Pharmacodynamics and bactericidal activity of ceftriaxone (CRO) therapy in eiperimental cephalosporin-resistant pneumococcal (CRSP) meningitis

Adequate cerebrospinal fluid (CSF) concentrations and activity of β-lactam antibiotics are difficult to achieve in meningitis caused by drug-resistant Streptococcus pneumonias. Aim: To compare the pharmacodynamic and bacteriologic effectiveness of different dosing regimens of CRO in experimental CRSP meningitis. Methods: Meningitis was induced in rabbits by intracisternal inoculation of CRSP (MIC & MBC = 4μg/ml). CRO (150-400 mg/kg/day) was given IV in one or two doses. The correlation between bacterial killing rate (BKR) (Δ log ₁₀ CFU/ml/h) and percentage of time that CRO conc, exceeded the MBC (T > MBC), C _peak/MBC or AUC/MBC in CSF was determined. Results: CSF CRO conc exceeded the MBC within 30 minutes of administration in all animals. In the first 24 hours the 200 mg/kg/q12h regimen, compared with 400 mg/kg/q24h regimen, was associated with a greater T > MBC (87 ± 10% vs 60 ± 22%; p = 0.03) and greater BKR (0.2 ± 0.04 vs 0.13 ± 0.07; p = 0.003). However, CSF bacterial concentrations were similar by 48 h. By stepwise multiple regression only T > MBC in CSF during the first 24 h of therapy correlated independently with the BKR (p = 0.001); other indices (C _peak/MBC and AUC/MBC) were strongly related to T > MBC and did not correlate independently with BKR. T > MBC of 95-100% was needed for sterilization of the CSF in 24 h. Conclusion: The T > MBC of CRO in CSF is the most important determinant of bacteriologic effictiveness in experimental highly CRSP meningitis. In the first 24 h twice daily dosing of CRO was more rapidly bactericidal than daily dosing.