There are a number of effective but highly toxic drugs that exhibit a narrow therapeutic index and marked interpatient pharmacokinetic variability. Individualized therapy with such drugs requires therapeutic drug monitoring (TDM) to obtain the desired clinical effects safely. Cost-effectiveness analysis in health care is still at an early stage of development, especially for TDM. A systematic review was carried out to document studies that have addressed the cost-effectiveness of TDM. The Cochrane database and Medline were searched. References identified by this approach were then searched manually for relevant articles. Very few studies have been performed that document the cost-effectiveness of TDM, and TDM has been demonstrated to be cost-effective only for aminoglycosides. For the other classes of drugs that are monitored, the rationale for TDM has been supported, but appropriate cost-effectiveness analyses have not been performed. Because the use of many of these drugs without TDM would increase the risk of under- or overdosing, emphasis should not be placed solely on cost-effectiveness but rather on how such interventions can be applied in the most cost-effective and clinically useful manner.

The pharmacokinetics of tobramycin do not differ significantly in CF patients compared with patients without CF when subject age, fat-free mass, sex and renal function are taken into consideration. Variations in tobramycin dosing between CF and non-CF patients should therefore reflect target concentrations or exposures based on differences in expected pathogen sensitivity and not the presence of CF.

AIMSVancomycin is one of the most evaluated antibiotics in neonates using modeling and simulation approaches. However no clear consensus on optimal dosing has been achieved. The objective of the present study was to perform an external evaluation of published models, in order to test their predictive performances in an independent dataset and to identify the possible study-related factors influencing the transferability of pharmacokinetic models to different clinical settings. METHODPublished neonatal vancomycin pharmacokinetic models were screened from the literature. The predictive performance of six models was evaluated using an independent dataset (112 concentrations from 78 neonates). The evaluation procedures used simulation-based diagnostics [visual predictive check (VPC) and normalized prediction distribution errors (NPDE)]. RESULTSDifferences in predictive performances of models for vancomycin pharmacokinetics in neonates were found. The mean of NPDE for six evaluated models were 1.35, -0.22, -0.36, 0.24, 0.66 and 0.48, respectively. These differences were explained, at least partly, by taking into account the method used to measure serum creatinine concentrations. The adult conversion factor of 1.3 (enzymatic to Jaffé) was tested with an improvement in the VPC and NPDE, but it still needs to be evaluated and validated in neonates. Differences were also identified between analytical methods for vancomycin. CONCLUSIONThe importance of analytical techniques for serum creatinine concentrations and vancomycin as predictors of vancomycin concentrations in neonates have been confirmed. Dosage individualization of vancomycin in neonates should consider not only patients' characteristics and clinical conditions, but also the methods used to measure serum creatinine and vancomycin. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Population pharmacokinetics of vancomycin have been widely studied in neonates.• Many covariates including bodyweight, gestational age and post-natal age, renal function, co-administered drugs, etc. have been evaluated and some of them are associated with inter-individual pharmacokinetic variability. WHAT THIS STUDY ADDS• The analytical technique used for measuring serum creatinine concentrations has been confirmed as a study-related factor influencing the transferability of published models to different clinical settings.• Different predictive performances were demonstrated between analytical methods (FPIA and EMIT).• The neonatal conversion factor of serum creatinine concentrations between the Jaffé and enzymatic methods and the interferences/cross-reactivity of analytical methods need to be evaluated in neonates in future studies.