Pharmacodynamics of ceftazidime and meropenem in cerebrospinal fluid: results of population pharmacokinetic modelling and Monte Carlo simulation

• Published in: Journal of antimicrobial chemotherapy Vol. 60; no. 5; pp. 1038 - 1044
• Main Authors: Lodise, T. P., Nau, R., Kinzig, M., Drusano, G. L., Jones, R. N., Sörgel, F.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01-11-2007; Oxford Publishing Limited (England)
• Subjects: Adult; Aged; Anti-Bacterial Agents - cerebrospinal fluid; Anti-Bacterial Agents - pharmacokinetics; Antibiotics. Antiinfectious agents. Antiparasitic agents; Bacteria; Biological and medical sciences; Ceftazidime - cerebrospinal fluid; Ceftazidime - pharmacokinetics; Central Nervous System Infections - microbiology; Central Nervous System Infections - prevention & control; Chemotherapy; CSF; Drug Resistance, Bacterial; Female; Gram-negative bacteria; Gram-Negative Bacteria - drug effects; Gram-Negative Bacterial Infections - drug therapy; Humans; Infections; Male; Medical sciences; Middle Aged; Models, Biological; Monte Carlo Method; Monte Carlo simulation; Pharmacology; Pharmacology. Drug treatments; population PK; Pseudomonas aeruginosa; Thienamycins - cerebrospinal fluid; Thienamycins - pharmacokinetics; population PK; CSF; Gram-negative bacteria; Human; Population pharmacokinetics; Pharmacodynamics; β-Lactams; Cerebrospinal fluid; Modeling; Biological activity; Carbapenem derivatives; Cephalosporin derivatives; Antibiotic; Simulation; Meropenem; Antibacterial agent; Ceftazidime; Gram negative bacteria
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dkm325

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.