micafungin and Intraabdominal-Infections

Severely burned patients have altered drug pharmacokinetics (PKs), but it is unclear how different they are from those in other critically ill patient groups. The aim of the present study was to compare the population pharmacokinetics of micafungin in the plasma and burn eschar of severely burned patients with those of micafungin in the plasma and peritoneal fluid of postsurgical critically ill patients with intra-abdominal infection. Fifteen burn patients were compared with 10 patients with intra-abdominal infection; all patients were treated with 100 to 150 mg/day of micafungin. Micafungin concentrations in serial blood, peritoneal fluid, and burn tissue samples were determined and were subjected to a population pharmacokinetic analysis. The probability of target attainment was calculated using area under the concentration-time curve from 0 to 24 h/MIC cutoffs of 285 for Candida parapsilosis and 3,000 for non-parapsilosis Candida spp. by Monte Carlo simulations. Twenty-five patients (18 males; median age, 50 years; age range, 38 to 67 years; median total body surface area burned, 50%; range of total body surface area burned, 35 to 65%) were included. A three-compartment model described the data, and only the rate constant for the drug distribution from the tissue fluid to the central compartment was statistically significantly different between the burn and intra-abdominal infection patients (0.47 ± 0.47 versus 0.15 ± 0.06 h(-1), respectively; P < 0.05). Most patients would achieve plasma PK/pharmacodynamic (PD) targets of 90% for non-parapsilosis Candida spp. and C. parapsilosis with MICs of 0.008 and 0.064 mg/liter, respectively, for doses of 100 mg daily and 150 mg daily. The PKs of micafungin were not significantly different between burn patients and intra-abdominal infection patients. After the first dose, micafungin at 100 mg/day achieved the PK/PD targets in plasma for MIC values of ≤0.008 mg/liter and ≤0.064 mg/liter for non-parapsilosis Candida spp. and Candida parapsilosis species, respectively.

Topics: Adult; Aged; Antifungal Agents; Ascitic Fluid; Burns; Critical Illness; Echinocandins; Female; Humans; Intraabdominal Infections; Lipopeptides; Male; Micafungin; Middle Aged; Monte Carlo Method; Prospective Studies; Tissue Distribution

Patients undergoing emergency gastrointestinal surgery for intra-abdominal infection are at risk of invasive candidiasis (IC) and candidates for preemptive antifungal therapy.. This exploratory, randomized, double-blind, placebo-controlled trial assessed a preemptive antifungal approach with micafungin (100 mg/d) in intensive care unit patients requiring surgery for intra-abdominal infection. Coprimary efficacy variables were the incidence of IC and the time from baseline to first IC in the full analysis set; an independent data review board confirmed IC. An exploratory biomarker analysis was performed using logistic regression.. The full analysis set comprised 124 placebo- and 117 micafungin-treated patients. The incidence of IC was 8.9% for placebo and 11.1% for micafungin (difference, 2.24%; [95% confidence interval, -5.52 to 10.20]). There was no difference between the arms in median time to IC. The estimated odds ratio showed that patients with a positive (1,3)-β-d-glucan (ßDG) result were 3.66 (95% confidence interval, 1.01-13.29) times more likely to have confirmed IC than those with a negative result.. This study was unable to provide evidence that preemptive administration of an echinocandin was effective in preventing IC in high-risk surgical intensive care unit patients with intra-abdominal infections. This may have been because the drug was administered too late to prevent IC coupled with an overall low number of IC events. It does provide some support for using ßDG to identify patients at high risk of IC.. NCT01122368.

