Open AccessImpact of Loading Dose of Caspofungin in Pharmacokinetic-Pharmacodynamic Target Attainment for Severe Candidiasis Infections in Patients in Intensive Care Units: the CASPOLOAD Study
Author(s) -
Sébastien Bailly,
Élodie Gautier-Veyret,
Minh Patrick Lê,
Lila Bouadma,
Olivier Andremont,
Mathilde Neuville,
Bruno Mourvillier,
Romain Sonneville,
Eric Magalhaes,
Jordane Lebut,
Aguila Radjou,
Roland Smonig,
Michel Wolff,
Laurent Massias,
Claire Dupuis,
Jean François Timsit
Publication year - 2020
Publication title -
antimicrobial agents and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.07
H-Index - 259
eISSN - 1070-6283
pISSN - 0066-4804
DOI - 10.1128/aac.01545-20
Subject(s) - pharmacokinetics , pharmacodynamics , caspofungin , medicine , loading dose , intensive care , pharmacology , invasive candidiasis , population , intensive care medicine , antifungal , voriconazole , environmental health , fluconazole , dermatology
This study evaluated the impact of a high loading dose of caspofungin (CAS) on the pharmacokinetics of CAS and the pharmacokinetic-pharmacodynamic (PK-PD) target attainment in patients in intensive care units (ICU). ICU patients requiring CAS treatment were prospectively included to receive a 140-mg loading dose of CAS. Plasma CAS concentrations (0, 2, 3, 5, 7, and 24 h postinfusion) were determined to develop a two-compartmental population PK model. A Monte Carlo simulation was performed and the probabilities of target attainment (PTAs) were computed using previously published MICs. PK-PD targets were ratios of area under the concentration-time curve from 0 to 24 h (AUC 0-24h ) divided by the MIC (AUC 0-24h /MIC) of 250, 450, and 865 and maximal concentration ( C max ) divided by the MIC ( C max /MIC) of 5, 10, 15, and 20. Among 13 included patients, CAS clearance was 0.98 ± 0.13 liters/h and distribution volumes were V 1 = 9.0 ± 1.2 liters and V 2 = 11.9 ± 2.9 liters. Observed and simulated CAS AUC 0-24h were 79.1 (IQR 55.2; 108.4) and 81.3 (IQR 63.8; 102.3) mg · h/liter during the first 24 h of therapy, which is comparable to values usually observed in ICU patients at day 3 or later. PTAs were >90% for MICs of 0.19 and 0.5 mg/liter, considering AUC/MIC = 250 and C max /MIC = 10 as PK-PD targets, respectively. Thus, a high loading dose of CAS (140 mg) increased CAS exposure in the first 24 h of therapy, allowing early achievement of PK-PD targets for most Candida strains. Such a strategy seems to improve treatment efficacy, though further studies are needed to assess the impact on clinical outcomes. (This study has been registered at ClinicalTrials.gov under identifier NCT02413892.).