Prospective Cohort Study of Micafungin Population Pharmacokinetic Analysis in Plasma and Peritoneal Fluid in Septic Patients with Intra-abdominal Infections

Abstract

Objectives: To describe the pharmacokinetics (PK) of micafungin in plasma and peritoneal fluid in septic patients with intra-abdominal infections. Methods: Twelve patients with secondary peritonitis in septic shock receiving 100 mg micafungin once daily were included. Total micafungin plasma and peritoneal fluid were subject to a population pharmacokinetic analysis using Pmetrics®. Monte Carlo simulations were performed considering total AUC0-24h/MIC ratios in plasma. Results: Micafungin concentrations in both plasma and peritoneal exudate were best described by a three-compartmental PK model with the fat free mass (FFM) as a covariate of clearance (CL) and volume of the central compartment (Vc). The mean parameter estimates (standard deviation, SD) were 1.18 (0.40) L/h for CL and 12.85 (4.78) L for Vc. The mean peritoneal exudate/plasma ratio (SD) of micafungin was 25% (5%) on day 1 and 40% (8%) between day 3-5. Dosing simulations supported the use of standard 100 mg daily dosing for C. albicans (FFM < 60 kg), C. glabrata (FFM < 50 kg) and C. tropicalis (FFM < 30 kg) on the second day of therapy. Conclusions: There is a moderate penetration of micafungin into peritoneal cavity (25 to 40%). For empirical treatment, a dose escalation of at least a loading dose of 150 mg depending on the FFM of patients and Candida species is suggested to be effective from the first day of therapy.

Critical appraisal beyond clinical guidelines for intraabdominal candidiasis

“…Table 2 shows PK data in peritoneal fluid from published studies [ 38 , 39 , 50 ]. The percentage of reduction in peritoneal concentrations of echinocandins with respect to serum concentrations was reported to be approximately 33% [ 38 , 39 , 51 ]. Table 3 shows MIC 90 values of echinocandins for different Candida species [ 52 , 53 ] and CLSI [ 54 ] and EUCAST [ 55 ] breakpoints values.…”

“…IAC represents a frequent entity among critically ill patients, with characteristics in relation to dosages and drug distribution, and it is not addressed in the clinical guidelines issued by the principal infectious diseases’ scientific societies, probably due to the lack of good quality treatment evidence for this entity [ 11 , 69 ]. The current guidelines assume the same criteria as for candidemia [ 12 ], without any other type of assessment, regardless of published data on the low peritoneal drug penetration [ 38 , 39 , 50 , 51 ].…”

“…Echinocandins are well-tolerated antifungals since they inhibit beta-glucan synthesis, a target not found in humans [ 27 , 44 , 73 ]. A Monte Carlo simulation justified higher doses of echinocandins, especially in those patients weighing > 70 kg and infected by non- albicans species [ 51 ]. Several clinical trials have investigated high dosages, with a favourable safety outcome [ 74 – 77 ].…”

Micafungin Population PK Analysis in Healthy and Septic Pigs: Can the Septic Porcine Model Predict the Micafungin PK in Septic Patients?

“…Given the greater number of observed concentrations between 8 and 12 h, penetration into peritoneal cavity was assessed by observed AUC 8-12 h peritoneal fluid/plasma ratio calculated from patients with both peritoneal and plasma concentrations available. Also, the data set from Garbez et al (17,18) were used to compare micafungin PK between septic pig model and septic patients, where a total of 16 septic patients were treated with the standard 100 mg daily dosing of micafungin for invasive candidiasis.…”

“…Finally, the validation of the PK models was applied to visual predictive check (VPC). Furthermore, the PK model which compared septic pig model and septic patients used a half of the data set from Garbez et al (17,18) for internal validation, while the other half was used for external validation.…”