amphotericin-b and Pulmonary-Aspergillosis

Although the treatment of aspergillosis has been studied for years, the optimal nonsurgical treatment of chronic cavitary pulmonary aspergillosis (CCPA) remains unsatisfactory, especially in lung cancer. We report two advanced non-small cell lung cancer (NSCLC) patients who recovered from CCPA following instillation of Amphotericin B (AmB) by bronchoscopy combined with systemic voriconazole. The first patient was diagnosed with lung adenocarcinoma after right upper lobe resection and was treated with anaplastic lymphoma kinase-targeted therapy. Chest computed tomography (CT) revealed a right pulmonary cavity containing solid materials. The second patient was diagnosed with squamous cell carcinoma and received immunotherapy following surgery, chemotherapy, and radiotherapy. Chest CT tomography revealed a mass in the right lung cavity. Both patients' cultures and next-generation sequencing of their bronchoalveolar lavage (BAL) samples revealed presence of Aspergillus fumigatus. In addition, the galactomannan test of both patients BAL samples was positive. Systemic voriconazole was prescribed based on in vitro susceptibility testing. The chest images and clinical symptoms of both patients did not improve after one month of voriconazole therapy within the therapeutic blood concentration. Considering the low local concentrations of antifungals against CCPA, AmB instillation by bronchoscopy combined with systemic voriconazole was utilized. The chest CT images and clinical symptoms of both patients markedly improved in the following third month. Instillation of AmB combined with systemic voriconazole may be a promising treatment option for NSCLC patients with CCPA who fail voriconazole monotherapy.

Topics: Amphotericin B; Antifungal Agents; Bronchoscopy; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Pulmonary Aspergillosis; Voriconazole

Severe acute respiratory syndrome coronavirus 2 causes direct damage to the airway epithelium, enabling aspergillus invasion. Reports of COVID-19-associated pulmonary aspergillosis have raised concerns about it worsening the disease course of COVID-19 and increasing mortality. Additionally, the first cases of COVID-19-associated pulmonary aspergillosis caused by azole-resistant aspergillus have been reported. This article constitutes a consensus statement on defining and managing COVID-19-associated pulmonary aspergillosis, prepared by experts and endorsed by medical mycology societies. COVID-19-associated pulmonary aspergillosis is proposed to be defined as possible, probable, or proven on the basis of sample validity and thus diagnostic certainty. Recommended first-line therapy is either voriconazole or isavuconazole. If azole resistance is a concern, then liposomal amphotericin B is the drug of choice. Our aim is to provide definitions for clinical research and up-to-date recommendations for clinical management of the diagnosis and treatment of COVID-19-associated pulmonary aspergillosis.

Topics: Amphotericin B; Antifungal Agents; Azoles; Coinfection; COVID-19; Humans; Nitriles; Pulmonary Aspergillosis; Pyridines; SARS-CoV-2; Triazoles; Voriconazole

The biological properties of elastase and Aspergillus flavus elastase inhibitor (AFLEI) from A. flavus were examined. Pathogenicity of elastase was investigated in mice immunocompromised with cyclophosphamide, cyclosporine, prednisolone and carrageenan. Compared to cyclophosphamide immunocompromised mice treated with the spores of elastase nonproducing strain, cyclophosphamide immunocompromised mice treated with the spores of elastase producing strain had a significantly shorter survival rate. Molecular mass of AFLEI was determined to be 7525.8 Da. The elastolytic activity of elastases from A. flavus, and human leukocytes were inhibited by AFLEI. The primary structure of AFLEI was determined by the Edman sequencing procedure. The search for amino acid homology with other proteins demonstrated that amino acid residues 1 to 68 of AFLEI are 100% identical to residues 20 to 87 of the hypothetical protein AFUA_3G14940 of A. fumigatus. When immunocompromised mice administered of cyclophosphamide were infected by inhalation of A. flavus then administered amphotericin B (AMPH) alone or in combination with AFLEI, survival rate tended to be higher with combination treatment than with AMPH alone. Moreover, although extensive bleeding was seen in pathology sections taken from rat lung resected 24 h after elastase was administered to the lung via the bronchus, this bleeding was inhibited by AFLEI. The X-ray analysis has revealed that the structure of this inhibitor was wedge shaped and composed of a binding loop and a scaffold protein core. As synthetic-inhibitor strongly inhibited cytotoxicity induced by elastase in human-derived cells, it could prove beneficial for the treatment of pulmonary aspergillosis.

Topics: Amphotericin B; Animals; Aspergillus flavus; Disease Models, Animal; Enzyme Inhibitors; Hemorrhage; Humans; Immunocompromised Host; Lung Diseases; Mice; Pancreatic Elastase; Pulmonary Aspergillosis; Rats

Aspergilloma, also known as mycetoma or fungus ball, is the most common manifestation of pulmonary involvement by Aspergillus species. The fungal ball typically forms within preexisting cavities of the lungs. Diagnosis requires both radiographic evidence along with serologic or microbiologic evidence of Aspergillus species involvement. While clinical features such as hemoptysis, chest pain, shortness of breath, cough, and fever are helpful in diagnosis, they are non-specific symptoms. Surgery is currently the mainstay of treatment for aspergilloma but is associated with considerable mortality and morbidity. Alternative options exist for patients who are poor surgical candidates and for those who prefer a less invasive treatment modality. Systemic treatment with amphotericin B is ineffective and is not recommended as a monotherapy, but systemic azoles is effective in approximately 50-80% of patients. Potential alternatives to surgery include intracavitary instillation or endobronchial administration of antifungal medication, as well as direct transbronchial aspergilloma removal. Bronchial artery embolization and radiotherapy are options to manage hemoptysis until definite eradication of the aspergilloma. More rigorous studies are needed to better establish non-surgical treatment paradigm for inoperable patients.

Topics: Amphotericin B; Antifungal Agents; Azoles; Bronchial Arteries; Conservative Treatment; Embolization, Therapeutic; Female; Hemoptysis; Humans; Instillation, Drug; Male; Pulmonary Aspergillosis

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

Aspergillus fumigatus is the most frequent filamentous fungus isolated from respiratory specimens from patients with cystic fibrosis (CF). Triazoles are the most widely used antifungals in the treatment of allergic bronchopulmonary aspergillosis (ABPA) and invasive aspergillosis (IA) in CF patients. Treatment success could be severely compromised by the occurrence of azole-resistant A. fumigatus (ARAf), which is increasingly reported worldwide from both clinical samples and the environment. In previous studies, ARAf has been detected in up to 8% of CF patients. Isolates from CF patients requiring antifungal treatment should therefore be routinely subjected to antifungal susceptibility testing. The optimal treatment of ABPA or IA in CF patients with azole-resistant isolates has not been established; treatment options include liposomal amphotericin B i.v. and/or echinocandins i.v.

Topics: Amphotericin B; Antifungal Agents; Aspergillus fumigatus; Azoles; Cystic Fibrosis; Drug Resistance, Fungal; Echinocandins; Humans; Microbial Sensitivity Tests; Pulmonary Aspergillosis

Triazole antifungal drugs may rarely cause serious allergic reactions including angioedema. No standardized tests are available to predict cross-reactivity within the azole class and little guiding information exists on whether to change therapy within the class or to another class after a serious allergic reaction. Herein we report the first successful use, to our knowledge, of graded isavuconazole introduction for treatment of aspergillosis in a liver transplant recipient with severe voriconazole allergy.

Topics: Amphotericin B; Angioedema; Antifungal Agents; Aspergillus; Desensitization, Immunologic; Drug Administration Schedule; Drug Hypersensitivity; Female; Humans; Liver Cirrhosis; Liver Transplantation; Lung; Middle Aged; Nitriles; Pulmonary Aspergillosis; Pyridines; Tomography, X-Ray Computed; Treatment Outcome; Triazoles; Voriconazole

Over the past 10 years the incidence of Aspergillus spp. has significantly increased, and it is now the most widespread air transmission fungal pathogen in developed countries. Whatever the clinical expression of the pulmonary disease and despite recent progress in antifungal drug therapy, morbidity and mortality related to aspergillosis lung disease still constitute a serious threat for immunosuppressed or mildly immunocompromised patients. Moreover, the treatments currently used have many limitations due to adverse effects and drug interactions. Finally, subjects exposed to azoles present an increased risk of Aspergillus-resistant strain emergence. We have reported five cases with aspergillosis lung diseases that were either difficult to control or in which patients had a contra-indication to triazole therapy, but which showed durable improvement following the administration of nebulised liposomal amphotericin B. Our alternative strategy could be of interest for patients with aspergillosis lung disease who otherwise cannot be conventionally treated by triazoles.

