micafungin and AIDS-Related-Opportunistic-Infections

Esophageal candidiasis (EC) is a common and serious complication in patients infected with the human immunodeficiency virus (HIV). Micafungin has been shown to have dose-related efficacy and to be well tolerated in patients with HIV and EC. This analysis of data from a randomized, double-blind study examined pharmacokinetic parameters of micafungin (dosed at 50, 100, and 150 mg/day) and its metabolites in a subset of patients with HIV and EC. Micafungin exhibited linear, predictable pharmacokinetics, similar to the previous observations in healthy control subjects. Micafungin peak plasma concentration and exposure were increased with dose, while half-life and clearance remained consistent with increasing dose. Plasma concentrations of the metabolites M-1, M-2, and M-5 remained low throughout the study (24 h exposure ≤14% relative to micafungin at end of therapy for each). No differences in micafungin pharmacokinetic parameters were observed according to the sex or race of the patients. The high systemic exposures associated with micafungin 100 and 150 mg/day relative to micafungin 50 mg/day were found to directly correlate with endoscopic clearance. These data provide evidence that the pharmacokinetics of micafungin underlie the dose-related efficacy in patients with HIV and EC.

Topics: Adult; Aged; AIDS-Related Opportunistic Infections; Antifungal Agents; Candidiasis; Dose-Response Relationship, Drug; Double-Blind Method; Echinocandins; Esophageal Diseases; Esophagoscopy; Female; Half-Life; HIV Infections; Humans; Lipopeptides; Male; Micafungin; Middle Aged; Prospective Studies; Young Adult

Severely immunocompromised individuals are highly susceptible to Candida infection of the esophagus. This randomized, double-blind study assessed the dose-response relationship of the new echinocandin antifungal, micafungin, compared with that of standard fluconazole treatment.. A total of 245 patients (age, > or =18 years) with a prior diagnosis of acquired immunodeficiency syndrome/human immunodeficiency virus (HIV) infection and esophageal candidiasis, confirmed by endoscopy and culture, were randomized to receive micafungin (50, 100, or 150 mg per day) or fluconazole (200 mg per day). Both agents were administered once per day by a 1-h intravenous infusion for 14-21 days. The primary efficacy end point was endoscopic cure rate, defined as endoscopy grade of 0 at the end of therapy.. The endoscopic cure rate (grade 0) was dose-dependent with 50, 100, and 150 mg of micafungin per day at 68.8%, 77.4%, and 89.8%, respectively. Symptoms improved or resolved rapidly (3-7 days of treatment in the majority of patients). The endoscopic cure rate for 100 and 150 mg of micafungin per day (83.5%) was comparable to that for 200 mg of fluconazole per day (86.7%; 95% confidence interval for the difference in endoscopic cure rate, -14.0% to 7.7%). The overall safety and tolerability was acceptable, with no important differences between micafungin (all doses) and fluconazole.. The dose-response findings demonstrate a greater efficacy with micafungin at 100 and 150 mg per day than at 50 mg per day. This study also indicates that the efficacy of micafungin (at dosages of 100 and 150 mg per day) was comparable to that of fluconazole, suggesting that micafungin represents a valuable new treatment option for esophageal candidiasis in HIV-positive patients.

Topics: Adolescent; Adult; Aged; AIDS-Related Opportunistic Infections; Antifungal Agents; Candidiasis; Double-Blind Method; Echinocandins; Esophageal Diseases; Female; Fluconazole; HIV Infections; Humans; Lipopeptides; Lipoproteins; Male; Micafungin; Middle Aged; Peptides, Cyclic

Micafungin is an echinocandin-class antifungal agent licensed for treatment of invasive disease in adults. The optimal dosing regimens have not been established for infants. We describe a premature infant who developed hepatitis and cholestasis during micafungin therapy initiated for protracted candidemia. Practitioners should be aware of this potential adverse effect if using micafungin in young patients.

Topics: AIDS-Related Opportunistic Infections; Alanine Transaminase; Amphotericin B; Antifungal Agents; Aspartate Aminotransferases; Candidiasis; Chemical and Drug Induced Liver Injury; Cholestasis; Dose-Response Relationship, Drug; Drug Therapy, Combination; Echinocandins; Female; Fungemia; Humans; Infant; Infant, Newborn; Infant, Premature, Diseases; Lipopeptides; Liver Function Tests; Micafungin

