Vancomycin: a review of population pharmacokinetic analyses

Despite nearly five decades of clinical use, vancomycin has retained a significant and uncontested niche in the antibacterial arsenal because of its consistent activity against almost all Gram-positive bacteria. Nevertheless, major vancomycin toxicities have been reported in the literature - in particular, nephrotoxicity and ototoxicity. Vancomycin pharmacokinetics have been described in numerous studies for 25 years. This review presents a synthesis of the reported population pharmacokinetic models of vancomycin. The objective was to determine if there was a consensus on a structural model and which covariates were identified. A literature search was conducted from the PubMed database, from its inception through December 2010, using the following terms: 'vancomycin', 'pharmacokinetic(s)', 'population', 'model(ling)' and 'nonlinear mixed effect'. Articles were excluded if they were not pertinent. The reference lists of all selected articles were also evaluated. Twenty-five articles were included in this review: 15 models concerned paediatric patients and ten models were conducted in adults. In neonates and infants, the pharmacokinetics of vancomycin were mainly described by a one-compartment model, whereas in adults, a two-compartment model was preferentially used. Various covariates were tested but only three (age, creatinine clearance [CL(CR)] and body weight) were included in almost all of the described models. After inclusion of these covariates, the mean (range) values of the interindividual variability in the clearance and volume of distribution were 30% (15.6-45%) and 23% (12.6-48%), respectively. The mean (range) value of the residual variability was 20% (7-39.6%). This review highlights the numerous population pharmacokinetic models of vancomycin developed in recent decades and concludes with relevant information for clinicians and researchers. To optimize vancomycin dosage, this review points out the relevant covariates according to the target population. In adults, dosage optimization depends on CL(CR) and body weight, while in children, it depends on age, body weight and CL(CR). For future population pharmacokinetic studies, a sensitive liquid chromatography-tandem mass spectrometry method could be used and new covariates such as cardiac output or possible renal transporters could be tested. Finally, we suggest that external evaluation should be the first step in a pharmacokinetic analysis of vancomycin rather than describing a new model.