Topics: Aged; Amphotericin B; Antifungal Agents; Aspergillus; Contraindications; Female; Humans; Immunocompromised Host; Immunosuppressive Agents; Male; Middle Aged; Nebulizers and Vaporizers; Pulmonary Aspergillosis; Triazoles

Aspergillosis remains a significant cause of morbidity and mortality. The spectrum of disease is diverse and ranges from noninvasive disease with an excessive immune response, such as in allergic bronchopulmonary aspergillosis (ABPA), to a lack of an immune response as seen in patients with quantitative or qualitative granulocyte deficits and subsequent invasive pulmonary aspergillosis. Noninvasive diagnostic testing has improved the time to initiation of effective antifungal therapy, and numerous agents in different therapeutic classes are now available as treatment options. Voriconazole remains the preferred agent in the treatment of invasive pulmonary aspergillosis, and recent data have increased interest in the potential of combination therapy against this often lethal infection. The role of host genetics in selecting patients that may benefit from more aggressive antifungal prophylaxis or treatment practices remains unclear but is likely to guide therapeutic choices as newer data become available.

Topics: Amphotericin B; Antifungal Agents; Aspergillus; Disease Susceptibility; Drug Resistance, Fungal; Echinocandins; Humans; Immunocompromised Host; Invasive Pulmonary Aspergillosis; Opportunistic Infections; Pulmonary Aspergillosis; Triazoles

We present a case of a patient with hairy cell leukemia and pulmonary aspergillosis who developed a cycotic pulmonary artery aneurysm despite prolonged antifungal therapy. A review of the literature in regards to incidence, etiology, clinical manifestations and treatment options is included.

Topics: Abscess; Acyclovir; Amphotericin B; Aneurysm, Infected; Anti-Bacterial Agents; Antifungal Agents; Antineoplastic Agents; Antiviral Agents; Aspergillus; Caspofungin; Ceftazidime; Clindamycin; Echinocandins; Fluconazole; Humans; Leukemia, Hairy Cell; Lipopeptides; Male; Middle Aged; Mouth; Ofloxacin; Pneumonia; Pulmonary Artery; Pulmonary Aspergillosis; Valacyclovir; Valine; Vancomycin

When functioning properly, the immune system recognizes inhaled fungi and controls their growth, while avoiding injurious inflammation and allergy. 'Aspergillosis' represents a spectrum of clinical diseases resulting from impaired or excessive immune responses. Invasive aspergillosis is principally disease of severely immunocompromised patients, whereas allergic forms of aspergillosis result from an excessive inflammatory response to hyphae colonizing the sinopulmonary tract. We will review insights gained in host defense against Aspergillus species and the immunopathogenesis of Aspergillus-related diseases as well as important advances made in fungal diagnostics and antifungal therapy.. Important advances have been made in diagnosis of invasive aspergillosis and in antifungal agents. Voriconazole was superior to amphotericin B deoxycholate as primary therapy for invasive aspergillosis. There is significant interest in combination antifungal therapy for invasive aspergillosis. Fungal genomics offers a powerful opportunity to gain knowledge about fungal virulence factors that can be targets for drug development. In addition, new insights have been gained regarding host defense against Aspergillus species that may be exploited therapeutically.. We have gained substantial knowledge regarding how the immune system recognizes inhaled fungi and calibrates the inflammatory response. There has also been substantial progress in tools to diagnose aspergillosis and in antifungal therapeutics. Future progress will likely involve the development of more refined diagnostic tools, new classes of antifungal agents, and greater knowledge of pathogen and host factors that predispose to aspergillosis.

Topics: Amphotericin B; Antifungal Agents; Antigens, Fungal; Aspergillus; DNA, Fungal; Female; Fungemia; Humans; Immunocompromised Host; Incidence; Male; Prognosis; Pulmonary Aspergillosis; Pyrimidines; Risk Assessment; Severity of Illness Index; Survival Rate; Triazoles; Voriconazole

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

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

Pulmonary aspergilloma (PA) is a common complication seen in patients with pulmonary tuberculosis sequelae. Antifungal therapy, including oral azoles, is commonly used though only surgical resection offers curative benefit. Local administration of amphotericin B, like intracavitary instillation, has been effective in aspergilloma patients though nebulised amphotericin B (nAB) has never been formally assessed.. The aim of this prospective, non-inferior, open-label, randomised control trial is to evaluate the efficacy and safety of nebulised amphotericin B compared to oral itraconazole therapy in the treatment of PA.. Diagnosed cases of PA (n=33) were randomised into the control group receiving oral itraconazole (n=18) and intervention group receiving nebulised amphotericin B (n = 15). Response to treatment was assessed both clinically and radiologically at the end 6 months.. The number of patients showing overall improvement at the end of 6 months in the control arm(oral itraconazole) vs intervention arm(nebulised amphotericin B) was 65% (95% CI 38.3-85.8) and 67%(95% CI 38.4%-88.2%), respectively, in the intention-to-treat and 79% (95% CI 49.2%-95.3%), and 65% (95% CI 38.4%-88.2%), respectively, in the per-protocol analysis. While there was no statistically significant difference between the intervention and control arm in both the analyses, non-inferiority was shown in the per-protocol but not in the intention-to-treat analysis. No major adverse events were noted in either group; however, a significant proportion of patients receiving nAB reported minor cough (40%), which, however, did not lead to discontinuation of therapy in any patients. Nebulised amphotericin B can be an effective therapeutic option for pulmonary aspergilloma patients.

Topics: Amphotericin B; Antifungal Agents; Humans; Itraconazole; Prospective Studies; Pulmonary Aspergillosis

Nebulized amphotericin B deoxycholate (n-ABD) is used to prevent Aspergillus infection in lung transplantation. Nebulized liposomal amphotericin B (n-LAB) is another option; however, no clinical data are available on the results of n-LAB for this purpose.. In an observational study performed in 2 centers to assess the feasibility, tolerability, and outcomes of n-LAB prophylaxis, 104 consecutive patients undergoing prophylaxis with n-LAB were compared with 49 historical controls who received n-ABD. Patient follow-up lasted 12 months. The n-LAB prophylaxis regimen was 25 mg thrice weekly starting on the first post-operative day and continuing to 60 days, 25 mg once weekly from 60 to 180 days, and the same dose once every 2 weeks thereafter.. Aspergillus infection developed in 8 of 104 patients (7.7%) with n-LAB prophylaxis (5 colonization, 1 simple tracheobronchitis, 1 ulcerative tracheobronchitis, and 1 invasive pulmonary infection). Ulcerative tracheobronchitis and invasive pulmonary aspergillosis were regarded as invasive disease; hence, the rate of invasive disease was 1.9% (2 patients). The control group had similar rates of Aspergillus infection (10.2%; p = 0.6) and invasive disease (4.1%; p = 0.43). In 3 patients (2.9%), n-LAB was withdrawn due to bronchospasm in 2 and nausea in 1. In the control group, prophylaxis was stopped in 2 patients (4.1%) because of bronchospasm (p = 0.7).. At the dose and frequency described, n-LAB seems effective, safe, and convenient for the prevention of Aspergillus infection in lung transplant patients.

