major impact of POS and AMB combination therapy is on brain fungal burden rather than on survival.

Topics: AIDS-Related Opportunistic Infections; Amphotericin B; Animals; Antifungal Agents; Brain; Colony Count, Microbial; Cryptococcosis; Cryptococcus neoformans; Disease Progression; Drug Therapy, Combination; Humans; Lung; Male; Mice; Survival Analysis; Triazoles

Invasive aspergillosis (IA) has emerged as a common cause of morbidity and mortality among immunocompromised patients. At The University of Texas M. D. Anderson Cancer Center (Houston, TX), Aspergillus terreus is second to A. fumigatus as the most common cause of IA. In the current study, the authors compared the risk factors and outcomes associated with IA caused by A. terreus and IA caused by A. fumigatus.. The authors retrospectively reviewed the medical records of 300 patients who received care at our institution between 1995 and 2001 and who had cultures that were positive for Aspergillus infection, including 90 patients whose cultures were positive for A. fumigatus and 70 patients whose cultures were positive for A. terreus.. Thirty-two patients with IA caused by A. terreus and 33 patients with IA caused by A. fumigatus were evaluated. The two groups were comparable in terms of age, gender, and underlying disease. Leukemia was the most common underlying malignancy (84%). More than 40% of patients in each group had undergone bone marrow transplantation. There was a trend toward a higher frequency of neutropenia among patients with IA caused by A. terreus (P = 0.12). IA caused by A. terreus was considered to be nosocomial in origin significantly more frequently compared with IA caused by A. fumigatus (P = 0.03). In vitro, A. terreus was found to be more resistant to amphotericin B (minimal inhibitory concentration [MIC90], 4.0 microg/mL) than to antifungal therapy (MIC90, 1.0 Hg/mL) in the isolates that were tested (< 50% of all isolates). The overall rate of response to antifungal therapy was 39% for patients with A. fumigatus infection, compared with 28% for patients with A. terreus infection (P = 0.43).. Despite the decreased in vitro susceptibility of A. terreus (relative to A. fumigatus) to amphotericin B, the two groups within the current patient population had comparably poor responses to amphotericin B preparation and somewhat improved responses to posaconazole.

Topics: Adult; Aged; Amphotericin B; Aspergillosis; Aspergillus; Aspergillus fumigatus; Cross Infection; Drug Resistance, Fungal; Female; Humans; Leukemia; Male; Middle Aged; Neutropenia; Opportunistic Infections; Retrospective Studies; Risk Factors; Triazoles

Human central nervous system (CNS) aspergillosis has >90% mortality. We compared posaconazole with other antifungals for efficacy against murine CNS aspergillosis. All tested regimens of posaconazole were equivalent to those of amphotericin B and superior in prolonging survival and reducing CFU to those of itraconazole and caspofungin and to vehicle controls. No antifungal regimen effected cure. No toxicity was noted. Overall, posaconazole shows potential for treating CNS aspergillosis.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Central Nervous System Fungal Infections; Male; Mice; Survival; Survival Analysis; Triazoles

We examined the in vitro activity of caspofungin, posaconazole, voriconazole, ravuconazole, itraconazole, and amphotericin B against 448 recent clinical mold isolates. The endpoint for reading caspofungin was the minimum effective concentration (MEC). Among the triazoles, posaconazole was most active, inhibiting 95% of isolates at 95% of Aspergillus spp. at

Topics: Amphotericin B; Anti-Bacterial Agents; Aspergillus; Caspofungin; Echinocandins; Fungi; Humans; Itraconazole; Lipopeptides; Microbial Sensitivity Tests; Mycoses; Penicillium; Peptides; Peptides, Cyclic; Pyrimidines; Thiazoles; Triazoles; Voriconazole

Three isolates of zygomycetes were used to produce a disseminated infection in nonimmunocompromised mice. Against all zygomycete strains, amphotericin B significantly prolonged survival. Itraconazole was inactive against Rhizopus microsporus and Rhizopus oryzae but was partially active against Absidia corymbifera. Posaconazole had no beneficial effects against R. oryzae but showed partial activity against A. corymbifera. Posaconazole had a clear dose-response effect against R. microsporus.

Topics: Absidia; Amphotericin B; Animals; Antifungal Agents; Brain; Female; Itraconazole; Kidney; Mice; Microbial Sensitivity Tests; Rhizopus; Triazoles; Zygomycosis

The effect of the medium composition on the fungistatic (MIC) and fungicidal (MLC) activity of amphotericin B, itraconazole, voriconazole, posaconazole and terbinafine against four Aspergillus fumigatus strains has been investigated by four European laboratories. MICs were determined by broth microdilution, using RPMI 1640 and Antibiotic Medium 3 (AM3), three times in three independent determinations by the four laboratories. MLCs were determined for the three independent determinations by the four laboratories, subculturing 100 microl from each well showing no visible growth after 48 hours. Except for a 2-dilution difference observed in three cases, no differences were observed between MICs determined on the two media. In contrast, a 3- to 6-dilution discrepancy between the MLCs was observed for the azoles. Endpoints on RPMI were higher than those on AM3. A 1-2 dilution difference was noted between both the endpoints of amphotericin B and of terbinafine. The highest inter- and intra-laboratory agreements were reached on AM3. The azoles showed a medium-dependent fungicidal activity.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Culture Media; France; Humans; Itraconazole; Laboratories; Microbial Sensitivity Tests; Naphthalenes; Observer Variation; Pyrimidines; Terbinafine; Triazoles; Voriconazole

