title: Low Caspofungin Exposure in Patients in Intensive Care Units.
abstract: In critically ill patients, drug exposure may be influenced by altered drug distribution and clearance. Earlier studies showed that the variability in caspofungin exposure was high in intensive care unit (ICU) patients. The primary objective of this study was to determine if the standard dose of caspofungin resulted in adequate exposure in critically ill patients. A multicenter prospective study in ICU patients with (suspected) invasive candidiasis was conducted in the Netherlands from November 2013 to October 2015. Patients received standard caspofungin treatment, and the exposure was determined on day 3 of treatment. An area under the concentration-time curve from 0 to 24 h (AUC0-24) of 98 mg · h/liter was considered adequate exposure. In case of low exposure (i.e., <79 mg · h/liter, a ≥20% lower AUC0-24), the caspofungin dose was increased and the exposure reevaluated. Twenty patients were included in the study, of whom 5 had a positive blood culture. The median caspofungin AUC0-24at day 3 was 78 mg · h/liter (interquartile range [IQR], 69 to 97 mg · h/liter). A low AUC0-24(<79 mg · h/liter) was seen in 10 patients. The AUC0-24was significantly and positively correlated with the caspofungin dose in mg/kg/day (P = 0.011). The median AUC0-24with a caspofungin dose of 1 mg/kg was estimated using a pharmacokinetic model and was 114.9 mg · h/liter (IQR, 103.2 to 143.5 mg · h/liter). In conclusion, the caspofungin exposure in ICU patients in this study was low compared with that in healthy volunteers and other (non)critically ill patients, most likely due to a larger volume of distribution. A weight-based dose regimen is probably more suitable for patients with substantially altered drug distribution. (This study has been registered at ClinicalTrials.gov under registration no. NCT01994096.).
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, the Netherlands.
authors.forename: Kim C M
authors.initials: KC
authors.lastname: van der Elst
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, the Netherlands.
authors.forename: Anette
authors.initials: A
authors.lastname: Veringa
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Critical Care, Groningen, the Netherlands.
authors.forename: Jan G
authors.initials: JG
authors.lastname: Zijlstra
authors.affiliation: Medisch Spectrum Twente, Intensive Care Center, Enschede, the Netherlands.
authors.forename: Albertus
authors.initials: A
authors.lastname: Beishuizen
authors.affiliation: Medisch Spectrum Twente, Department of Medical Microbiology, Enschede, the Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Klont
authors.affiliation: ZGT Hospital Group Twente, Department of Clinical Pharmacy, Hengelo, the Netherlands.
authors.forename: Petra
authors.initials: P
authors.lastname: Brummelhuis-Visser
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, the Netherlands.
authors.forename: Donald R A
authors.initials: DR
authors.lastname: Uges
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, the Netherlands.
authors.forename: Daan J
authors.initials: DJ
authors.lastname: Touw
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, the Netherlands.|University of Groningen, Department of Pharmacy, Section Pharmacotherapy and Pharmaceutical Care, Groningen, the Netherlands.
authors.forename: Jos G W
authors.initials: JG
authors.lastname: Kosterink
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Groningen, the Netherlands.|University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases and Tuberculosis, Groningen, the Netherlands.
authors.forename: Tjip S
authors.initials: TS
authors.lastname: van der Werf
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, the Netherlands j.w.c.alffenaar@umcg.nl.
authors.forename: Jan-Willem C
authors.initials: JC
authors.lastname: Alffenaar
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D019540:Area Under Curve; D002176:Candida albicans / Q000187:drug effects; D058365:Candidiasis, Invasive / Q000188:drug therapy; D000077336:Caspofungin; D016638:Critical Illness; D054714:Echinocandins / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D015725:Fluconazole / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007362:Intensive Care Units; D055666:Lipopeptides / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D015725:Fluconazole; D000077336:Caspofungin
keywords: antifungal therapy; intensive care; pharmacokinetics; therapeutic drug monitoring