Topics: Administration, Inhalation; Adult; Amphotericin B; Antifungal Agents; Cohort Studies; Deoxycholic Acid; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; Feasibility Studies; Female; Humans; Immunosuppressive Agents; Liposomes; Lung Transplantation; Male; Middle Aged; Opportunistic Infections; Pulmonary Aspergillosis

Bacterial or virus co-infections with SARS-CoV-2 have been reported in many studies; however, the knowledge on Aspergillus co-infection among patients with COVID-19 was limited. This study was conducted to identify and isolate fungal agents and to evaluate the prevalence of pulmonary aspergillosis (CAPA) as well as antifungal susceptibility patterns of Aspergillus species in patients with COVID-19 admitted to Shahid Beheshti Hospital, Kashan, Iran.. The study involved 119 patients with severe COVID-19 pneumonia referred to the Shahid Beheshti Hospital, Kashan, Iran. A total of 17 Aspergillus spp. that were isolated from COVID-19 patients suspected of CAPA were enrolled in the study. CAPA was defined using ECMM/ISHAM consensus criteria. The PCR amplification of the β-tubulin gene was used to identify the species. The antifungal activities of fluconazole, itraconazole, voriconazole, amphotericin B against Aspergillus spp. were evaluated according to the Clinical and Laboratory Standards Institute manual (M38-A3).. From the 119 patients with severe COVID-19 pneumonia, CAPA was confirmed in 17 cases (14.3%). Of these, 12 (70.6%) were males and 5 (29.4%) were females; the mean age at presentation was 73.8 years (range: 45-88 years; median = 77; IQR = 18). Aspergillus fumigatus (9/17; 52.9%), Aspergillus flavus (5/17; 29.4%), Aspergillus oryzae (3/17, 17.6%), were identified as etiologic agents of CAPA, using the molecular techniques. Voriconazole and amphotericin B showed more activity against all isolates. Moreover, the MIC of fluconazole, itraconazole varied with the tested isolates. For 3 clinical isolates of A. fumigatus, 2 isolate of A. flavus and 3 A. oryzae, the MIC of fluconazole and itraconazole were ≥ 16 µg/mL.. We observed a high incidence (14.3%) of probable aspergillosis in 119 patients with COVID-19, which might indicate the risk for developing IPA in COVID-19 patients. When comparing patients with and without CAPA regarding baseline characteristics, CAPA patients were older (p =0 .024), had received more frequent systemic corticosteroids (p = 0.024), and had a higher mortality rate (p = 0.018). The outcome of CAPA is usually poor, thus emphasis shall be given to screening and/or prophylaxis in COVID-19 patients with any risk of developing CAPA.

Topics: Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus; COVID-19; Female; Fluconazole; Humans; Iran; Itraconazole; Male; Microbial Sensitivity Tests; Middle Aged; Pulmonary Aspergillosis; SARS-CoV-2; Voriconazole

Coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) is being increasingly recognized as a severe complication that contributes to poor prognoses among patients with COVID-19. However, little is known regarding the clinical course of CAPA with hematological malignancies, especially after allogeneic hematopoietic stem cell transplantation (HSCT). A 29-year-old woman was diagnosed with proven CAPA with an Aspergillus fumigatus identified by cultures of bronchoalveolar lavage and lung biopsy four years after haploidentical HSCT for acute myelogenous leukemia. She had been taking oral prednisolone for bronchiolitis obliterans syndrome that developed after HSCT. Although prolonged RT-PCR positivity for SARS-CoV-2 (133 days after the onset of COVID-19) without shedding of viable virus was observed, the COVID-19 was treated with favipiravir, remdesivir, dexamethasone, and enoxaparin. However, the CAPA did not respond to combination therapy, which included triazole (voriconazole, itraconazole, posaconazole) and echinocandin (caspofungin, micafungin), even though the Aspergillus fumigatus isolate was found to be susceptible to these agents in vitro. Nevertheless, a total of 16 weeks of liposomal amphotericin B (L-AMB) therapy led to a favorable response, and the patient was discharged from the hospital on day 213. This case provided essential experience of CAPA treated with L-AMB in a recipient with chronic respiratory disease after HSCT.

Topics: Adult; Antifungal Agents; Aspergillus fumigatus; Bronchiolitis Obliterans Syndrome; COVID-19; Female; Hematopoietic Stem Cell Transplantation; Humans; Pulmonary Aspergillosis; SARS-CoV-2

A 67-year-old obese man (BMI 38.0) with type 2 diabetes mellitus (DM), chronic atrial fibrillation, and chronic lymphocytic leukemia stage II, stable for 8 years after chemotherapy, and a history of smoking presented to the ED with progressive dyspnea and fever due to SARS-CoV-2 infection. He was admitted to a general ward and treated with dexamethasone (6 mg IV once daily) and oxygen. On day 3 of hospital admission, he became progressively hypoxemic and was admitted to the ICU for invasive mechanical ventilation. Dexamethasone treatment was continued, and a single dose of tocilizumab (800 mg) was administered. On day 9 of ICU admission, voriconazole treatment was initiated after tracheal white plaques at bronchoscopy, suggestive of invasive Aspergillus tracheobronchitis, were noticed. However, his medical situation dramatically deteriorated.

Topics: Acute Kidney Injury; Aged; Amphotericin B; Antibodies, Monoclonal, Humanized; Antifungal Agents; Atrial Fibrillation; Bronchoscopy; COVID-19; Dexamethasone; Diabetes Mellitus, Type 2; Fatal Outcome; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Mucormycosis; Nitriles; Obesity; Oxygen Inhalation Therapy; Pulmonary Aspergillosis; Pyridines; Respiration, Artificial; SARS-CoV-2; Smoking; Tomography, X-Ray Computed; Triazoles; Voriconazole

Advances in medicine have led to a growing number of people with compromised or suppressed immune systems who are susceptible to invasive fungal infections. In particular, severe fungal infections are becoming increasingly common in ICUs, affecting people within and outside of traditional risk groups alike. This is exemplified by the emergence of severe viral pneumonia as a significant risk factor for invasive pulmonary aspergillosis, and the recognition of influenza-associated pulmonary aspergillosis and, more recently, COVID-19-associated pulmonary aspergillosis. The treatment landscape for haematological malignancies has changed considerably in recent years, and some recently introduced targeted agents, such as ibrutinib, are increasing the risk of invasive fungal infections. Consideration must also be given to the risk of drug-drug interactions between mould-active azoles and small-molecule kinase inhibitors. At the same time, infections caused by rare moulds and yeasts are increasing, and diagnosis continues to be challenging. There is growing concern about azole resistance among both moulds and yeasts, mandating continuous surveillance and personalized treatment strategies. It is anticipated that the epidemiology of fungal infections will continue to change and that new populations will be at risk. Early diagnosis and appropriate treatment remain the most important predictors of survival, and broad-spectrum antifungal agents will become increasingly important. Liposomal amphotericin B will remain an essential therapeutic agent in the armamentarium needed to manage future challenges, given its broad antifungal spectrum, low level of acquired resistance and limited potential for drug-drug interactions.

Topics: Antifungal Agents; Azoles; COVID-19 Drug Treatment; Fungi; Humans; Invasive Fungal Infections; Mycoses; Pulmonary Aspergillosis

We experienced a case of the successful treatment of intractable pulmonary aspergillosis with inhaled liposomal amphotericin B (L-AMB) and oral voriconazole (VRCZ). A 52-year-old man was admitted to our hospital with a fever. Chest computed tomography (CT) revealed an infiltrative shadow. Two separate sputum cultures detected Aspergillus niger. Although we treated the patient with single and combined antifungal agents, the infiltrative shadow worsened. After obtaining sufficient informed consent from the patient, we switched him to an inhaled L-AMB. The infiltrative shadow subsequently improved. The patient has remained well for one year without exacerbation. We herein report the usefulness of inhaled L-AMB and oral VRCZ.