Subgingival colonization by Candida albicans has been described in human immunodeficiency virus (HIV)-infected individuals, but subgingival isolates have scarcely been characterized, particularly with respect to genotype and antifungal susceptibility. A series of 29 subgingival strains of C. albicans isolated from nine HIV-infected individuals was typed by electrophoretic karyotyping and tested for susceptibility to fluconazole, itraconazole, the new investigational triazole posaconazole and amphotericin B. DNA typing showed genetic heterogeneity within subgingival isolates, as almost every individual harbored his/her own specific isolate. Genetic identity was usually demonstrated within oral and subgingival isolates simultaneously collected from the same individual, but a number of DNA types were found to be unique to subgingival strains. These findings suggest that colonization is not just the result of Candida spreading from oral surfaces, and that subgingivally adapted strains could be involved. All isolates were susceptible to all the triazole drugs tested and amphotericin B. Additional studies on subgingival Candida colonization and further characterization of subgingival isolates are now required to clarify the role of Candida as opportunistic periodontal pathogen.

Topics: Adult; Amphotericin B; Antifungal Agents; Candida albicans; Dental Plaque; DNA, Fungal; Drug Resistance, Fungal; Female; Fluconazole; Genetic Heterogeneity; HIV Infections; Humans; Itraconazole; Karyotyping; Male; Microbial Sensitivity Tests; Mycological Typing Techniques; Triazoles

Posaconazole, ravuconazole, and voriconazole are new triazole derivatives that possess potent, broad-spectrum antifungal activity. We evaluated the in vitro activity of these investigational triazoles compared with that of itraconazole and amphotericin B against 239 clinical isolates of filamentous fungi from the SENTRY Program, including Aspergillus spp. (198 isolates), Fusarium spp. (7 isolates), Penicillium spp. (19 isolates), Rhizopus spp. (4 isolates), Mucor spp. (2 isolates), and miscellaneous species (9 isolates). The isolates were obtained from 16 different medical centers in the United States and Canada between January and December 2000. In vitro susceptibility testing was performed using the microdilution broth method outlined in the National Committee for Clinical Laboratory Standards M38-P document. Overall, posaconazole was the most active compound, inhibiting 94% of isolates at a MIC of < or = 1 microg/ml, followed by voriconazole (91%), amphotericin B (89%), ravuconazole (88%), and itraconazole (70%). All three new triazoles demonstrated excellent activity (MIC, < or = 1 microg/ml) against Aspergillus spp. (114 Aspergillus fumigatus, 22 Aspergillus niger, 13 Aspergillus flavus, 9 Aspergillus versicolor, 8 Aspergillus terreus, and 32 Aspergillus spp.): posaconazole (98%), voriconazole (98%), ravuconazole (92%), amphotericin B (89%), and itraconazole (72%). None of the triazoles were active against Fusarium spp. (MIC at which 50% of the isolates tested were inhibited [MIC(50)], >8 microg/ml) or Mucor spp. (MIC(50), >8 microg/ml). Posaconazole and ravuconazole were more active than voriconazole against Rhizopus spp. (MIC(50), 1 to 2 microg/ml versus >8 microg/ml, respectively). Based on these results, all three new triazoles exhibited promising activity against Aspergillus spp. and other less commonly encountered isolates of filamentous fungi. The clinical value of these in vitro data remains to be seen, and in vitro-in vivo correlation is needed for both new and established antifungal agents. Surveillance efforts should be expanded in order to monitor the spectrum of filamentous fungal pathogens and their in vitro susceptibility as these new antifungal agents are introduced into clinical use.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus; Canada; Fungi; Humans; Microbial Sensitivity Tests; Mycoses; Pyrimidines; Quality Control; Thiazoles; Triazoles; United States; Voriconazole

