Disposition and elimination of meropenem in cerebrospinal fluid of hydrocephalic patients with external ventriculostomy

The broad antibacterial spectrum and the low incidence of seizures in meropenem-treated patients qualifies meropenem for therapy of bacterial meningitis. The present study evaluates concentrations in ventricular cerebrospinal fluid (CSF) in the absence of pronounced meningeal inflammation. Patients with occlusive hydrocephalus caused by cerebrovascular diseases, who had undergone external ventriculostomy (n = 10, age range 48 to 75 years), received 2 g of meropenem intravenously over 30 min. Serum and CSF were drawn repeatedly and analyzed by liquid chromatography-mass spectroscopy. Pharmacokinetics were determined by noncompartmental analysis. Maximum concentrations in serum were 84.7 +/- 23.7 mu g/ml. A CSF maximum (C(maxCSF)) of 0.63 +/- 0.50 mu g/ml (mean +/- standard deviation) was observed 4.1 +/- 2.6 h after the end of the infusion. C(maxCSF) and the area under the curve for CSF (AUC(CSF)) depended on the AUC for serum (AUC(S)), the CSF-to-serum albumin ratio, and the CSF leukocyte count. Elimination from CSF was considerably slower than from serum (half-life at beta phase [t(1/2 beta)] of 7.36 +/- 2.89 h in CSF versus t(1/2 beta) of 1.69 +/- 0.60 h in serum). The AUC(CSF)/AUC(S) ratio for meropenem, as a measure of overall CSF penetration, was 0.047 +/- 0.022, The AUC(CSF)/AUC(S) ratio for meropenem was similar to that for other p-lactam antibiotics with a low binding to serum proteins. The concentration maxima of meropenem in ventricular CSF observed in this study are high enough to kill fully susceptible pathogens. They may not be sufficient to kill bacteria with a reduced sensitivity to carbapenems, although clinical success has been reported for patients with meningitis caused by penicillin-resistant pneumococci and Pseudomonas aeruginosa.