Topics: Amphotericin B; Antifungal Agents; Humans; Male; Middle Aged; Pulmonary Aspergillosis; Voriconazole

Topics: Amphotericin B; Antifungal Agents; Humans; Infant, Newborn; Male; Pulmonary Aspergillosis; Voriconazole

Topics: Amphotericin B; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Artifacts; Biomarkers; Blood Chemical Analysis; Child; False Positive Reactions; Female; Humans; Hyperphosphatemia; Leukemia, Myeloid, Acute; Phosphates; Predictive Value of Tests; Pulmonary Aspergillosis

Topics: Amphotericin B; Antifungal Agents; Antirheumatic Agents; Aspergillus fumigatus; Bronchoscopy; Humans; Interleukin 1 Receptor Antagonist Protein; Lung; Male; Middle Aged; Pulmonary Aspergillosis; Still's Disease, Adult-Onset; Tomography, X-Ray Computed; Treatment Outcome

An experimental micellar formulation of 1:1.5 amphotericin B-sodium deoxycholate (AMB:DCH 1:1.5) was obtained and characterized to determine its aggregation state and particle size. The biodistribution, nephrotoxicity, and efficacy against pulmonary aspergillosis in a murine model were studied and compared to the liposomal commercial formulation of amphotericin B after intravenous administration. The administration of 5 mg/kg AMB:DCH 1:1.5 presented 2.8-fold-higher lung concentrations (18.125 ± 3.985 μg/g after 6 daily doses) and lower kidney exposure (0.391 ± 0.167 μg/g) than liposomal commercial amphotericin B (6.567 ± 1.536 and 5.374 ± 1.157 μg/g in lungs and kidneys, respectively). The different biodistribution of AMB:DCH micelle systems compared to liposomal commercial amphotericin B was attributed to their different morphologies and particle sizes. The efficacy study has shown that both drugs administered at 5 mg/kg produced similar survival percentages and reductions of fungal burden. A slightly lower nephrotoxicity, associated with amphotericin B, was observed with AMB:DCH 1:1.5 than the one induced by the liposomal commercial formulation. However, AMB:DCH 1:1.5 reached higher AMB concentrations in lungs, which could represent a therapeutic advantage over liposomal commercial amphotericin B-based treatment of pulmonary aspergillosis. These results are encouraging to explore the usefulness of AMB:DCH 1:1.5 against this disease.

Topics: Amphotericin B; Animals; Antifungal Agents; Deoxycholic Acid; Drug Combinations; Kidney; Lung; Male; Mice; Pulmonary Aspergillosis

Surgical treatment with lung resection has traditionally been the treatment of choice for pulmonary cavities containing aspergillomas that cause hemoptysis. Endobronchial ultrasound (EBUS) is a minimally invasive bronchoscopic technique that is commonly used for transbronchial needle aspiration of hilar and mediastinal lymph nodes as well as centrally located parenchymal lesions. Here, we describe a case of a 71-year-old woman who was found to have a cavitary lesion in the lung containing aspergillomas. Under direct ultrasound visualization with EBUS, liposomal amphotericin B was injected into the aspergillomas. These aspergillomas regressed after treatment. To our knowledge, this is the first reported treatment of aspergilloma with EBUS-guided transbronchial needle injection of liposomal amphotericin B.

Topics: Aged; Amphotericin B; Antifungal Agents; Endoscopic Ultrasound-Guided Fine Needle Aspiration; Female; Humans; Lung; Pneumonectomy; Pulmonary Aspergillosis; Tomography, X-Ray Computed; Treatment Outcome; Ultrasonography

Chaetomium atrobrunneum has never been reported to be associated with pneumonia. We report the isolation of C. atrobrunneum and Aspergillus fumigatus from a Chinese elderly patient with fatal pneumonia. Branched, long, and septate hyphae were observed in potassium hydroxide preparations and Gram-stained smears, and confluent C. atrobrunneum growth and a few A. fumigatus colonies were found in tracheal aspirates (nine separate occasions). These isolates were identified by conventional morphological methods and by sequencing the internal transcribed spacer and the D1/D2 domain of the 26S rRNA gene. The patient responded poorly to the combination therapy of amphotericin B and caspofungin. This report adds C. atrobrunneum to the list of fungal pneumonia in immunocompromised hosts. This case report also illustrated the presence of a growth symbiosis between Chaetomium species and A. fumigatus.

Topics: Aged, 80 and over; Amphotericin B; Antifungal Agents; Aspergillus fumigatus; Bodily Secretions; Caspofungin; Chaetomium; China; DNA, Fungal; DNA, Ribosomal; DNA, Ribosomal Spacer; Echinocandins; Humans; Lipopeptides; Male; Microbiological Techniques; Pulmonary Aspergillosis; RNA, Ribosomal; Sequence Analysis, DNA; Symbiosis; Trachea; Treatment Outcome

To assess the clinical response and renal toxicity observed in chronic pulmonary aspergillosis (CPA) patients receiving ≥1 short-courses of liposomal amphotericin (LAmB) (AmBisome. A retrospective audit of clinical response and renal function was undertaken in 71 CPA patients (41 male) treated with LAmB at the National Aspergillosis Centre, including 20 patients receiving repeated treatment courses or long-term therapy (n = 5).. Median age was 64 years (range 29-86 years). Treatment indications included respiratory symptoms (n = 33; 46.5%), constitutional symptoms (n = 2; 2.8%) or both (n = 36; 50.7%). 48 patients (73.8%) responded to their first LAmB course. Quality of life (QOL) improvements occurred in 37 (92.5%) of 40 patients with sufficient data available. Response rates for repeated short-courses of LAmB were 76.6%; QOL improvements were observed in 91.7% of treatment courses. All patients on long-term therapy demonstrated a response. 34 (50%) and 17 (25%) patients respectively developed an increased risk of acute kidney injury (AKI) or actual AKI with their first treatment; a significant reduction in geometric mean eGFR was observed and a similar pattern occurred following their second treatment course.. Whilst CPA is responsive to LAmB, caution should be exercised with repeated courses, if other treatments are available.

Topics: Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Chronic Disease; Female; Humans; Male; Middle Aged; Pulmonary Aspergillosis; Quality of Life; Regression Analysis; Retrospective Studies; Treatment Outcome; United Kingdom

Topics: Aged; Amphotericin B; Antifungal Agents; Bronchoscopy; Caspofungin; Drug Therapy, Combination; Echinocandins; Fatal Outcome; Humans; Lipopeptides; Male; Pulmonary Aspergillosis; Tomography Scanners, X-Ray Computed; Voriconazole

In this study, we report the first isolation of Aspergillus allahabadii from a Japanese cormorant with pulmonary aspergillosis. We performed molecular identification and antifungal susceptibility testing with the E-test. A 7-month-old male cormorant died because of uric acid deposition secondary to dehydration. Whitish nodular lesions were present on the caudal thoracic air sac in the right thoracic cavity. Histopathology revealed multifocal pyogranulomatous necrotic lesions with numerous fungal hyphae in the thoracic air sac. Identification of the etiologic agent was confirmed by comparative analyses of the sequences of the internal transcribed spacer (ITS) region and β-tubulin-encoding genes. According to the E-test, the minimum inhibitory concentrations of the isolate to amphotericin B, fluconazole, itraconazole, and voriconazole were 0.75 μg/ml, >256 μg/ml, 0.38 μg/ml, and 0.38 μg/ml, respectively.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillus; Bird Diseases; Birds; Child; Drug Resistance, Fungal; Fluconazole; Humans; Itraconazole; Male; Microbial Sensitivity Tests; Pulmonary Aspergillosis; Voriconazole

Aspergillus species are the major life threatening fungal pathogens in transplant patients. Germination of inhaled fungal spores initiates infection, causes severe pneumonia, and has a mortality of >50%. This is leading to the consideration of pre-exposure prophylaxis to prevent infection. We made a very low MWt amphotericin B-polymethacrylic acid nanoparticle. It was not toxic to lung epithelial cells or monocyte-derived-macrophages in-vitro, or in an in-vivo transplant immuno-suppression mouse model of life threatening invasive aspergillosis. Three days of nebuliser based prophylaxis delivered the nanoparticle effectively to lung and prevented both fungal growth and lung inflammation. Protection from disease was associated with >99% killing of the Aspergillus and a 90% reduction in lung TNF-α; the primary driver of tissue destructive immuno-pathology. This study provides in-vivo proof-of-principle that very small and cost-effective nanoparticles can be made simply, and delivered safely and effectively to lung by the aerosol route to prevent fungal infections.. Aspergillus is an opportunistic pathogen, which affects immunocompromised patients. One novel way to help fight against this infection is pre-exposure prophylaxis. The authors here made PMA based anionic hydrogels carrying amphotericin B, with mucoadhesive behavior. They showed that aerosol route of the drug was very effective in protecting against the disease in an in-vivo model and should provide a stepping-stone towards clinical trials in the future.

Topics: Administration, Inhalation; Amphotericin B; Animals; Antifungal Agents; Aspergillus fumigatus; Interferon-gamma; Lung; Mice, Inbred BALB C; Mice, Inbred C57BL; Nanoparticles; Nebulizers and Vaporizers; Polymethacrylic Acids; Pulmonary Aspergillosis; Tumor Necrosis Factor-alpha

Topics: Administration, Inhalation; Amphotericin B; Antifungal Agents; Aspergillus fumigatus; Bronchial Fistula; Empyema; Humans; Male; Middle Aged; Pleural Diseases; Pulmonary Aspergillosis

Immunocompromised individuals are susceptible to pulmonary Aspergillus infections, whereas invasive Aspergillus infection is extremely rare in the presence of normal immunity. A case of larynx-tracheobronchial-pulmonary aspergillosis in an immunocompetent 57-year-old female host who was successfully treated with amphotericin-B and voriconazole is reported here.