To select voriconazole-resistant mutants of Aspergillus fumigatus in the laboratory from drug-susceptible clinical isolates and examine their in vitro susceptibility to amphotericin B and investigational azoles, and to compare the intramycelial accumulation of voriconazole in the resistant isolates with that in the susceptible parent.. Voriconazole-resistant Aspergillus fumigatus isolates were selected in the laboratory from three highly susceptible (MIC < or = 0.5 mg/L) clinical isolates by stepwise selection on peptone yeast extract glucose (PYG) agar containing 0.5 mg and 4 mg voriconazole/L. Twenty-three colonies that grew in the presence of 4 mg voriconazole/L on PYG agar (frequency 1.9 x 10(-8)) were tested for their in vitro susceptibility to amphotericin B, itraconazole, voriconazole and posaconazole by a broth macrodilution technique. The accumulation of voriconazole in the mycelia of two representative resistant isolates (VCZ-W42 and VCZ-W45) was determined by a previously described bioassay.. The geometric mean MICs (mg/L) of amphotericin B, itraconazole, voriconazole and posaconazole for these isolates were 0.45 +/- 0.19, 0.69 +/- 0.45, 5.24 +/- 3.74 and 0.27 +/- 0.18, respectively. A comparison of the geometric mean MICs of the antifungals obtained for the resistant isolates to those of the susceptible parents showed 1.15-, 2.76-, 16.90- and 1.42-fold increases, respectively, for amphotericin B, itraconazole, voriconazole and posaconazole, suggesting that low-level cross-resistance exists between the azole antifungals. The susceptible parent and the resistant isolates accumulated similar amounts of voriconazole.. These results suggest that spontaneous mutants of Aspergillus fumigatus resistant to voriconazole could emerge among clinical isolates under selection pressure and that the observed reduced in vitro susceptibility to voriconazole may not be due to reduced accumulation of the drug in the mycelia.

Topics: Amphotericin B; Antifungal Agents; Aspergillus fumigatus; Drug Resistance, Microbial; Humans; Itraconazole; Microbial Sensitivity Tests; Pyrimidines; Triazoles; Voriconazole

We investigated the frequency of clinical isolation and the in vitro susceptibility to antifungal agents of Aspergillus species obtained from patients at the Detroit Medical Center from January 1994 to December 1999. During this period, 593 clinical isolates of Aspergillus species [406 A. fumigatus, 68%; 82 A. niger, 14%; 42 A. flavus, 7%; 63 Aspergillus spp., 11%] were recovered from hospitalized patients. From January 1996 to December 1999, approximately 2.5-4.5 fold yearly increase of the number of aspergillus isolates occurred compared to that of 1994. Conidial suspensions from clinical isolates were prepared and their in vitro susceptibility to amphotericin B and three azoles were determined. All four agents examined were extremely active. The minimum inhibitory concentrations (MIC(90)) (microg/mL) of amphotericin B, itraconazole, voriconazole and posaconazole for A. fumigatus (n = 406) were 0.5, 1.0, 0.5 and 0.25. Similar values were noted for non-A. fumigatus isolates. A year-to-year comparison of the MIC(90) of the four agents for A. fumigatus and non-A. fumigatus isolates over the 6-year study period showed no significant differences. Our study showed a steady increase in the frequency of clinical isolation of Aspergillus species; and the organism has remained susceptible to amphotericin B/triazoles without any change in susceptibility levels during the 6-year study period.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus; Aspergillus flavus; Aspergillus fumigatus; Aspergillus niger; Humans; Itraconazole; Pyrimidines; Triazoles; Voriconazole

SCH56592 (SCH) was evaluated in an immunosuppressed rabbit model of invasive aspergillosis. SCH was more effective than similar doses of itraconazole and as effective as amphotericin B in the clearance of Aspergillus spp. from tissues. Compared with controls, SCH regimens reduced mortality, improved survival, and significantly reduced tissue colony counts.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Aspergillus; Colony Count, Microbial; Disease Models, Animal; Female; Immunosuppression Therapy; Itraconazole; Microbial Sensitivity Tests; Rabbits; Triazoles

Ramichloridium obovoideum ("Ramichloridium makenziei") is a rare cause of lethal cerebral phaeohyphomycosis. It has been, so far, geographically restricted to the Middle East. BALB/c mice were inoculated with two strains of R. obovoideum intracranially. Therapy with amphotericin B, itraconazole, or the investigational triazole SCH 56592 was conducted for 10 days. Half the mice were monitored for survival and half were killed for determination of the fungal load in brain tissue. Recipients of SCH 56592 had significantly prolonged survival and lower brain fungal burden, and this result was found for mice infected with both of the fungal strains tested. Itraconazole reduced the brain fungal load in mice infected with one strain but not the other, while amphotericin B had no effect on brain fungal concentrations. This study indicates a possible role of SCH 56592 in the treatment of the serious cerebral phaeohyphomycosis due to R. obovoideum.

Topics: Amphotericin B; Animals; Antifungal Agents; Ascomycota; Central Nervous System Fungal Infections; Disease Models, Animal; Female; Itraconazole; Mice; Mice, Inbred BALB C; Mice, Inbred ICR; Mycoses; Triazoles

