Pharmacokinetic variability and exposures of fluconazole, anidulafungin, and caspofungin in intensive care unit patients: Data from multinational Defining Antibiotic Levels in Intensive care unit (DALI) patients Study.

Mahipal G Sinnollareddy,Matteo Bassetti,Jordi Rello,George Dimopoulos,On Behalf Of The Dali Study Authors ,Claude Martin,Murat Akova,Jeffrey Lipman,Kirsi-Maija Kaukonen,Steven C Wallis,Despoina Koulenti,Jason A Roberts,Andrew Rhodes,Therese Starr,Jan J De Waele,Philippe Montravers

doi:10.1186/s13054-015-0758-3

Abstract

IntroductionThe objective of the study was to describe the pharmacokinetics (PK) of fluconazole, anidulafungin, and caspofungin in critically ill patients and to compare with previously published data. We also sought to determine whether contemporary fluconazole doses achieved PK/pharmacodynamic (PD; PK/PD) targets in this cohort of intensive care unit patients.MethodsThe Defining Antibiotic Levels in Intensive care unit patients (DALI) study was a prospective, multicenter point-prevalence PK study. Sixty-eight intensive care units across Europe participated. Inclusion criteria were met by critically ill patients administered fluconazole (n = 15), anidulafungin (n = 9), and caspofungin (n = 7). Three blood samples (peak, mid-dose, and trough) were collected for PK/PD analysis. PK analysis was performed by using a noncompartmental approach.ResultsThe mean age, weight, and Acute Physiology and Chronic Health Evaluation (APACHE) II scores of the included patients were 58 years, 84 kg, and 22, respectively. Fluconazole, caspofungin, and anidulafungin showed large interindividual variability in this study. In patients receiving fluconazole, 33% did not attain the PK/PD target, ratio of free drug area under the concentration-time curve from 0 to 24 hours to minimum inhibitory concentration (fAUC0–24/MIC) ≥100. The fluconazole dose, described in milligrams per kilogram, was found to be significantly associated with achievement of fAUC0–24/MIC ≥100 (P = 0.0003).ConclusionsConsiderable interindividual variability was observed for fluconazole, anidulafungin, and caspofungin. A large proportion of the patients (33%) receiving fluconazole did not attain the PK/PD target, which might be related to inadequate dosing. For anidulafungin and caspofungin, dose optimization also appears necessary to minimize variability.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-015-0758-3) contains supplementary material, which is available to authorized users.

Highlights

The objective of the study was to describe the pharmacokinetics (PK) of fluconazole, anidulafungin, and caspofungin in critically ill patients and to compare with previously published data
The epidemiology of invasive fungal infections (IFIs) in intensive care units (ICUs) is shifting away from those patients traditionally considered at risk because of advances in diagnostic and therapeutic interventions [1]
C. albicans was isolated from six patients, of whom minimum inhibitory concentration (MIC) was reported in one case (MIC = 0.75 mg/L), C. glabrata was isolated from one patient, and Number of patients

Summary

Introduction

The objective of the study was to describe the pharmacokinetics (PK) of fluconazole, anidulafungin, and caspofungin in critically ill patients and to compare with previously published data. The epidemiology of invasive fungal infections (IFIs) in intensive care units (ICUs) is shifting away from those patients traditionally considered at risk because of advances in diagnostic and therapeutic interventions [1]. Candida spp. are the third leading cause of infections in ICUs globally, accounting for up to 90% of all fungal infections [2]. C. albicans is still the leading cause of fungal infections in ICUs, accounting for 40% to 60% of all invasive Candida infections [3]. Invasive Candida spp. infections are associated with high crude and attributable mortalities as high as 60% and 40%, respectively [1]. The incidence is not as high as that of Candida spp. infections, invasive aspergillosis is a debilitating infection with mortality rates as high as 90% being reported [5]

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