Topics: Amphotericin B; Bronchi; Bronchoscopy; Female; Fiber Optic Technology; Humans; Immunocompetence; Larynx; Middle Aged; Pulmonary Aspergillosis; Tomography, X-Ray Computed; Trachea; Voriconazole

Treatment for chronic pulmonary aspergillosis is difficult and frequently is required for prolong period. In outpatients setting, only voriconazole and itraconazole could be used. Since liposomal amphotericin B (L-AMB) demonstrated prolonged half-time, we have investigated the feasibility of L-AMB in outpatient setting. Three cases of chronic pulmonary aspergillosis were treated with intermittent administration of 2.5 mg/kg of L-AMB twice weekly for one month in outpatient settings. Improve of symptoms was attained in 2 of 3 cases. Improvement of chest images were in 2 of 3, improvement of laboratory test were in 2 of 3. Adverse events were only fatigue and short period of fever. No recurrence of pulmonary aspergillosis has been found after treatment. Intermittent administration of L-AMB in outpatient settings could be an option for pulmonary aspergillosis.

Topics: Aged; Amphotericin B; Antifungal Agents; Chronic Disease; Female; Humans; Male; Pilot Projects; Pulmonary Aspergillosis

To describe the clinical features of mixed types of pulmonary aspergillosis (MTPA), and therefore to improve the diagnosis and treatment of MTPA.. This study retrospectively analyzed 3 patients with MTPA in Peking University First Hospital from November 2010 to 2012. "Invasive pulmonary aspergillosis (IPA), pulmonary aspergilloma, allergic bronchopulmonary aspergillosis (ABPA)" were used as the Chinese and English keywords, to search the literatures from Wanfang database and Pubmed database until to May 2014.. There were 3 patients with MTPA, respectively with aspergilloma and IPA (patient 1), ABPA and IPA (patient 2), aspergilloma and IPA (patient 3). The cultures of respiratory secretions of the patients all yielded A.fumigatus. Patient 1 was treated by amphotericin B; Patient 2 was treated by intravenous itraconazole and glucocorticoid; Patient 3 was treated by oral voriconazole and inhaled corticosteroid, and the aspergilloma was surgically removed at the same time. Eventually, patients 1 and 2 died, while the symptoms of patient 3 were significantly improved. Drug sensitivity test of A. fumigatus showed resistance to amphotericin B or itraconazole. By far there was no concept of MTPA in the literatures and there were only 3 relevant case reports.. MTPA is a new subtype of pulmonary aspergillosis, which is more complicated and severe, and perhaps with drug resistance. MTPA should be treated by comprehensive therapies on the basis of sensitive and effective antifungal drugs.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis, Allergic Bronchopulmonary; Aspergillus fumigatus; Glucocorticoids; Humans; Invasive Pulmonary Aspergillosis; Pulmonary Aspergillosis; Retrospective Studies; Voriconazole

We report a case of pulmonary aspergillosis in lung transplant recipient who was successfully treated with inhalation administration of anti-fungal agent. The case was 33-year-old female. Two years ago, she had received lung transplant because of lymphangioleiomyomatosis. One year ago, she had diagnosed of pulmonary aspergillosis and successfully treated with micafungin and itraconazole. Then she had been continuous administered with itraconazole. In June 20xx, she had nausea and vomiting and was diagnosed of viral enteritis. Although abdominal symptoms were relieved, ground glass opacity was discovered in her right lung. Bronchoscopic examination revealed ulceration of bronchus with white necrotic substance. Laboratory culture test demonstrated Aspergillus spp. Finally she was diagnosed of recurrent pulmonary aspergillosis. First, she was treated with intravascular administration of micafungin. Then, inhalation administration of liposomal amphotericin B was changed. Ground glass opacity and bronchial region of pulmonary aspergillosis was improved. Thereafter, inhalation of amphotericin B was continued and no recurrence of pulmonary aspergillosis has been found. Inhalation of anti-fungal agent could be an option for pulmonary aspergillosis.

Topics: Administration, Inhalation; Adult; Amphotericin B; Antifungal Agents; Female; Humans; Lung Transplantation; Pulmonary Aspergillosis

An allogeneic hematopoietic cell transplantation (allo-HCT) patient presented with chronic pulmonary aspergillosis associated to pulmonary graft versus host disease (GVHD) and was treated for a long time with several antifungal agents that were administered as prophylaxis, combination therapies, and maintenance treatment. The patient suffered from a breakthrough invasive pulmonary aspergillosis due to Aspergillus fumigatus after long-term antifungal therapy.. Several isolates were analyzed. First isolates were susceptible in vitro to all azole agents. However, after prolonged treatment with itraconazole and voriconazole a multiple azole resistant A. fumigatus isolate was cultured from bronchoalveolar lavage (BAL) when the patient was suffering from an invasive infection, and cavitary lesions were observed.. Analysis of the resistant mechanisms operating in the last strain led us to report the first isolation in Spain of an azole resistant A. fumigatus strain harboring the L98H mutation in combination with the tandem repeat (TR) alteration in CYP51A gene (TR-L98H). Long-term azole therapy may increase the risk of resistance selecting strains exhibiting reduced susceptibility to these compounds. However, since the isolates were genetically different the suggestion that could be made is that the resistance was not induced during the prolonged azole therapy but the patient might simply have acquired this resistant isolate from the environment, selected by the therapy.. These findings suggest that in all long-term treatments with antifungal agents, especially with azoles, repeated sampling and regular susceptibility testing of strains isolated is necessary as resistant isolates could be selected.

Topics: Adult; Amphotericin B; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Aspergillus fumigatus; Caspofungin; Combined Modality Therapy; Cytochrome P-450 Enzyme System; Drug Resistance, Multiple, Fungal; Echinocandins; Fatal Outcome; Female; Fungal Proteins; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Immunosuppressive Agents; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Lipopeptides; Point Mutation; Postoperative Complications; Pulmonary Aspergillosis; Recurrence; Spain; Species Specificity; Transplantation Conditioning; Transplantation, Homologous; Triazoles

Pulmonary aspergillomas may cause life-threatening hemoptysis. The treatment of this condition is problematic because poor pulmonary function often precludes definitive surgical resection.. We retrospectively reviewed all patients hospitalized at our institution for hemoptysis associated with an aspergilloma over an 8-year period and who underwent percutaneous intracavitary instillation of amphotericin B (ICAB). ICAB consisted of catheter placement into the aspergilloma cavity with subsequent instillation of 50 mg amphotericin B in 20 mL 5% dextrose solution daily for 10 days.. ICAB was attempted for 23 distinct episodes of severe hemoptysis in 20 individual patients. Catheter placement was successful in 21 of the 23 episodes (91%), and of these, ICAB instillation was successfully completed in 20 episodes (95%). In these 20 episodes, hemoptysis ceased by hospital discharge in 17 of 20 patients (85%) and in all 18 who survived until a follow-up visit 1-month after treatment. Pneumothorax occurred in six of 23 (26%) catheter placement attempts without long-term complications. Recurrence of serious hemoptysis occurred after six of 18 episodes for which follow-up was available. Potential risk factors associated with severe, recurrent hemoptysis were a size increase or reappearance of the aspergilloma on a chest CT scan (P = .001), bleeding diathesis (P = .08), and lack of bronchial artery embolization during index hospitalization (P = .07).. Our data suggest that ICAB is an effective short-term treatment to control severe hemoptysis caused by pulmonary aspergilloma. The long-term benefit of this procedure is unknown. We identified several potential risk factors for recurrent hemoptysis after ICAB that could be examined prospectively in future trials.