We investigated the in vitro susceptibilities of clinical and laboratory-selected Aspergillus spp. to posaconazole, and compared the results with those obtained for amphotericin B, itraconazole and voriconazole. Conidial suspensions from clinical isolates (284 Aspergillus fumigatus, 66 Aspergillus niger, 31 Aspergillus flavus and 43 Aspergillus spp.) and laboratory-selected resistant A. fumigatus isolates (15 resistant to amphotericin B, 25 to itraconazole and 12 to voriconazole) were prepared and their susceptibilities to various antifungal agents determined using a previously described broth macrodilution technique. The geometric mean MICs (mg/L) of posaconazole for A. fumigatus (0.17 +/- 0.11) and non-A. fumigatus aspergilli (0.16 +/- 0.28) were significantly lower (P 0.05) than those for amphotericin B, itraconazole and voriconazole. Amphotericin B-resistant A. fumigatus isolates were as susceptible to posaconazole as the parental strain. Itraconazole- and voriconazole-resistant isolates showed low-level (two- to three-fold increase in MICs) cross-resistance to posaconazole. The minimum fungicidal concentrations (mg/L) of posaconazole for A. fumigatus (n = 58) and non-A. fumigatus aspergilli (n = 40) were 4. 45 +/- 2.70 (range 0.25-8) and 4.14 +/- 3.03 (range 0.5-8), respectively. Time-kill studies showed that the fungicidal activity of posaconazole against A. fumigatus is time- and concentration-dependent (for example, posaconazole 4 mg/L killed >99% of A. fumigatus conidia within 24 h). These results suggest that overall, posaconazole has better activity and a smaller range of MICs for Aspergillus spp., including those with reduced susceptibility to amphotericin B, itraconazole and voriconazole.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus; Itraconazole; Microbial Sensitivity Tests; Mutation; Pyrimidines; Triazoles; Voriconazole

The interaction of amphotericin B (AmB) and azole antifungal agents in the treatment of fungal infections is still a controversial issue. A checkerboard titration broth microdilution-based method that adhered to the recommendations of the National Committee for Clinical Laboratory Standards was applied to study the in vitro interactions of AmB with fluconazole (FLC), itraconazole (ITC), and the new investigational triazole SCH 56592 (SCH) against 15 clinical isolates of Cryptococcus neoformans. Synergy, defined as a fractional inhibitory concentration (FIC) index of < or =0.50, was observed for 7% of the isolates in studies of the interactions of both FLC-AmB and ITC-AmB and for 33% of the isolates in studies of the SCH-AmB interactions; additivism (FICs, >0.50 to 1.0) was observed for 67, 73, and 53% of the isolates in studies of the FLC-AmB, ITC-AmB, and SCH-AmB interactions, respectively; indifference (FICs, >1.0 to < or =2.0) was observed for 26, 20, and 14% of the isolates in studies of the FLC-AmB, ITC-AmB, and SCH-AmB interactions, respectively. Antagonism (FIC >2.0) was not observed. When synergy was not achieved, there was still a decrease, although not as dramatic, in the MIC of one or both drugs when they were used in combination. To investigate the effects of FLC-AmB combination therapy in vivo, we established an experimental model of systemic cryptococcosis in BALB/c mice by intravenous injection of cells of C. neoformans 2337, a clinical isolate belonging to serotype D against which the combination of FLC and AmB yielded an additive interaction in vitro. Both survival and tissue burden studies showed that combination therapy was more effective than FLC alone and that combination therapy was at least as effective as AmB given as a single drug. On the other hand, when cells of C. neoformans 2337 were grown in FLC-containing medium, a pronounced increase in resistance to subsequent exposures to AmB was observed. In particular, killing experiments conducted with nonreplicating cells showed that preexposure to FLC abolished the fungicidal activity of the polyene. However, this apparent antagonism was not observed in vivo. Rather, when the two drugs were used sequentially for the treatment of systemic murine cryptococcosis, a reciprocal potentiation was often observed. Our study shows that (i) the combination of triazoles and AmB is significantly more active than either drug alone against C. neoformans in vitro and (ii) the concomitant or sequenti

Topics: Amphotericin B; Animals; Antifungal Agents; Cryptococcosis; Cryptococcus neoformans; Disease Models, Animal; Drug Therapy, Combination; Fluconazole; Humans; Itraconazole; Male; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Triazoles

A murine model of intratracheally induced histoplasmosis in immunocompromised B6C3F(1) mice was used to evaluate a new triazole antifungal agent, posaconazole. This compound was previously shown to be comparable to amphotericin B and superior to itraconazole for the treatment of histoplasmosis in immunocompetent mice. The current study used mice that were depleted of T lymphocytes by intraperitoneal injection of anti-CD4 and anti-CD8 monoclonal antibodies beginning 2 days before infection and continuing at 5-day intervals until completion of the study. Groups of B6C3F(1) mice that were depleted of CD4 and CD8 T cells were infected with an inoculum of 10(4) Histoplasma capsulatum yeasts. All mice receiving posaconazole at 1 or 0.1 mg/kg of body weight/day, amphotericin B at 2 mg/kg every other day (qod), or itraconazole at 75 mg/kg/day survived to day 29. Only 60% of mice receiving itraconazole at 10 mg/kg/day and none receiving amphotericin B at 0.2 mg/kg qod survived to that date. Fungal burdens were determined at day 14 of infection, 1 day after discontinuation of therapy. Quantitative colony counts and Histoplasma antigen levels in lung and spleen tissues declined following treatment with amphotericin B at 2 mg/kg qod, posaconazole at 5 and 1 mg/kg/day, and itraconazole at 75 mg/kg/day but not in mice treated with amphotericin B at 0.2 mg/kg qod or itraconazole at 10 mg/kg/day. Posaconazole at 0.1 mg/kg/day reduced fungal colony counts and antigen levels in spleens but not in lungs. This study shows posaconazole activity for the treatment of histoplasmosis in immunosuppressed animals.

