Efficacy of Standard Meropenem Dosing in Healthcare-Associated Meningitis: Is It Universal?

Central nervous system (CNS) infections related to external ventricular drains (EVD) represent a frequent and serious complication of invasive CNS procedures, particularly those due to Gram-negative bacilli (GNB). Meropenem is one of the first-line treatments recommended whereas its limited CSF diffusion, with few studies with proven CNS infections. The multicenter PK/PD study evaluated the impact of EVD-related infections on meropenem distribution in cerebrospinal fluid (CSF) in 28 neuro-ICU patients with EVD, receiving meropenem via intermittent or continuous infusions (6-8 g/day), by comparing patients with confirmed CNS infection (n = 14) to those with extra-CNS infection (n = 14). Theoretical efficacy of different dosing strategies was assessed by Monte Carlo simulations. Probability of target attainment (PTA) and cumulative fractions of response (CFRs) were derived as the percentage of individuals achieving at steady-state 100% T > MIC for each dosing regimen using meropenem MIC frequency distributions for P. aeruginosa, K. pneumoniae, E. cloacae, and S. marcescens. A limited penetration of meropenem into CSF was observed, with a CSF/plasma AUC ratio of 16.3 ± 11.4% in CNS infections compared to 6.0 ± 4.5% in extra-CNS infections, highlighting the significant impact of infection. In patients with CNS infection, PTA in CSF was> 90% for MIC up to 0.25 mg/L with 6 g/d and reached 89.7% with 8 g/d for MIC of 1 mg/L. Overall, a daily dose of 6 g appears sufficient to treat CNS infections caused by E. cloacae, K. pneumoniae, and S. marcescens, whereas none of the dosing regimens tested seem adequate for P. aeruginosa, which more frequently exhibits high MICs > 1 mg/L.