Comparison of the probability of target attainment between ceftriaxone and cefepime in the cerebrospinal fluid and serum against Streptococcus pneumoniae

• Published in: Diagnostic microbiology and infectious disease Vol. 58; no. 4; pp. 445 - 452
• Main Authors: Lodise, Thomas P, Nau, Roland, Kinzig, Martina, Jones, Ronald N, Drusano, G.L, Sörgel, Fritz
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.08.2007; Elsevier
• Subjects: Anti-Bacterial Agents - blood; Anti-Bacterial Agents - cerebrospinal fluid; Anti-Bacterial Agents - pharmacokinetics; Bacteriology; Biological and medical sciences; Blood Chemical Analysis; Cefepime; Ceftriaxone; Ceftriaxone - blood; Ceftriaxone - cerebrospinal fluid; Ceftriaxone - pharmacokinetics; Cephalosporins - blood; Cephalosporins - cerebrospinal fluid; Cephalosporins - pharmacokinetics; Cerebrospinal Fluid - chemistry; CSF; Female; Fundamental and applied biological sciences. Psychology; Humans; Infectious Disease; Internal Medicine; Male; Meningitis, Pneumococcal - drug therapy; Microbiology; Middle Aged; Miscellaneous; Monte Carlo Method; Monte Carlo simulation; Population PK; Streptococcus pneumoniae; Streptococcus pneumoniae - drug effects; Population PK; Ceftriaxone; Cefepime; Monte Carlo simulation; CSF; β-Lactams; Cerebrospinal fluid; Streptococcus pneumoniae; Streptococcaceae; Cephalosporin derivatives; Antibiotic; Simulation; Bacteria; Micrococcales; Serum; Antibacterial agent
• ISSN: 0732-8893; 1879-0070
• DOI: 10.1016/j.diagmicrobio.2007.03.015

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 γ). 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.