Topics: Amphotericin B; Animals; Antifungal Agents; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Histoplasma; Histoplasmosis; Immunocompromised Host; Immunosuppression Therapy; Itraconazole; Lung; Mice; Mice, Inbred Strains; Spleen; Survival Analysis; Time Factors; Triazoles

A murine model of intratracheally induced histoplasmosis was used to evaluate a new triazole antifungal agent, Schering (SCH) 56592, for treatment of histoplasmosis. MICs were determined for SCH 56592, amphotericin B, and itraconazole by testing yeast-phase isolates from 20 patients by a macrobroth dilution method. The MICs at which 90% of the isolates are inhibited were for 0.019 microgram/ml for SCH 56592, 0.5 microgram/ml for amphotericin B, and < or = 0.019 microgram/ml for itraconazole. Survival studies were done on groups of 10 B6C3F1 mice with a lethal inoculum of 10(5). All mice receiving 5, 1, or 0.25 mg of SCH 56592 per kg of body weight per day, 2.5 mg of amphotericin B per kg every other day (qod), or 75 mg of itraconazole per kg per day survived to day 29. Only 44% of mice receiving 5 mg of itraconazole/kg/day survived to day 29. Fungal burden studies done in similar groups of mice with a sublethal inoculum of 10(4) showed a reduction in CFUs and Histoplasma antigen levels in lung and spleen tissue in animals treated with 2 mg of amphotericin B/kg qod, 1 mg of SCH 56592/kg/day, and 75 mg of itraconazole/kg/day, but not in those treated with lower doses of the study drugs (0.2 mg of amphotericin B/kg qod, 0.1 mg of SCH 56592/kg/day, or 10 mg of itraconazole/kg/day). Serum drug concentrations were measured 3 and 24 h after the last dose in mice (groups of five to seven mice), each treated for 7 days with SCH 56592 (10 and 1 mg/kg/day) and itraconazole (75 and 10 mg/kg/day). Mean levels measured by bioassay were as follows: SCH 56592, 10 mg/kg/day (2.15 micrograms/ml at 3 h and 0.35 microgram/ml at 24 h); SCH 56592, 1 mg/kg/day (0.54 microgram/ml at 3 h and none detected at 24 h); itraconazole, 75 mg/kg/day (22.53 micrograms/ml at 3 h and none detected at 24 h); itraconazole, 10 mg/kg/day (1.33 micrograms/ml at 3 h and none detected at 24 h). Confirmatory results were obtained by high-pressure liquid chromatography assay. These studies show SCH 56592 to be a promising candidate for studies of treatment of histoplasmosis in humans.

Topics: Amphotericin B; Animals; Antifungal Agents; Disease Models, Animal; Histoplasma; Histoplasmosis; Immunocompetence; Itraconazole; Mice; Microbial Sensitivity Tests; Triazoles

Conidia are used as inocula for the in vitro susceptibility testing of Aspergillus fumigatus. Since the MIC is defined on the basis of visible mycelial growth, conidia should germinate and produce sporelings (germinated conidia) for monitoring of the growth inhibition and fungicidal activity of a drug. If a compound is capable of inhibiting germination of conidia while affecting or not affecting the growth of the organism, the MIC obtained will be the concentration of the drug required for the inhibition of conidial germination but not necessarily that required for inhibition of the growth of the organism. We investigated the susceptibility of germinated and ungerminated conidia to amphotericin B, itraconazole, voriconazole, and SCH56592. The MICs of various antifungal agents for germinated conidia were almost identical to those obtained for ungerminated conidia. In addition, both the germinated and ungerminated conidia were killed with almost equal efficiency by all of the compounds tested when exposed to the drugs for 24 h. These results suggest that either germinated or ungerminated conidia could be used as inocula for in vitro susceptibility studies of A. fumigatus with identical results.

Topics: Amphotericin B; Antifungal Agents; Aspergillus fumigatus; Itraconazole; Kinetics; Microbial Sensitivity Tests; Pyrimidines; Time Factors; Triazoles; Voriconazole

Candida dubliniensis is a newly recognized fungal pathogen causing mucosal disease in AIDS patients. Although preliminary studies indicate that most strains of C. dubliniensis are susceptible to established antifungal agents, fluconazole-resistant strains have been detected. Furthermore, fluconazole-resistant strains are easily derived in vitro, and these strains exhibit increased expression of multidrug resistance transporters, especially MDR1. Because of the potential for the development of resistant strains of C. dubliniensis, it is prudent to explore the in vitro activities of several of the newer triazole and echinocandin antifungals against isolates of C. dubliniensis. In this study we tested 71 isolates of C. dubliniensis against the triazoles BMS-207147, Sch 56592, and voriconazole and a representative of the echinocandin class of antifungal agents, MK-0991. We compared the activities of these agents with those of the established antifungal agents fluconazole, itraconazole, amphotericin B, and 5-fluorocytosine (5FC) by using National Committee for Clinical Laboratory Standards microdilution reference methods. Our findings indicate that the vast majority of clinical isolates of C. dubliniensis are highly susceptible to both new and established antifungal agents. Strains with decreased susceptibilities to fluconazole remained susceptible to the investigational agents as well as to amphotericin B and 5FC. The increased potencies of the new triazole and echinocandin antifungal agents may provide effective therapeutic options for the treatment of infections due to C. dubliniensis.

