Pharmacokinetic Variability and Target Attainment of Fluconazole in Critically Ill Patients

Abstract

Background: Fluconazole is one of the oldest antifungal drugs. Previous studies have raised concerns considering variability in exposure and inadequate target attainment in critically ill patients. The current study aims to define variability and target attainment for fluconazole exposure in a large group of critically ill patients. Methods: In this pharmacokinetic study, daily plasma trough samples and, if possible, 24 h urine samples were collected to determine fluconazole concentration. A minimum target trough concentration of 10–15 mg/L was selected, corresponding to a free area under the concentration–time curve above the minimum inhibitory concentration (fAUC/MIC) of at least 100 for an MIC of 4 mg/L. Covariates that significantly influenced fluconazole exposure were identified. Results: In total, 288 plasma samples from 43 patients, with a median age of 66 years, were included. The median fluconazole trough concentration was 22.9 mg/L. A notable component of the measured concentrations was below the target trough concentrations (13% <10 mg/L and 27% <15 mg/L). The intra- and intersubject variability were 28.3% and 50.5%, respectively. The main covariates determining fluconazole exposure were the administered dose (mg/kg), augmented renal clearance, and renal replacement therapy. Conclusions: Fluconazole trough concentrations are variable in critically ill patients and a considerable number of these concentrations was below the predefined target trough concentrations.

Invasive candidiasis: current clinical challenges and unmet needs in adult populations

“…mucositis, administration via nasogastric tube or gastrostomy, or in critically ill patients undergoing continuous renal replacement therapy (CRRT)], TDM should also be considered. 109 , 110 Finally, TDM may also be helpful in those cases of treatment failure, breakthrough infections, serious toxicity or those Candida infections caused by species with high minimum inhibitory concentration (MIC). 111 …”

Candidemia in Adult Patients in the ICU: A Reappraisal of Susceptibility Testing and Antifungal Therapy

“…97 Critical illness, body weight, augmented renal function, and continuous veno-venous hemofiltration may affect fluconazole exposure. 71,98 Previous data suggest weight-based dosing is more likely than "standard dosing" to achieve PK/PD targets in critically ill adults with Candida species displaying higher MICs. 71,72,98,99 While TDM-guided dosing may be useful in certain situations (eg, those undergoing RRT), it is not routinely recommended as weight-based dosing (12 mg/kg as a loading dose followed by 6 mg/kg as a maintenance dose, both based on total body weight) often achieves optimal exposure.…”

Editorial for the Special Issue: “Therapeutic Drug Monitoring of Antimicrobials”

“…In addition to target attainment, the need for azole TDM is mainly driven by risk of toxicity and high probability of drug–drug interactions. Nevertheless, there have been reports that TDM of azoles, such as fluconazole, may also be beneficial to avoid underexposure [ 10 ]. Echinocandins, although generally considered safe, should also be considered candidates for TDM, as suboptimal exposure has been documented in critically ill patients.…”