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; Aspergillus; Catheters; Female; Hemoptysis; Humans; Instillation, Drug; Longitudinal Studies; Lung; Male; Middle Aged; Pulmonary Aspergillosis; Retrospective Studies; Risk Factors; Secondary Prevention; Severity of Illness Index; Treatment Outcome

Aspergillus terreus is considered to be resistant to amphotericin B (AMB). However, it is unknown whether higher daily doses of liposomal AMB (L-AMB) can overcome this resistance in vivo. We evaluated the efficacy and total lung homogenate AMB concentrations of escalating intravenous doses of L-AMB (3-20 mg/kg daily) versus an induction-de-escalation dosing strategy (10 mg/kg/day ×3 days, then 3 mg/kg/day) in an experimental neutropenic murine model of A. terreus pneumonia.. BALB/c mice were rendered neutropenic with cyclophosphamide and administered cortisone acetate prior to intranasal inoculation (3.5 × 10(6) conidia) with A. terreus (Etest MIC 8 mg/L). Mice were then treated with L-AMB regimens for 5-7 days. The efficacy was assessed by animal survival and quantitative PCR lung fungal burden. Total AMB lung homogenate concentrations were determined by HPLC.. Compared with untreated controls, 10 mg/kg/day L-AMB prolonged survival (mean >7 versus 3-4 days, P < 0.003) and reduced A. terreus lung fungal burden (median log10 conidial DNA 5.0 versus 6.7, P < 0.05). Daily L-AMB regimens >10 mg/kg/day were associated with poorer survival and higher lung fungal burden. The induction-de-escalation strategy of 10 mg/kg/day ×3 days followed by 3 mg/kg/day was as effective as 10 mg/kg daily dosing, and resulted in higher mean AMB lung homogenate concentrations compared with a continuous 10 mg/kg regimen (23.2 ± 6.7 versus 16.4 ± 4.4 μg/g, P = 0.09).. A high-dose induction-de-escalation L-AMB dosing strategy was an effective treatment for experimental A. terreus pneumonia in neutropenic mice.

Topics: Administration, Intravenous; Amphotericin B; Animals; Antifungal Agents; Aspergillus; Disease Models, Animal; Female; Mice; Mice, Inbred BALB C; Neutropenia; Pulmonary Aspergillosis; Survival Analysis; Treatment Outcome

The activity of antimicrobial peptides (AMPs) that contain a large proportion of histidine residues (pK(a) ∼ 6) depends on the physiological pH environment. Advantages of these AMPs include high activity in slightly acidic areas of the human body and relatively low toxicity in other areas. Also, many AMPs are highly active in a multivalent form, but this often increases toxicity. Here we designed pH dependent amphiphilic compounds consisting of multiple ultrashort histidine lipopeptides on a triazacyclophane scaffold, which showed high activity toward Aspergillus fumigatus and Cryptococcus neoformans at acidic pH, yet remained nontoxic. In vivo, treatment with a myristic acid conjugated trivalent histidine-histidine dipeptide resulted in 55% survival of mice (n = 9) in an otherwise lethal murine lung Aspergillus infection model. Fungal burden was assessed and showed completely sterile lungs in 80% of the mice (n = 5). At pH 5.5 and 7.5, differing peptide-membrane interactions and peptide nanostructures were observed. This study underscores the potential of unique AMPs to become the next generation of clinical antimicrobial therapy.

Topics: Animals; Anti-Bacterial Agents; Antifungal Agents; Antimicrobial Cationic Peptides; Aspergillus fumigatus; Candida albicans; Cell Line; Cryptococcus neoformans; Female; Gram-Negative Bacteria; Gram-Positive Bacteria; Hemolysis; Humans; Hydrogen-Ion Concentration; Lipopeptides; Lung; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Nanostructures; Polymers; Pulmonary Aspergillosis; Structure-Activity Relationship

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

Aspergillus fumigatus is the most common airborne fungal pathogen for humans. In this mold, iron starvation induces production of the siderophore triacetylfusarinine C (TAFC). Here we demonstrate a link between TAFC and ergosterol biosynthetic pathways, which are both critical for virulence and treatment of fungal infections. Consistent with mevalonate being a limiting prerequisite for TAFC biosynthesis, we observed increased expression of 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase (Hmg1) under iron starvation, reduced TAFC biosynthesis following lovastatin-mediated Hmg1 inhibition, and increased TAFC biosynthesis following Hmg1 overexpression. We identified enzymes, the acyl-CoA ligase SidI and the enoyl-CoA hydratase SidH, linking biosynthesis of mevalonate and TAFC, deficiency of which under iron starvation impaired TAFC biosynthesis, growth, oxidative stress resistance, and murine virulence. Moreover, inactivation of these enzymes alleviated TAFC-derived biosynthetic demand for mevalonate, as evidenced by increased resistance to lovastatin. Concordant with bilateral demand for mevalonate, iron starvation decreased the ergosterol content and composition, a phenotype that is mitigated in TAFC-lacking mutants.

Topics: Amphotericin B; Animals; Aspergillus fumigatus; Biomass; Biosynthetic Pathways; Enoyl-CoA Hydratase; Ergosterol; Ferric Compounds; Gene Deletion; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Fungal; Gene Silencing; Genes, Fungal; Hydroxamic Acids; Hydroxymethylglutaryl CoA Reductases; Iron Deficiencies; Ligases; Lovastatin; Mevalonic Acid; Mice; Microbial Sensitivity Tests; Oxidative Stress; Pulmonary Aspergillosis; Pyrimidines; Siderophores; Triazoles; Up-Regulation; Virulence; Voriconazole

Amphotericin B (AMB) is used to treat both fungal and leishmanial infections, which are of major significance to human health. Clinical use of free AMB is limited by its nephrotoxicity, whereas liposomal AMB is costly and requires parenteral administration, thus development of novel formulations with enhanced efficacy, minimal toxicity and that can be applied via non-invasive routes is required. In this study we analysed the potential of non-ionic surfactant vesicles (NIV) given by nebulisation to deliver AMB to the lungs, liver and skin. Treatment with AMB-NIV resulted in significantly higher drug levels in the lungs and skin (p<0.05) compared to similar treatment with AMB solution but significantly lower plasma levels (p<0.05). Treatment with AMB-NIV resulted in a significant reduction in fungal lung burdens in a rat model of invasive pulmonary aspergillosis (p<0.05) compared to treatment with the carrier alone. Treatment with AMB-NIV but not AMB solution significantly suppressed Leishmania donovani liver parasite burdens (p<0.05) but could not inhibit the growth of cutaneous Leishmania major lesions. The results of this study indicate that aerosolised NIV enhanced pulmonary and hepatic delivery whilst minimising systemic exposure and toxicity.

Topics: Aerosols; Amphotericin B; Animals; Antifungal Agents; Cricetinae; Disease Models, Animal; Drug Carriers; Female; Firefly Luciferin; Leishmaniasis; Liver; Lung; Mesocricetus; Mice; Mice, Inbred BALB C; Pulmonary Aspergillosis; Rats; Rats, Sprague-Dawley; Surface-Active Agents

A 10-year-old boy with high-risk acute lymphoblastic leukemia treated with hematopoietic stem-cell transplantation developed pulmonary aspergillosis while receiving prophylactic voriconazole. A transpleural aspirate culture revealed a pan-azole-resistant Aspergillus fumigatus. Treatment with liposomal amphotericin B resulted in complete recovery. As the frequency of azole resistance in A. fumigatus increases, invasive procedures to isolate fungi for species identification and susceptibility testing becomes even more important.

Topics: Amphotericin B; Antifungal Agents; Aspergillus fumigatus; Azoles; Chemoprevention; Child; Drug Resistance, Multiple, Fungal; Hematopoietic Stem Cell Transplantation; Humans; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pulmonary Aspergillosis; Pyrimidines; Treatment Outcome; Triazoles; Voriconazole

Topics: Amphotericin B; Antifungal Agents; Antineoplastic Agents; Drug Administration Schedule; Echinocandins; Fatal Outcome; Female; Humans; Lipopeptides; Liposomes; Lymphoma, T-Cell; Maxillary Sinus Neoplasms; Micafungin; Middle Aged; Nasal Cavity; Nose Neoplasms; Pulmonary Aspergillosis

A 64-year-old diabetic man was admitted because his general condition had not improved despite the admini stration of voriconazole in another hospital, and his condition had become critical. Chest CT demonstrated a large fungus ball and consolidation around a cavity in the right lung. Aspergillusfumigatus was detected on a sputum culture. Based on these findings, we diagnosed invasive aspergillosis and administered high-dose (5mg/kg) liposomal amphotericin B (L-AMB) for 8 weeks, which resulted in the improvement of his general condition and the disappearance of the fungus ball, without severe adverse events.

