title: Comparison of the probability of target attainment between ceftriaxone and cefepime in the cerebrospinal fluid and serum against Streptococcus pneumoniae.
abstract: Although the disposition of ceftriaxone and cefepime in the cerebrospinal fluid (CSF) has been described, the ability of these agents to achieve critical pharmacodynamic targets against Streptococcus pneumoniae in CSF has not been reported. Plasma and CSF pharmacokinetic data were obtained from hospital patients with external ventricular drains and receiving ceftriaxone or cefepime. Concentration-time profiles in plasma and CSF were modeled using a 3-compartment model with 0-order infusion and 1st-order elimination and transfer. The model parameters were identified with population pharmacokinetic analysis (Big Non-Parametric Adaptive Grid with adaptive gamma). 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 ceftriaxone 2G IV Q12H and cefepime 2G IV Q8H. The S. pneumoniae bloodstream infection isolates from the SENTRY Antimicrobial Surveillance Program (USA) provided the distribution of contemporary (2003-2004) MICs. Post-Bayesian measures of bias and precision, observed-predicted plots, and R2 values were highly acceptable for both drugs. The probabilities of achieving 50% and 100% T>MIC in the CSF for ceftriaxone were 76% and 65%, respectively. For cefepime, the PTA at 50% and 100% T>MIC in the CSF were 91.8% and 82%, respectively. The CSF pharmacodynamics against S. pneumoniae for cefepime were superior to that of ceftriaxone. The implications of these findings need to be reexamined in the clinical setting.
authors.affiliation: Institute for Biomedical and Pharmaceutical Research, Nürnberg-Heroldsberg, 90562 Germany.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Lodise
authors.forename: Roland
authors.initials: R
authors.lastname: Nau
authors.forename: Martina
authors.initials: M
authors.lastname: Kinzig
authors.forename: Ronald N
authors.initials: RN
authors.lastname: Jones
authors.forename: G L
authors.initials: GL
authors.lastname: Drusano
authors.forename: Fritz
authors.initials: F
authors.lastname: Sörgel
mesh_terms: D000900:Anti-Bacterial Agents / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D001774:Blood Chemical Analysis; D000077723:Cefepime; D002443:Ceftriaxone / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D002511:Cephalosporins / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D002555:Cerebrospinal Fluid / Q000737:chemistry; D005260:Female; D006801:Humans; D008297:Male; D008586:Meningitis, Pneumococcal / Q000188:drug therapy*; D008875:Middle Aged; D009010:Monte Carlo Method; D013296:Streptococcus pneumoniae / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D002443:Ceftriaxone; D000077723:Cefepime