DIFFERENT RATIOS OF THE PIPERACILLIN-TAZOBACTAM COMBINATION FOR TREATMENT OF EXPERIMENTAL MENINGITIS DUE TO KLEBSIELLA-PNEUMONIAE PRODUCINGTHE TEM-3 EXTENDED-SPECTRUM BETA-LACTAMASE

We evaluated the pharmacokinetics and therapeutic efficacies of pipera cillin and tazobactam, a beta-lactamase inhibitor, given either alone or in different combinations (80:10, 200:10, and 80:25 mg/kg/h), in ex perimental meningitis due to a strain of Klebsiella pneumoniae produci ng the TEM-3 extended-spectrum beta-lactamase, Treatment was administe red intravenously as a 7-h constant infusion preceded by a bolus of 20 % of the total dose. The mean (+/- standard deviation) rates of penetr ation into the cerebrospinal fluid (CSF) of infected animals were 6.7 +/- 3.9% for piperacillin given alone and 36.3 +/- 21.9% for tazobacta m given alone. Combination treatment significantly magnified the conce ntration of either drug in CSF. Concentrations of bacteria in CSF incr eased throughout therapy in animals given either drug alone, even at h igh dosages. In animals given the combination at dosages of 80:10 and 200/10 mg/kg/h, only a suboptimal reduction of CSF bacterial titers wa s obtained in vivo, i.e. - 0.49 +/- 0.34 and - 0.73 +/- 0.49 log CFU/m l/h, respectively. An increase in the tazobactam dosage within the com bination (80:25 mg/kg/h) was required in order to obtain a significant ly faster elimination of viable organisms from the CSF (- 0.97 +/- 0.3 5 log CFU/ml/h). The study shows that tazobactam is able to provide ef fective protection against piperacillin hydrolysis by the TEM-3 enzyme within the CSF. Appropriate dosage regimens of various beta-lactam-ta zobactam combinations may deserve comparative studies in experimental meningitis caused by organisms producing extended-spectrum beta-lactam ases.