JAC Advance Access originally published online on September 4, 2007
Journal of Antimicrobial Chemotherapy 2007 60(5):1038-1044; doi:10.1093/jac/dkm325
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Pharmacodynamics of ceftazidime and meropenem in cerebrospinal fluid: results of population pharmacokinetic modelling and Monte Carlo simulation
1 Institute for Biomedical and Pharmaceutical Research, Nürnberg-Heroldsberg, Germany 2 Albany College of Pharmacy, Albany, NY, USA 3 Ordway Research Institute, Albany, NY, USA 4 University of Göttingen, Göttingen, Germany 5 JMI Laboratories, North Liberty, IA, USA
Received 26 February 2007; returned 12 May 2007; revised 23 July 2007; accepted 2 August 2007
* Corresponding author. Tel: +49-911-518290; Fax: +49-911-5182920; E-mail: ibmp{at}osn.de
Background: Ceftazidime and meropenem are frequently used in the empirical treatment of hospital-acquired cerebrospinal fluid (CSF) infections. Although their dispositions in CSF have been described, the ability of these agents to achieve critical pharmacodynamic targets against the array of nosocomial CSF Gram-negative bacteria encountered in practice has not been reported.
Methods: Serum and CSF pharmacokinetic data were obtained from hospital patients with external ventricular drains and who received ceftazidime or meropenem. Concentration–time profiles in serum and CSF were modelled using a three-compartment model with zero-order infusion and first-order elimination and transfer. The model parameters were identified using population pharmacokinetic analysis [Big Non-Parametric Adaptive Grid (BigNPAG)]. A Monte Carlo simulation (9999 subjects) estimated the probability of target attainment (PTA) for total drug CSF concentrations at 50% and 100% T>MIC for ceftazidime 2 g intravenously every 8 h and meropenem 2 g intravenously every 8 h. The Gram-negative infection isolates of the seven most prevalent Gram-negative bacilli from the Meropenem Yearly Susceptibility Test Information Collection Program were used as a measure of contemporary MIC distribution.
Results: Post-Bayesian measures of bias and precision, observed-predicted plots and R2 values were highly acceptable for both drugs. Although the PTA in CSF was approximately one dilution higher for ceftazidime compared with meropenem at a given MIC value, the cumulative fraction of response (CFR) in CSF against all Gram-negatives was markedly higher for meropenem when compared with ceftazidime secondary to the higher occurrence of lower MIC values for meropenem. Both agents had a low CFR against Pseudomonas aeruginosa.
Conclusions: The pharmacodynamics of meropenem was superior to that of ceftazidime against Gram-negative pathogens in the CSF.
Keywords: population PK , CSF , Gram-negative bacteria