micafungin and HIV-Infections

Intravenous micafungin (Mycamine; Fungard), an echinocandin, inhibits the synthesis of 1,3-beta-D-glucan, an essential cell wall component in many fungi. It is approved in adults (focus of this review) and in neonates and paediatric patients (Pediatric Drugs [in press]) in the EU and elsewhere for the treatment of invasive candidiasis and oesophageal candidiasis, and as prophylactic treatment to prevent Candida infections in haematopoietic stem cell transplant (HSCT) recipients.Intravenous micafungin shows very good activity against clinically relevant isolates of Candida spp. Furthermore, the pharmacokinetic profile of micafungin permits once-daily treatment and means that it is associated with relatively few drug-drug interactions. However, like all of the echinocandins and all formulations of amphotericin B, micafungin must be given intravenously. In large, well designed clinical trials in adult patients (>or=16 years of age) with invasive candidiasis, intravenous micafungin was shown to be noninferior to intravenous caspofungin or liposomal amphotericin B. In similarly designed trials in adult patients with oesophageal candidiasis, intravenous micafungin was shown to be noninferior to fluconazole or caspofungin treatment. As prophylactic treatment in adult and paediatric patients who had undergone HSCT, micafungin was superior to fluconazole therapy in a large, well designed trial. Micafungin was generally well tolerated by participants in these clinical trials. Furthermore, it was as well tolerated as caspofungin and fluconazole, and better tolerated than liposomal amphotericin B. The position of micafungin relative to newer antifungal therapies, such as anidulafungin, voriconazole and posaconazole, remains to be fully determined. Thus, micafungin is an emerging option for the treatment of adult patients with invasive or oesophageal candidiasis, and as prophylaxis against Candida infections in HSCT recipients.

Topics: Antifungal Agents; Candida; Candidiasis; Drug Interactions; Drug Resistance, Fungal; Drug Therapy, Combination; Echinocandins; Esophageal Diseases; HIV Infections; Humans; Lipopeptides; Micafungin

In recent decades, the incidence of aspergillosis, candidiasis and clinically important deep mycoses has been increasing, with advances in transplantation medicine and anticancer chemotherapy. Micafungin (FK463, Fujisawa Healthcare) has been developed as a novel type of antifungal agent, which inhibits 1,3-beta-D-glucan synthase in the fungal cell wall. Micafungin, one of the echinocandins, exhibits extremely high antifungal activity against Aspergillus spp. and Candida spp. in vitro. It is also characterized by a linear pharmacokinetic profile and a much lower prevalence of adverse reactions than amphotericin B. Micafungin is quite useful in the treatment of deep mycoses. In clinical studies in Japan, micafungin was found to be highly effective against aspergillosis (57.1% overall efficacy rate) and candidiasis (78.6%). Micafungin is expected to increase the efficacy rate of treatment in patients with severe aspergillosis or candidiasis when used in combination with amphotericin B or mold azoles.

Topics: Animals; Antifungal Agents; Aspergillosis; Candidiasis, Oral; Child; Clinical Trials as Topic; Drug Interactions; Echinocandins; Fungi; HIV Infections; Humans; Lipopeptides; Lipoproteins; Micafungin; Mycoses; Peptides, Cyclic

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

Talaromyces marneffei (T. marneffei) can cause talaromycosis, a fatal systemic mycosis, in patients with AIDS. With the increasing number of talaromycosis cases in Guangdong, China, we aimed to investigate the susceptibility of 189 T. marneffei clinical strains to eight antifungal agents, including three echinocandins (anidulafungin, micafungin, and caspofungin), four azoles (posaconazole, itraconazole, voriconazole, and fluconazole), and amphotericin B, with determining minimal inhibition concentrations (MIC) by Sensititre YeastOne™ YO10 assay in the yeast phase. The MICs of anidulafungin, micafungin, caspofungin, posaconazole, itraconazole, voriconazole, fluconazole, and amphotericin B were 2 to > 8 μg/ml, >8 μg/ml, 2 to > 8 μg/ml, ≤ 0.008 to 0.06 μg/ml, ≤ 0.015 to 0.03 μg/ml, ≤ 0.008 to 0.06 μg/ml, 1 to 32 μg/ml, and ≤ 0.12 to 1 μg/ml, respectively. The MICs of all echinocandins were very high, while the MICs of posaconazole, itraconazole, and voriconazole, as well as amphotericin B were comparatively low. Notably, fluconazole was found to have a higher MIC than other azoles, and exhibited particularly weak activity against some isolates with MICs over 8 μg/ml. Our data in vitro support the use of amphotericin B, itraconazole, voriconazole, and posaconazole in management of talaromycosis and suggest potential resistance to fluconazole.