Topics: Amphotericin B; Antifungal Agents; Humans; Liposomes; Long-Term Care; Male; Middle Aged; Pulmonary Aspergillosis; Treatment Outcome

Aspergillus fumigatus is an opportunistic fungal pathogen responsible for invasive aspergillosis in immunocompromised individuals. The high morbidity and mortality rates as well as the poor efficacy of antifungal agents remain major clinical concerns. Allicin (diallyl-dithiosulfinate), which is produced by the garlic enzyme alliinase from the harmless substrate alliin, has been shown to have wide-range antifungal specificity. A monoclonal antibody (MAb) against A. fumigatus was produced and chemically ligated to the enzyme alliinase. The purified antibody-alliinase conjugate bound to conidia and hyphae of A. fumigatus at nanomolar concentrations. In the presence of alliin, the conjugate produced cytotoxic allicin molecules, which killed the fungus. In vivo testing of the therapeutical potential of the conjugate was carried out in immunosuppressed mice infected intranasally with conidia of A. fumigatus. Intratracheal (i.t.) instillation of the conjugate and alliin (four treatments) resulted in 80 to 85% animal survival (36 days), with almost complete fungal clearance. Repetitive intratracheal administration of the conjugate and alliin was also effective when treatments were initiated at a more advanced stage of infection (50 h). The fungi were killed specifically without causing damage to the lung tissue or overt discomfort to the animals. Intratracheal instillation of the conjugate without alliin or of the unconjugated monoclonal antibody significantly delayed the death of the infected mice, but only 20% of the animals survived. A limitation of this study is that the demonstration was achieved in a constrained setting. Other routes of drug delivery will be investigated for the treatment of pulmonary and extrapulmonary aspergillosis.

Topics: Animals; Antibodies, Monoclonal; Antifungal Agents; Aspergillus fumigatus; Carbon-Sulfur Lyases; Enzyme-Linked Immunosorbent Assay; Female; Immunocompromised Host; Kaplan-Meier Estimate; Mice; Mice, Inbred ICR; Pulmonary Aspergillosis

Generally, the primary lesion of a mold infection is in the airway, an extravascular site. Therefore, the antifungal drug concentration at the actual tissue lesion of a mold infection is as important as in the blood compartment. Although our antifungal armamentarium has expanded recently, polyenes are still often needed in clinical practice because of their potent fungicidal activity and the rarity of resistance. Nevertheless, the distribution of amphotericin B (AmB) in infected lung tissue has not yet been evaluated. Using high-performance liquid chromatography analysis, we determined the concentrations of AmB in plasma and infected and uninfected tissues of resected lung simultaneously, in a patient with pulmonary aspergillosis treated with liposomal amphotericin B (L-AmB). The AmB concentration in the infected lesion of the lung was approximately 5.2 times higher than that in plasma and 3.7 times higher than in uninfected lung tissue. L-AmB accumulated in the infected lesion of the lung at a higher concentration. Although our data are from only one patient, they may be useful in helping to develop better strategies for the use of L-AmB against pulmonary fungal infections.

Topics: Amphotericin B; Antifungal Agents; Aspergillus niger; Humans; Liposomes; Lung; Male; Middle Aged; Pulmonary Aspergillosis; Tissue Distribution

Topics: Amphotericin B; Antifungal Agents; Cord Blood Stem Cell Transplantation; Echinocandins; Humans; Leukemia; Lung; Male; Middle Aged; Neutropenia; Postoperative Complications; Pulmonary Aspergillosis; Pyrimidines; Triazoles; Voriconazole

This study aimed to document outcome of invasive respiratory aspergillosis (IRA) in pediatric malignancy patients. Patients with febrile neutropenia episodes followed between January 2003 and May 2007 were enrolled. Antifungal therapy was added to those who were still febrile on the 5th day of febrile neutropenia treatment. Patients were screened with computerized tomographies. IRA was identified in 22 of 98 patients. There were 13 males and the mean age was 97 months. Proven infection was established in 3, probable in 7, and possible in 12 patients. Liposomal amphotericin B was administered to all patients and was successful in 10 patients. Modifications with caspofungin or voriconazole were done in liposomal amphotericin B failures. The median duration of antifungal therapy was 5.5 months. The median follow-up time was 29 months. There was no evidence of IRA in 12 patients after completion of cancer chemotherapy. Six patients died due to underlying disease, whereas IRA was either in remission or stable disease. Four patients were lost due to IRA. The remission rate for IRA was 82%. Survival at 37 months was 55% (95% confidence interval 25-47 months). The amount of time that absolute neutrophil count after initiation of treatment for IRA remained at zero was found to be an independent prognostic factor on survival (P = .01). These results suggest that early diagnosis and aggressive treatment may increase the successful outcome of IRA.

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Child; Early Diagnosis; Echinocandins; Female; Fever; Hematologic Neoplasms; Humans; Lipopeptides; Male; Neutropenia; Prognosis; Pulmonary Aspergillosis; Pyrimidines; Retrospective Studies; Treatment Outcome; Triazoles; Voriconazole

Monotherapy and combination therapy were compared using optimal doses of liposomal amphotericin B, micafungin, or caspofungin in Aspergillus fumigatus pulmonary and disseminated infections. Mice were challenged intravenously (2.8 x 10(4) to 5.7 x 10(4) conidia) or intranasally (5.8 x 10(7) conidia) with A. fumigatus. Drugs (5, 10, or 15 mg/kg of body weight) were given for 3 or 6 days as single, concomitant, or sequential therapy (i.e., days 1 to 3 and then days 4 to 6). Mice were monitored for survival, and tissues were assayed for fungal burden and drug concentrations. Treatments starting 24 h postchallenge significantly prolonged survival in disseminated aspergillosis (P < 0.002), but only liposomal amphotericin B treatments or treatments beginning with liposomal amphotericin B increased survival to 100% in the pulmonary aspergillosis model. Fungi in kidneys and spleens (disseminated) and lungs (pulmonary) were significantly decreased (P < or = 0.04) by liposomal amphotericin B, liposomal amphotericin B plus echinocandin, or liposomal amphotericin B prior to echinocandin. In the disseminated infection, liposomal amphotericin B and micafungin (10 or 15 mg/kg) had similar kidney drug levels, while in the spleen, 5 and 15 mg/kg liposomal amphotericin B gave higher drug levels than micafungin (P < 0.02). In the pulmonary infection, drug levels in lungs and spleen with 5-mg/kg dosing were significantly higher with liposomal amphotericin B than with caspofungin (P < or = 0.002). In summary, treatment of A. fumigatus infections with liposomal amphotericin B plus echinocandin or liposomal amphotericin B prior to echinocandin was as effective as liposomal amphotericin B alone, and a greater decrease in the fungal burden with liposomal amphotericin B supports using liposomal amphotericin B prior to echinocandin.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillus fumigatus; Echinocandins; Female; Mice; Microbial Sensitivity Tests; Pulmonary Aspergillosis

Zygomycosis and aspergillosis are two serious opportunistic fungal infections that are commonly seen in immunocompromised patients. Since both these fungi invade vessels of the arterial system, an early and rapid diagnosis by direct examination of KOH mounts of the relevant clinical sample can confirm the diagnosis. Here, we present an unusual case of a diabetic patient who presented with nasal blockade and bleeding for 2 months, along with occasional haemoptysis for 15 days. On investigation, the patient was diagnosed with a case of rhinocerebral zygomycosis and was treated with amphotericin B (1 mg kg(-1) day(-1)), which was subsequently replaced with liposomal amphotericin B (2 mg kg(-1) day(-1)). However, the patient did not completely respond to therapy as haemoptysis continued. Further investigations revealed the presence of Aspergillus flavus in respiratory specimens. Thus, a final diagnosis of rhinocerebral zygomycosis with pulmonary aspergillosis in a non-HIV-infected patient was made, but due to infection of two vital sites by these fungi, the patient could not be saved.