To illustrate the progressive loss of cross-echinocandin activity on Candida albicans isolates with strong clonal homology from a patient with advanced HIV infection and chronic oesophagitis progressively resistant to uninterrupted micafungin treatment.. Antifungal susceptibility profiles for different antifungal agents were determined against serial C. albicans isolates retrieved before and during therapy. Multilocus sequencing typing (MLST) was performed on each of the isolates. FKS1 mutations conferring reduced susceptibility to echinocandin drugs were determined by DNA sequence analysis.. Four C. albicans isolates showing identical allelic homology were retrieved from the patient at the initiation and during therapy with micafungin. The progressive lack of clinical response to micafungin therapy was associated with increased MICs of all three echinocandin drugs (caspofungin, micafungin and anidulafungin) in association with the acquisition of mutations in the FKS1 gene.. This report documents for the first time a progressive loss of activity of all three echinocandin drugs against clonally related C. albicans isolates following long-term clinical exposure to this new class of antifungal agents.

Topics: Adult; AIDS-Related Opportunistic Infections; Antifungal Agents; Candida albicans; Candidiasis; Drug Resistance, Fungal; Echinocandins; Esophagitis; Fatal Outcome; Glucosyltransferases; HIV Infections; Humans; Lipopeptides; Lipoproteins; Male; Membrane Proteins; Micafungin; Microbial Sensitivity Tests; Peptides, Cyclic; Saccharomyces cerevisiae Proteins

To compare the Clinical Laboratory Standards Institute CLSI M44-A disc diffusion (DD) and M27-A2 broth microdilution (MD) methods for determining the susceptibility of Candida spp. to micafungin (FK463).. A total of 355 clinical yeast isolates including 270 Candida albicans, 45 Candida glabrata, 24 Candida krusei, 11 Candida tropicalis and 5 Candida parapsilosis were studied. The MIC of micafungin was determined by following the CLSI M27-A2 guidelines (MD). Endpoints were defined as the lowest concentration of micafungin resulting in partial inhibition (IC(50)) of visual growth after 24/48 h of incubation at 35 degrees C. Final concentrations were 0.008-4 mg/L of micafungin. DD testing was performed using a CLSI M44-A document with 2.5 mug micafungin discs. Zone diameter endpoints were read after 24/48 h of incubation at 35 degrees C. Arbitrary breakpoints were 4 mg/L for MD and 15 mm for DD.. The best correlation was observed when we read MD 48 h/DD 24 and 48 h (97%). When the reading was MD 24 h/DD 24 and 48 h the percentage of correlation was 95.2%.. The DD method performs well for testing the susceptibility of Candida spp. to micafungin. More studies involving more Candida strains with elevated MIC values are needed.

Topics: AIDS-Related Opportunistic Infections; Antifungal Agents; Candida; Candida albicans; Candidiasis, Oral; Culture Media; Drug Resistance, Fungal; Echinocandins; HIV Infections; Humans; Lipopeptides; Lipoproteins; Micafungin; Microbial Sensitivity Tests; Peptides, Cyclic

Long-term inserted and surgically implanted catheters can be colonised by Candida spp. Candida biofilms in vitro are often resistant to antifungal agents. The aim of this study was to investigate the in vitro activity of micafungin (MFG) against six Candida spp. biofilms on polystyrene (PS) and central venous catheter (CVC) sections. Safranin staining and differential interference contrast microscopy were used to demonstrate biofilm production. MFG activity was determined by the reduction in metabolic activity (%RMA) by tetrazolium reduction assay on both substrates. In vitro, Candida albicans, Candida parapsilosis, Candida glabrata, Candida tropicalis, Candida dubliniensis and Candida kefyr produced mature biofilms on PS and CVC sections. MFG was active against C. kefyr (0.5 microg/mL) and C. glabrata (<0.5 microg/mL) on PS. However, MFG displayed resistance (>16 microg/mL) against C. albicans, C. dubliniensis,C. tropicalis and C. parapsilosis. On CVC disks, MFG was active against C. glabrata (1 microg/mL) as well as C. parapsilosis and C. albicans (<0.5 microg/mL). MFG was resistant (>16 microg/mL) against C. dubliniensis, C. tropicalis and C. kefyr. MFG was active in vitro against all six Candida spp. on both substrates. However, MFG could not reduce the metabolic activity completely even at the highest concentration.

Topics: Adult; AIDS-Related Opportunistic Infections; Antifungal Agents; Biofilms; Candida; Candidiasis; Catheterization, Central Venous; Catheters, Indwelling; Child; Echinocandins; Humans; Infant, Newborn; Infant, Premature, Diseases; Lipopeptides; Lipoproteins; Micafungin; Microbial Sensitivity Tests; Microscopy, Interference; Peptides, Cyclic; Phenazines; Polystyrenes; Staining and Labeling; Tetrazolium Salts