EVALUATION OF PIPERACILLIN-TAZOBACTAM IN EXPERIMENTAL MENINGITIS CAUSED BY A BETA-LACTAMASE-PRODUCING STRAIN OF K1-POSITIVE ESCHERICHIA-COLI

We evaluated the pharmacokinetics and therapeutic efficacy of piperacillin combined with tazobactam, a novel β-lactamase inhibitor, in experimental meningitis due to a β-lactamase-producing strain of K1-positive Escherichia coli. Different doses of piperacillin and tazobactam, as single agents and combined (8:1 ratio; dosage range, 40/5 to 200/25 mg/kg per h), and of ceftriaxone were given to experimentally infected rabbits by intravenous bolus injection followed by a 5-h constant infusion. The mean (± standard deviation) rates for penetration into the cerebrospinal fluid of infected animals after coadministration of both drugs were 16.6 ± 8.4% for piperacillin and 32.5 ± 12.6% for tazobactam. Compared with either agent alone, combination treatment resulted in significantly better bactericidal activity in the cerebrospinal fluid. The bactericidal activity of piperacillin-tazobactam was dose dependent: cerebrospinal fluid bacterial titers were reduced by 0.37 ± 0.19 log10 CFU/ml per h with the lowest dose versus 0.96 ± 0.25 log10 CFU/ml per h with the highest dose (P < 0.001). At the relatively high doses of 160/20 and 200/25 mg of piperacillin-tazobactam per kg per h, the bactericidal activity of the combination was comparable to that of 10 and 25 mg of ceftriaxone per kg per h, respectively.