Topics: Amphotericin B; Antifungal Agents; Diabetes Mellitus, Type 2; Female; HIV Infections; Humans; India; Middle Aged; Paranasal Sinus Diseases; Pulmonary Aspergillosis; Zygomycosis

No clinical studies have compared the efficacy of liposomal formulation AMB (L-AMB) and voriconazole (VRC) in the treatment of pulmonary aspergillosis. The aim of this study was to compare the efficacy of L-AMB and VRC in murine pulmonary aspergillosis.. Leucopenic mice were infected intratracheally with Aspergillus fumigatus and treated intravenously with L-AMB (once a day) or VRC (twice a day).. L-AMB and VRC at a dose of >or=5 and >or=20 mg/kg, respectively, significantly prolonged the survival time of infected mice and reduced the pulmonary fungal burden in comparison with the control group. At the maximum recommended dose for clinical use, 5 mg/kg of L-AMB exhibited greater efficacy than 10 mg/kg of VRC, which achieved an area under the concentration-time curve level equivalent to that of 6 mg/kg (loading dose) in humans, in terms of increasing survival and reducing the fungal burden.. The in vivo efficacy of L-AMB was superior to that of VRC at the maximum recommended dose in a murine pulmonary aspergillosis model.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillus fumigatus; Disease Models, Animal; Lung; Male; Mice; Pulmonary Aspergillosis; Pyrimidines; Triazoles; Voriconazole

The present study was aimed at the preparation, characterization, and evaluation of the performance of amphotericin B (AmB)-loaded aerosolized liposomes and emulsomes (core composed of solid lipid surrounded by phospholipid bilayers) for their selective presentation to lungs (alveolar macrophages), as this is the densest site of aspergillosis infection. Liposomes and emulsomes were modified by coating them with alveolar macrophage-specific ligands (O-palmitoyl mannan, OPM) and also with monoclonal antibody EBA-2. The prepared formulations were characterized in vitro for vesicle size, zeta potential and percent drug entrapment. We evaluated the therapeutic efficacy of the novel site-specific targetable lipid-based delivery systems in experimental pulmonary aspergillosis. Immunosuppressed rats with pulmonary aspergillosis were given 1 mg/kg of aerosolized liposomal and emulsomes formulations of AmB once by using an ultrasonic jet nebulizer on the third day after infection. The concentrations of AmB in lung were higher in surface modified liposomes and emulsomes than those of plain counterparts. Changes in lung histopathology were also assessed. Further, scintigraphy was also carried out using 99mTc labeled liposomes. From those results it was concluded that radiolabeled liposomes could be used for in vivo imaging of the infection site, and that site directed system(s) based on OPM/mAb coating exhibited great potential in targeted antifungal chemotherapy.

Topics: Administration, Inhalation; Amphotericin B; Animals; Antifungal Agents; Drug Carriers; Fungi; Liposomes; Lung; Macrophages; Pulmonary Aspergillosis; Rats; Staining and Labeling

Topics: AIDS-Related Opportunistic Infections; Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Brain Abscess; Caspofungin; Deoxycholic Acid; Drug Combinations; Drug Therapy, Combination; Echinocandins; Fatal Outcome; Humans; Leukoencephalopathy, Progressive Multifocal; Lipopeptides; Male; Middle Aged; Pulmonary Aspergillosis; Pyrimidines; Triazoles; Voriconazole

Topics: Adult; Amphotericin B; Antifungal Agents; Fluconazole; Glucocorticoids; Hepatitis B, Chronic; Humans; Male; Pulmonary Aspergillosis; Tomography, X-Ray Computed

Simultaneous mold infections in heart transplant recipients have not been previously reported. Here we describe early onset post-transplant pulmonary aspergillosis and cutaneous zygomycosis in a 46-year-old heart transplant recipient who was also treated with basiliximab. Along with surgical debridement, medical treatment of his cutaneous abdominal wall zygomycosis at the former left ventricular assist device driveline site with liposomal amphotericin B and voriconazole also led to cure of his pulmonary aspergillosis.

Topics: Amphotericin B; Antibodies, Monoclonal; Antifungal Agents; Aspergillus fumigatus; Basiliximab; Cardiomyopathy, Dilated; Debridement; Dermatomycoses; Heart Transplantation; Humans; Immunocompromised Host; Immunosuppressive Agents; Injections, Intravenous; Male; Middle Aged; Mucormycosis; Prosthesis-Related Infections; Pulmonary Aspergillosis; Pyrimidines; Recombinant Fusion Proteins; Rhizopus; Triazoles; Voriconazole

Chronic pulmonary aspergillosis is different from acute pulmonary aspergillosis in clinical picture, radiogram, diagnostic procedures and prognosis. Four patients with chronic pulmonary aspergillosis had been misdiagnosed as having pneumonia or pulmonary tuberculosis for a long time before admission to the hospital. The purpose of this report was to summarize the clinical manifestations and laboratory findings for correct diagnosis of chronic pulmonary aspergillosis.. Four patients with chronic pulmonary aspergillosis seen between October 2002 and October 2004 were retrospectively studied. Their clinical manifestations, chest radiographic feature, immune status, diagnostic procedure, therapy and prognosis were reviewed.. The chief complaints of these patients were chronic cough and fever for 3 to 12 months. Chest wall abscess developed in the late course in case 1 and 4. Fine moist rales were heard and hepatosplenomegaly was found in case 1 and 2. No abnormal sign was found in case 3 and 4. Chest radiographic feature: lobar consolidation with adjacent pleural thickening was present in all cases. In early phase, solitary or multiple small nodules were found in 2 cases. Case 1-3 had normal IgG, IgM, IgA, IgE, T Cell subsets and NBT test. Case 4 had chronic granulomatous disease. Etiologic evidences: culture was positive for Aspergillus (A.) fulmigatus in sputum and in chest wall abscess in case 1 and 4; for A. niger in sputum and spore existing in lung tissue in case 2; for A. fulmigatus in sputum and hypha existing in lung tissue in case 3. All patients were treated with combination of amphotericin B and itraconazole. Their symptoms were controlled 10-30 d after treatment. In case 1 the disease relapsed 6 months later and the patient died at last due to giving up treatment by his parents. Case 2 was free of symptom for 12 months and his chest radiographic lesion disappeared completely 6 months later. Treatment of case 4 was given up. Case 3 continued to receive treatment and observation.. Chronic pulmonary aspergillosis should be considered in children with long period fever and cough and lobar consolidation associated with adjacent pleural thickening or with nodular infiltration. The diagnosis of chronic pulmonary aspergillosis depended on identification of aspergillus from sputum or lung tissue. Combined amphotericin B and itraconazole might control the disease.

Topics: Amphotericin B; Child; Child, Preschool; Chronic Disease; Drug Therapy, Combination; Female; Humans; Infant; Itraconazole; Male; Pulmonary Aspergillosis

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Bronchial Diseases; Bronchial Fistula; Drug Therapy; Fistula; Humans; Lung Diseases, Fungal; Pleura; Pneumonectomy; Pulmonary Aspergillosis; Radiography, Thoracic; Tuberculosis, Pulmonary

Topics: Amphotericin B; Aspergillosis; Drug Therapy; Geriatrics; Lung Diseases; Lung Diseases, Fungal; Pulmonary Aspergillosis; Radiography, Thoracic

Topics: Amphotericin B; Aspergillosis; Dermatomyositis; Drug Therapy; Humans; Lung Diseases; Lung Diseases, Fungal; Prednisolone; Pulmonary Aspergillosis; Radiography, Thoracic; Toxicology

Topics: Amphotericin B; Aspergillosis; Bronchoscopy; Chloramphenicol; Datura stramonium; Iodides; Isoniazid; Lung Diseases; Nystatin; Penicillin G; Penicillin G Procaine; Pneumonectomy; Potassium Iodide; Procaine; Pulmonary Aspergillosis; Radiography, Thoracic; Stilbamidines; Streptomycin; Thoracoplasty; Toxicology

Topics: Amphotericin B; Aspergillosis; Fungi; Geriatrics; Humans; Japan; Lung Diseases, Fungal; Pathology; Pulmonary Aspergillosis; Radiography, Thoracic

Topics: Amphotericin B; Aspergillosis; Iodides; Lung Diseases, Fungal; Pathology; Pulmonary Aspergillosis; Radiography, Thoracic; Surgical Procedures, Operative; Tuberculosis; Tuberculosis, Pulmonary