Topics: AIDS-Related Opportunistic Infections; Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Candida; Candidiasis; Caspofungin; Echinocandins; Fluconazole; Flucytosine; Humans; Itraconazole; Lipopeptides; Microbial Sensitivity Tests; Peptides; Peptides, Cyclic; Pyrimidines; Thiazoles; Triazoles; Voriconazole

Current therapy for leishmaniasis is unsatisfactory. Efficacious and safe oral therapy would be ideal. We examined the efficacy of SCH 56592, an investigational triazole antifungal agent, against cutaneous infection with Leishmania amazonensis and visceral infection with Leishmania donovani in BALB/c mice. Mice were infected in the ear pinna and tail with L. amazonensis promastigotes and were treated with oral SCH 56592 or intraperitoneal amphotericin B for 21 days. At doses of 60 and 30 mg/kg/day, SCH 56592 was highly efficacious in treating cutaneous disease, and at a dose of 60 mg/kg/day, it was superior to amphotericin B at a dose of 1 mg/kg/day. The means of tail lesion sizes were 0.32 +/- 0.12, 0.11 +/- 0.06, 0.17 +/- 0.07, and 0.19 +/- 0.08 mm for controls, SCH 56592 at 60 and 30 mg/kg/day, and amphotericin B recipients, respectively (P = 0.0003, 0.005, and 0.01, respectively). Parasite burden in draining lymph nodes confirmed these efficacy findings. In visceral leishmaniasis due to L. donovani infection, mice treated with SCH 56592 showed a 0.5- to 1-log-unit reduction in parasite burdens in the liver and the spleen compared to untreated mice. Amphotericin B at 1 mg/kg/day was superior to SCH 56592 in the treatment of visceral infection, with a 2-log-unit reduction in parasite burdens in both the liver and spleen. These studies indicate very good activity of SCH 56592 against cutaneous leishmaniasis due to L. amazonensis infection and, to a lesser degree, against visceral leishmaniasis due to L. donovani infection in susceptible BALB/c mice.

Topics: Amphotericin B; Animals; Fluconazole; Leishmania donovani; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral; Liver; Lymph Nodes; Male; Mice; Mice, Inbred BALB C; Spleen; Time Factors; Triazoles; Trypanocidal Agents

Candida dubliniensis has been associated with oropharyngeal candidiasis in patients infected with human immunodeficiency virus (HIV). C. dubliniensis isolates may have been improperly characterized as atypical Candida albicans due to the phenotypic similarity between the two species. Prospective screening of oral rinses from 63 HIV-infected patients detected atypical dark green isolates on CHROMagar Candida compared to typical C. albicans isolates, which are light green. Forty-eight atypical isolates and three control strains were characterized by germ tube formation, differential growth at 37, 42, and 45 degreesC, identification by API 20C, fluorescence, chlamydoconidium production, and fingerprinting by Ca3 probe DNA hybridization patterns. All isolates were germ tube positive. Very poor or no growth occurred at 42 degreesC with 22 of 51 isolates. All 22 poorly growing isolates at 42 degreesC and one isolate with growth at 42 degreesC showed weak hybridization of the Ca3 probe with genomic DNA, consistent with C. dubliniensis identification. No C. dubliniensis isolate but only 18 of 28 C. albicans isolates grew at 45 degreesC. Other phenotypic or morphologic tests were less reliable in differentiating C. dubliniensis from C. albicans. Antifungal susceptibility testing showed fluconazole MICs ranging from

Topics: AIDS-Related Opportunistic Infections; Amphotericin B; Antifungal Agents; Candida; Candidiasis, Oral; Fluconazole; Genotype; HIV Infections; Humans; Itraconazole; Microbial Sensitivity Tests; Mouth; North America; Pharynx; Phenotype; Pyrimidines; Triazoles; Voriconazole