Topics: Adolescent; Adult; Aged; Antifungal Agents; beta-Glucans; Biomarkers; Candidiasis, Invasive; Double-Blind Method; Echinocandins; Female; Humans; Intensive Care Units; Intraabdominal Infections; Lipopeptides; Male; Micafungin; Middle Aged; Postoperative Complications; Pre-Exposure Prophylaxis; Proteoglycans; Young Adult

To compare the efficacy and safety of micafungin with caspofungin for the empirical treatment of severe intra-abdominal infections in surgical intensive care patients.. This was a retrospective cohort study.From May 1 st 2012 to April 30 2015, 47 patients with severe intra-abdominal infection complicated with specific risk of Intra-abdominal invasive candidiasis (IAC) receiving empirical treatment of echinocandins were enrolled in Department of Critical Care Medicine, Peking University First Hospital. Micafungin and caspofungin substituted each other every six months. The baseline information, risk factors of IAC, characteristics of intra-abdominal infections, antifungal treatment and other intra-abdominal infections(IAI) related treatment information, clinical outcome were collected and compared between the micafungin and caspofungin groups.. Forty-seven patients met inclusion/exclusion criteria. The average score of APACHE Ⅱ was (19.0±7.7), the incidence of IAC was 23.4%. The patients were divided into the micafungin group (n=26) and the caspofungin group (n=21). The average therapeutic course was 10 (5, 13) days.There were no significant differences in the baseline information, risk factors of IAC, characteristics of intra-abdominal infections and other IAI related treatment informations between the two groups. SOFA score, body temperature, persistence of extra-gastrointestinal fungal colonization significantly improved from the baseline in both groups. The leukocyte count decrease was different between the micafungin group and the caspofungin group respectively[(12.5±5.4)10(9)/L vs (9.8±4.3) 10(9)/L, P=0.013; (12.9±5.4) 10(9)/L vs (10.4±4.7) 10(9)/L, P=0.134]. There were no significantly differences in the recovery of GI function, the incidence of breakthrough IC, the incidence of newly developed organ failure, the 30-day mortality, the length of ICU stay and hospitalization period or the incidence of alternative antifungal therapy between the micafungin group and the caspofungin group. No drug-related adverse event requiring echinocandins discontinuation occurred.. The empirical treatment of echinocandins for patients with severe intra-abdominal infection and specific risk factors of IAC may be effective. The empirical treatment of micafungin and caspofungin were equally effective and safe.

Topics: Antifungal Agents; Candidiasis; Caspofungin; Critical Care; Echinocandins; Humans; Incidence; Intraabdominal Infections; Intraoperative Care; Lipopeptides; Micafungin; Retrospective Studies; Risk Factors

Invasive fungal infections are an important infection concern for patients with underlying immunosuppression. Antifungal therapy is a critical component of patient care, but therapeutic choices are limited due to few drug classes. Antifungal resistance, especially among Candida species, aggravates the problem. The echinocandin drugs (micafungin, anidulafungin, and caspofungin) are the preferred choice to treat a range of candidiasis. They target the fungal-specific enzyme glucan synthase, which is responsible for the biosynthesis of a major cell wall polymer. Therapeutic failure involves acquisition of resistance, although it is a rare event among most Candida species. However, in some settings, higher-level resistance has been reported among Candida glabrata, which is also frequently resistant to azole drugs, resulting in difficult-to-treat multidrug-resistant strains. The mechanism of echinocandin resistance involves amino acid changes in "hot spot" regions of FKS-encoded subunits of glucan synthase, which decreases the sensitivity of enzyme to drug, resulting in higher minimum inhibitory concentration values. The cellular processes promoting the formation of resistant FKS strains involve complex stress response pathways that yield a variety of adaptive compensatory genetic responses. Standardized broth microdilution techniques can be used to distinguish FKS mutant strains from wild type, but testing C. glabrata with caspofungin should be approached cautiously. Finally, clinical factors that promote echinocandin resistance include prophylaxis, host reservoirs including biofilms in the gastrointestinal tract, and intra-abdominal infections. An understanding of clinical and molecular factors that promote echinocandin resistance is critical to develop better diagnostic tools and therapeutic strategies to overcome resistance.

Topics: Anidulafungin; Antifungal Agents; Azoles; Candida; Candida glabrata; Candidiasis; Caspofungin; Drug Resistance, Multiple, Fungal; Echinocandins; Glucosyltransferases; Humans; Intraabdominal Infections; Lipopeptides; Micafungin; Mutation