Topics: Amphotericin B; Anidulafungin; Antifungal Agents; Azoles; Echinocandins; HIV Infections; Humans; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Mycoses; Reagent Kits, Diagnostic; Talaromyces; Voriconazole

Airway mucormycosis is a deadly opportunistic infection that affects immunocompromised persons, particularly diabetics and those undergoing chemotherapy. Although it is typically a pulmonary or sinonasal infection, mucormycosis can affect the larynx and trachea, with devastating results. We report the case of a 46-year-old man with human immunodeficiency virus infection, hepatitis C infection, neurosyphilis, and recently diagnosed Burkitt lymphoma who presented with dysphonia and stridor after receiving one dose of intrathecal chemotherapy. Flexible laryngoscopy detected the presence of fibrinous material that was obstructing nearly the entire glottis. Surgical debridement revealed a firm mucosal attachment; there was little bleeding when it was removed. After debridement, the patient's dyspnea improved only to recur 2 days later. After an awake tracheotomy, laryngoscopy and bronchoscopy identified necrosis extending from the supraglottic area to the carina tracheae. Biopsies demonstrated hyphal architecture consistent with mucormycosis. Despite continued debridements, the fibrinous material reaccumulated. The patient was placed in hospice care; his airway remained patent, but he died from other causes several weeks after presentation. The management of airway mucormycosis is challenging and complex. Fungal airway infections should be considered in the differential diagnosis of an immunosuppressed patient who presents with dyspnea, dysphonia, and vocal fold immobility. Timely diagnosis and management are critical for a successful outcome, although the prognosis is poor if the infection is widespread, even with the best of efforts.

Topics: Antifungal Agents; Burkitt Lymphoma; Debridement; Dysphonia; Echinocandins; Hepatitis C, Chronic; HIV Infections; Humans; Hyperbaric Oxygenation; Laryngitis; Laryngoscopy; Lipopeptides; Male; Micafungin; Middle Aged; Mucormycosis; Neurosyphilis; Respiratory Distress Syndrome; Respiratory Sounds; Tracheitis; Tracheotomy; Triazoles

Antifungal susceptibility of micafungin against isolates of C. glabrata was performed to evaluate the hypothesis that micafungin may be a suitable alternative in treating those patients whose infections are from C. glabrata and have developed resistance to fluconazole.. A total of 119 clinical isolates were obtained from the oral cavity of 22 patients with oropharyngeal candidiasis or oral colonization with C. glabrata. All strains evaluated were from patients who had either HIV infection or were receiving radiation therapy for head and neck cancer. Inocula were prepared using Clinical Laboratory and Standards Institute (CLSI) M27-A2 guidelines. The plates were incubated at 35 degrees C and the minimum inhibitory concentrations (MICs) were determined at 24 and 48 hours.. Micafungin exhibited good in vitro activity against most isolates, including those showing marked resistance to fluconazole.. Micafungin has excellent antifungal effects in vitro against C. glabrata isolates and appears to be a good treatment option even against those isolates resistant to fluconazole. A clinical trial should be performed to confirm these findings.

Topics: Antifungal Agents; Candida glabrata; Drug Resistance, Fungal; Echinocandins; Fluconazole; Head and Neck Neoplasms; HIV Infections; Humans; Lipopeptides; Lipoproteins; Micafungin; Microbial Sensitivity Tests

A patient with Candida albicans thrush and oesophagitis was treated with high doses of caspofungin but treatment eventually failed. Four C. albicans isolates were serially recovered before and after caspofungin treatment. A microbiological study was performed to characterize these four isolates.. In vitro antifungal susceptibility testing was performed by the EUCAST reference method in RPMI and AM3 and by Etest. Molecular typing of the four isolates was done by sizing three polymorphic microsatellite markers. To look for specific mutations, sequencing of a region of the gene encoding the 1-3-beta-D-glucan synthase was performed for the four isolates.. In vitro antifungal susceptibility testing showed an increase in both caspofungin and micafungin MICs for the two isolates recovered after caspofungin treatment failure. The best discrimination between the pre-treatment and post-treatment isolates was obtained with Etest. Molecular typing of the four isolates showed that the post-treatment isolates with reduced susceptibility were identical to a susceptible pre-treatment isolate, suggesting the acquisition of caspofungin resistance. Sequencing of the gene encoding the 1-3-beta-D-glucan synthase showed a mutation responsible for an amino acid change at Phe-641 that could confer reduced susceptibility to both echinocandins.. Our results indicate that is it useful to perform in vitro susceptibility testing in the cases of clinical failure during caspofungin therapy.

Topics: Adult; Amino Acid Sequence; Amino Acid Substitution; Amphotericin B; Antifungal Agents; Candida albicans; Candidiasis; Caspofungin; Drug Resistance, Fungal; Echinocandins; Fluconazole; Genotype; HIV Infections; HIV-1; Humans; Lipopeptides; Lipoproteins; Male; Micafungin; Microbial Sensitivity Tests; Molecular Sequence Data; Peptides, Cyclic; Pyrimidines; Treatment Failure; Triazoles; Voriconazole

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