Sch 56592 is a new triazole derivative that possesses potent, broad-spectrum antifungal activity. We evaluated the in vitro activity of Sch 56592 compared with that of itraconazole, amphotericin B and 5-fluorocytosine against 51 clinical isolates of filamentous fungi, including Aspergillus flavus (10), A. fumigatus (12), Fusarium spp. (13), Rhizopus spp. (6), Pseudallescheria boydii (5), and one isolate each of Acremonium spp., A. niger, A. terreus, Paecilomyces spp., and Trichoderma spp. In vitro susceptibility testing was performed using the microdilution broth method outlined in the NCCLS 27-A document. Sch 56592 was highly active against A. flavus (MIC90, 0.25 micrograms/ml), A. fumigatus (MIC90, 0.12 micrograms/ml), P. boydii (MIC50, 1 microgram/ml) and Rhizopus spp (MIC50, 1 microgram/ml). By comparison with itraconazole, Sch 56592 was four-to eight-fold more active against isolates of Aspergillus and both compounds showed equipotent in vitro activity against P. boydii and Rhizopus spp. Sch 56592 was four- to 16-fold more active than amphotericin B against Aspergillus spp. and P. boydii and both antifungal drugs displayed similar activity against Rhizopus spp. Overall, Sch 56592 showed good in vitro activity against all isolates tested (MIC, < or = 2 micrograms/ml) except isolates of Fusarium (MIC range, (1-->4 micrograms/ml). On the basis of these data Sch 56592 has promising activity against Aspergillus spp. and other species of filamentous fungi that are likely to be encountered clinically. Additional in vitro and in vivo studies are warranted.

Topics: Amphotericin B; Antifungal Agents; Flucytosine; Fungi; Humans; Itraconazole; Microbial Sensitivity Tests; Triazoles

Mice were immunosuppressed using corticosteroids and infected with conidia of Aspergillus fumigatus. Beginning 1 day after infection, mice were treated orally either with Noble agar or with SCH56592 suspended in Noble agar, or intraperitoneally with amphotericin B. SCH56592 prolonged survival and reduced lung tissue counts of A. fumigatus, while amphotericin B had marginal benefit. SCH56592 merits further development for treatment of aspergillosis.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Colony Count, Microbial; Lung; Lung Diseases, Fungal; Male; Mice; Mice, Inbred ICR; Triazoles

Sch 56592 is a new triazole agent with potent, broad-spectrum antifungal activity. The in vitro activities of Sch 56592, itraconazole, fluconazole, amphotericin B, and flucytosine (5-FC) against 404 clinical isolates of Candida spp. (382 isolates) and Saccharomyces cerevisiae (22 isolates) were investigated. In vitro susceptibility testing was performed by a broth microdilution method performed according to National Committee for Clinical Laboratory Standards guidelines. Overall, Sch 56592 was very active (MIC at which 90% of isolates are inhibited [MIC90], 0.5 microgram/ml) against these yeast isolates. Sch 56592 was most active against Candida tropicalis, Candida parapsilosis, candida lusitaniae, and Candida stellatoidea (MIC90, < or = 0.12 microgram/ml) and was least active against Candida glabrata (MIC90, 2.0 micrograms/ml). Sch 56592 was 2- to 32-fold more active than amphotericin B and 5-FC against all species except C. glabrata. By comparison with the other triazoles, Sch 56592 was equivalent to itraconazole and greater than or equal to eightfold more active than fluconazole. On the basis of these results, Sch 56592 has promising antifungal activity, and further in vitro and in vivo investigations are warranted.

Topics: Amphotericin B; Antifungal Agents; Candida; Fluconazole; Flucytosine; Humans; Itraconazole; Microbial Sensitivity Tests; Saccharomyces cerevisiae; Triazoles

In this study, we investigated the in vitro activity of SCH-56592 (SCH), a new triazole antifungal agent. We compared the activity of SCH with those of itraconazole (ITZ) and amphotericin B (AB) against 60 clinical isolates of Aspergillus spp. by using a microtiter format. Incubation was done at 37 degrees C for 48 h, and MIC endpoints (no growth) were read visually. The medium used for all of the drugs was RPMI 1640 buffered with morpholinepropanesulfonic acid (MOPS) and supplemented with 2% glucose. MICs and minimum fungicidal concentrations (MFCs; killing of > or = 99.99%) were measured for all isolates. The geometric mean (GM) MICs and ranges (in micrograms per milliliter) were as follows: SCH, 0.09 and < or = 0.01 to 1; ITZ, 0.25 and 0.06 to 32; AB, 1.46 and 0.25 to 32. Aspergillus terreus (n = 7) was markedly more susceptible to SCH (GM, 0.05 microg/ml) and ITZ (GM, 0.07 microg/ml) than to AB (GM, 8.8 microg/ml). For all isolates, the GM MFCs and ranges (in micrograms per milliliter) were as follows: SCH, 3.64 and 0.125 to 16; ITZ, 15.09 and 0.125 to 32; AB, 10.3 and 1 to 32. In the drug concentration range tested, 71, 32, and 64% of the isolates against which SCH, ITZ, and AB, respectively, were tested were killed. A reproducibility study was performed with 20% of the isolates; for 11 of the 12 isolates retested, the MIC was the same or within 1 well of the original MIC of each drug. Therefore, in vitro mould testing of SCH is feasible and reproducible. SCH was found to be very active against all species of Aspergillus and at lower concentrations than either ITZ or AB.

