Abstract
ABSTRACTTigecycline is a glycylcycline often used in critically ill patients as the antibiotic of last resort. The pharmacokinetics (PK) of tigecycline in intensive care unit (ICU) patients can be affected by severe pathophysiological changes so that standard dosing might not be adequate. The aim of this study was to describe population PK of high-dose tigecycline in patients with sepsis or septic shock and evaluate the relationship between individual PK parameters and patient covariates. The study population consisted of 37 adult ICU patients receiving a 200-mg loading dose of tigecycline followed by multiple doses of 100 mg every 12 h. Blood samples were collected at 0.5, 2, 4, 8, and 12 h after dose administration. A two-compartment model with interindividual (IIV) and interoccasion (IOV) variability in PK parameters was used to describe the concentration-time course of tigecycline. The estimated values of mean population PK parameters were 22.1 liters/h and 69.4 liters/h for elimination and intercompartmental clearance, respectively, and 162 liters and 87.9 liters for volume of the central and peripheral compartment, respectively. The IIV and IOV in clearance were less than 20%. The estimated values of distribution volumes were different from previously published values, which might be due to pathophysiological changes in ICU patients. No systematic relationship between individual PK parameters and patient covariates was found. The developed model does not show evidence that individual tigecycline dosing adjustment based on patient covariates is necessary to obtain the same target concentration in patients with sepsis or septic shock. Dosing adjustments should be based on the pathogens, their susceptibility, and PK targets.
Highlights
Tigecycline is a glycylcycline often used in critically ill patients as the antibiotic of last resort
Tigecycline is a glycylcycline antibiotic approved by the FDA for the treatment of complicated skin and skin structure infections, complicated intraabdominal infections, and community-acquired bacterial pneumonia (CABP) [1]
The objectives of this study were to describe population pharmacokinetics of high-dose tigecycline in patients with sepsis or septic shock treated in two tertiary medical/surgical intensive care units (ICUs) and examine the relationship between patient characteristics and individual PK parameters in order to propose dose adjustments according to patient covariate values
Summary
Tigecycline is a glycylcycline often used in critically ill patients as the antibiotic of last resort. The aim of this study was to describe population PK of high-dose tigecycline in patients with sepsis or septic shock and evaluate the relationship between individual PK parameters and patient covariates. The developed model does not show evidence that individual tigecycline dosing adjustment based on patient covariates is necessary to obtain the same target concentration in patients with sepsis or septic shock. Standard dosing of antimicrobials results in target drug concentrations in mild to moderately ill patients, but in critically ill patients the pathophysiological changes may influence drug PK and affect required dosing [10, 11]. Changes in PK of patients with sepsis or septic shock include changes in clearance caused by increased cardiac output or organ failure and shifts in volume of distribution as a result of increased vascular permeability or altered protein binding [12]. One has to identify the relationship between measurable patient covariates and pharmacokinetic parameters
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