amphotericin-b and Obesity

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

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

Gut fungi is known to play many important roles in human health regulations. Herein, we investigate the anti-obesity efficacy of the antifungal antibiotics (amphotericin B, fluconazole and 5-fluorocytosine) in the high fat diet-fed (HFD) mice. Supplementation of amphotericin B or fluconazole in water can effectively inhibit obesity and its related disorders, whereas 5-fluorocytosine exhibit little effects. The gut fungus Candida parapsilosis is identified as a key commensal fungus related to the diet-induced obesity by the culture-dependent method and the inoculation assay with C. parapsilosis in the fungi-free mice. In addition, the increase of free fatty acids in the gut due to the production of fungal lipases from C. parapsilosis is confirmed as one mechanism by which C. parapsilosis promotes obesity. The current study demonstrates the gut C. parapsilosis as a causal fungus for the development of diet-induced obesity in mice and highlights the therapeutic strategy targeting the gut fungi.

Topics: Amphotericin B; Animals; Antifungal Agents; Candida parapsilosis; Diet, High-Fat; Fluconazole; Flucytosine; Male; Mice; Mice, Inbred C57BL; Obesity; Symbiosis

Liposomal amphotericin B (LAmB) is used for various fungal infections, but it is unclear which dosing weight to use in obese patients. The purpose of this study was to compare clinical outcomes of adjusted body weight (adjBW) versus total body weight (TBW) dosing of LAmB. This single-center, retrospective cohort study included patients who received LAmB for definitive therapy and whose TBW exceeded 120% of their ideal body weight (IBW). Analyses were conducted for 3 mg/kg for adjBW versus TBW and 5 mg/kg for adjBW versus TBW. A total of 238 patients were included. For the 68 patients who received LAmB at 3 mg/kg, there were no differences in safety or efficacy outcomes. For the 170 patients who received LAmB at 5 mg/kg, significantly more patients in the TBW group experienced the primary outcome of nephrotoxicity (57% versus 35% [

Topics: Amphotericin B; Body Weight; Humans; Obesity; Retrospective Studies

Antibiotic-induced microbiome depletion (AIMD) has been used frequently to study the role of the gut microbiome in pathological conditions. However, unlike germ-free mice, the effects of AIMD on host metabolism remain incompletely understood. Here we show the effects of AIMD to elucidate its effects on gut homeostasis, luminal signaling, and metabolism. We demonstrate that AIMD, which decreases luminal Firmicutes and Bacteroidetes species, decreases baseline serum glucose levels, reduces glucose surge in a tolerance test, and improves insulin sensitivity without altering adiposity. These changes occur in the setting of decreased luminal short-chain fatty acids (SCFAs), especially butyrate, and the secondary bile acid pool, which affects whole-body bile acid metabolism. In mice, AIMD alters cecal gene expression and gut glucagon-like peptide 1 signaling. Extensive tissue remodeling and decreased availability of SCFAs shift colonocyte metabolism toward glucose utilization. We suggest that AIMD alters glucose homeostasis by potentially shifting colonocyte energy utilization from SCFAs to glucose.

Topics: Amphotericin B; Ampicillin; Animals; Anti-Bacterial Agents; Bile Acids and Salts; Blood Glucose; Body Composition; Body Weight; Cecum; Colon; Fatty Acids, Volatile; Gastrointestinal Microbiome; Gene Expression Regulation; Glucose; Homeostasis; Insulin; Insulin Resistance; Male; Metronidazole; Mice; Mice, Inbred C57BL; Neomycin; Obesity; RNA, Ribosomal, 16S; Vancomycin

The pharmacokinetics and toxicity of the lipophilic antifungal agent, amphotericin-B (AmpB), were studied in the hyperlipidemic obese rat model and compared with lean litter-mates. Serial blood samples were obtained for 36 h following a single intravenous infusion of AmpB (1.2 mg/kg) with pre- and post-drug measurements of renal function. Although triglyceride, cholesterol, HDL-cholesterol and LDL + VLDL-cholesterol levels were elevated in the obese compared with lean rats, protein: lipoprotein ratios were similar. There was a 2-fold increase in the area under the serum concentration-time curve of AmpB in obese rats compared to lean litter-mates (15,600 +/- 6900 v. 7800 +/- 2900 ng. h/ml; P less than 0.05); no differences in elimination rate constants were found between groups. Weight-corrected volume of distribution and total body clearance were significantly lower in obese compared with lean rats; no differences were found in absolute clearance or volume. Kidney levels of AmpB were markedly increased in obese versus lean rats. Similarly, kidney to serum ratios of AmpB were greater in obese compared with lean rats (152 +/- 113 v. 41 +/- 23; P less than 0.001). There was a significant decline in the creatinine clearance from baseline in the obese rats coupled with a rise in serum creatinine; no differences were found in lean rats. Similarities in absolute pharmacokinetic variables and protein: lipoprotein ratios suggest differences in AmpB disposition and toxicity are a result of differences in lipoprotein-mediated transport mechanisms between obese and lean rats.

Topics: Amphotericin B; Animals; Antifungal Agents; Body Weight; Deoxycholic Acid; Drug Combinations; Female; Kidney; Metabolic Clearance Rate; Obesity; Rats; Rats, Zucker

Topics: Aged; Amphotericin B; Cryptococcosis; Humans; Leukemia, Myeloid; Lung Diseases, Fungal; Male; Obesity

Deep-seated fungal infections with unusual clinical courses developed in three previously healthy patients following jejunoleal bypass surgery. Pulmonary blastomycosis disseminated and then relapsed despite repeated courses of amphotericin B in a 40-year-old man; chronic progressive pulmonary histoplasmosis developed in a 38-year-old nonsmoking man; and histoplasmosis of mediastinal nodes became symptomatic in a 32-year-old man. Cell-mediated immunity was evaluated in two patients; no defects were found. However, male patients were found to be at a significantly higher risk of infection than female patients (3/32 vs 0/101; P less than .02). A significantly higher percentage of prebypass weight was lost by the infected men than the uninfected men (P less than .05). Accelerated weight loss clearly preceded the onset of the infection in two of the patients. Jejunoileal bypass surgery should be regarded as a risk factor for serious fungal infection, especially in men with accelerated weight loss.

Topics: Adult; Amphotericin B; Blastomycosis; Female; Histoplasmosis; Humans; Ileum; Immunity, Cellular; Jejunum; Lung Diseases, Fungal; Male; Mediastinal Diseases; Mycoses; Obesity; Postoperative Complications; Risk; Sex Factors; Tuberculosis