Topics: Amphotericin B; Analysis of Variance; Antifungal Agents; Aspergillus; Itraconazole; Microbial Sensitivity Tests; Triazoles

SCH 56592 (SCH) is a new triazole antifungal with a broad spectrum of activity. In vitro susceptibility testing against five strains of Coccidioides immitis revealed MICs from 0.39 to 3.13 microg/ml and minimal fungicidal concentrations from 1.56 to 3.13 microg/ml. A murine model of systemic coccidioidomycosis was established in female CD-1 mice. Groups received either no treatment or oral therapy with fluconazole at 10 or 100 mg/kg of body weight; itraconazole at 10 or 100 mg/kg; SCH at 0.5, 2, 10, or 25 mg/kg; or its methylcellulose diluent alone. Therapy began 2 days postinfection and continued once daily for 19 days. Surviving mice were euthanized 49 days postinfection, and infectious burdens were determined by culture. All drugs were superior to no-treatment or diluent-treatment controls (P < 0.001) in prolonging survival but were not significantly different from one another. Itraconazole at 100 mg/kg was superior to fluconazole in reduction of CFU in the spleen, liver, and lung (P < 0.01 to 0.001). SCH at 0.5 mg/kg was superior to either fluconazole or itraconazole at 10 mg/kg in reduction of CFU in all three organs (P < 0.05 to 0.001). SCH at 2 mg/kg was not significantly different from itraconazole at 100 mg/kg in all three organs. SCH at 10 and 25 mg/kg was superior to either dose of fluconazole or itraconazole in all three organs (P < 0.05 to 0.001). In terms of reduction of CFU, SCH was > or = 200-fold as potent as fluconazole and > or = 50-fold as potent as itraconazole. There was a clear dose-responsive relationship for SCH in each of the organs. It is noteworthy that SCH effected cures (no detectable C. immitis in any organ) in 1 of 9, 6 of 10, or 9 of 9 surviving mice in animals given 2, 10, or 25 mg/kg, respectively. Neither fluconazole nor itraconazole cured any survivor. SCH has potent, fungicidal activity in vivo against C. immitis. It should be considered for clinical trials in patients with coccidioidomycosis.

Topics: Amphotericin B; Animals; Antifungal Agents; Coccidioides; Coccidioidomycosis; Drug Evaluation, Preclinical; Female; Itraconazole; Mice; Mice, Inbred Strains; Microbial Sensitivity Tests; Triazoles

The new triazole derivative SCH 56592 has been tested in a National Committee for Clinical Laboratory Standards-adapted in vitro susceptibility test, and its activity against 12 isolates of Blastomyces dermatitidis yeast-like forms has been compared with those of amphotericin B, itraconazole, and fluconazole. SCH 56592 was the most active of the four compounds, with an MIC at which 90% of the isolates are inhibited of 0.06 microgram/ml and a minimal fungicidal concentration at which 90% of the isolates are inhibited of 4 micrograms/ml. The results of the treatment of mice infected with B. dermatitidis with three different doses of SCH 56592 (25, 5, or 1 mg/kg of body weight), amphotericin B (1 mg/kg), or itraconazole (150 mg/kg) confirmed the potent activity of SCH 56592. Survival was prolonged at each dose of SCH 56592, and sterilization of the lungs occurred in the high-dose group but not in the groups treated with itraconazole or fluconazole. SCH 56592 is a promising new azole antifungal drug that should be studied in humans with blastomycosis.

Topics: Amphotericin B; Animals; Antifungal Agents; Blastomyces; Blastomycosis; Drug Evaluation, Preclinical; Fluconazole; Lethal Dose 50; Lung Diseases, Fungal; Male; Mice; Microbial Sensitivity Tests; Triazoles

Multiple isolates of Cryptococcus neoformans were tested to compare the in vitro activity of a new triazole, SCH56592, with those of amphotericin B, fluconazole, and itraconazole, MICs of each drug were determined, and minimum fungicidal concentrations of SCH56592 and amphotericin B were measured. MICs of SCH56592 were lower than those of amphotericin B and fluconazole but not those of itraconazole. Minimum fungicidal concentrations of SCH56592 were lower than those of amphotericin B. SCH56592 in the presence of human serum produces an in vitro fungicidal effect for Cryptococcus neoformans. The data indicate that SCH56592 might exert fungicidal as well as inhibitory properties in vivo. On the basis of these results, SCH56592 was evaluated with a rabbit model of experimental cryptococcal meningitis; SCH56592 treatment was compared with treatment with fluconazole. Despite no detectable drug concentrations in the cerebrospinal fluid, the activity of SCH56592 against C. neoformans infection was equivalent to that of fluconazole. SCH56592 has potent in vitro activity against C. neoformans and compares favorably to treatment with fluconazole for a central nervous system infection. SCH56592 should be studied for use in humans with cryptococcal infections.

Topics: Amphotericin B; Animals; Antifungal Agents; Blood; Cryptococcus neoformans; Fluconazole; Humans; Itraconazole; Meningitis, Cryptococcal; Microbial Sensitivity Tests; Rabbits; Triazoles