Population Pharmacokinetics of Fosfomycin in Critically Ill Patients

Suzanne L Parker; Frantzeska Frantzeskaki; Steven C Wallis; Chryssa Diakaki; Helen Giamarellou; Despoina Koulenti; Ilias Karaiskos; Jeffrey Lipman; George Dimopoulos; Jason A Roberts

doi:10.1128/AAC.01321-15

Population Pharmacokinetics of Fosfomycin in Critically Ill Patients

Antimicrob Agents Chemother. 2015 Oct;59(10):6471-6. doi: 10.1128/AAC.01321-15. Epub 2015 Aug 3.

Affiliations

¹ Burns, Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Australia.
² Critical Care Department, Attikon University Hospital, Athens, Greece Medical School, University of Athens, Athens, Greece.
³ 6th Department of Internal Medicine, Hygeia General Hospital, Athens, Greece.
⁴ Burns, Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Australia Critical Care Department, Attikon University Hospital, Athens, Greece.
⁵ Burns, Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Australia Royal Brisbane and Women's Hospital, Brisbane, Australia.
⁶ Burns, Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Australia Royal Brisbane and Women's Hospital, Brisbane, Australia [email protected].

Abstract

This study describes the population pharmacokinetics of fosfomycin in critically ill patients. In this observational study, serial blood samples were taken over several dosing intervals of intravenous fosfomycin treatment. Blood samples were analyzed using a validated liquid chromatography-tandem mass spectrometry technique. A population pharmacokinetic analysis was performed using nonlinear mixed-effects modeling. Five hundred fifteen blood samples were collected over one to six dosing intervals from 12 patients. The mean (standard deviation) age was 62 (17) years, 67% of patients were male, and creatinine clearance (CLCR) ranged from 30 to 300 ml/min. A two-compartment model with between-subject variability on clearance and volume of distribution of the central compartment (Vc) described the data adequately. Calculated CLCR was supported as a covariate on fosfomycin clearance. The mean parameter estimates for clearance on the first day were 2.06 liters/h, Vc of 27.2 liters, intercompartmental clearance of 19.8 liters/h, and volume of the peripheral compartment of 22.3 liters. We found significant pharmacokinetic variability for fosfomycin in this heterogeneous patient sample, which may be explained somewhat by the observed variations in renal function.

Publication types

Multicenter Study
Observational Study
Research Support, Non-U.S. Gov't

MeSH terms

APACHE
Aged
Anti-Bacterial Agents / blood
Anti-Bacterial Agents / pharmacokinetics*
Anti-Bacterial Agents / pharmacology
Biological Availability
Critical Illness
Drug Administration Schedule
Female
Fosfomycin / blood
Fosfomycin / pharmacokinetics*
Fosfomycin / pharmacology
Gram-Negative Bacterial Infections / blood
Gram-Negative Bacterial Infections / drug therapy*
Gram-Negative Bacterial Infections / microbiology
Gram-Positive Bacterial Infections / blood
Gram-Positive Bacterial Infections / drug therapy*
Gram-Positive Bacterial Infections / microbiology
Greece
Humans
Intensive Care Units
Male
Middle Aged
Models, Statistical*
Multiple Organ Failure / blood
Multiple Organ Failure / drug therapy*
Multiple Organ Failure / microbiology
Opportunistic Infections / blood
Opportunistic Infections / drug therapy*
Opportunistic Infections / microbiology

Substances

Anti-Bacterial Agents
Fosfomycin