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 beta-lactamase inhibitor, in experimental meningitis due to a beta-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 less than 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.
Kern
W
W
Medical Service, San Francisco General Hospital, California.
Kennedy
S L
SL
Sachdeva
M
M
Sande
E R
ER
Gunderson
D
D
Täuber
M G
MG
D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology*; D004927:Escherichia coli Infections / Q000188:drug therapy* / Q000382:microbiology; D008581:Meningitis / Q000188:drug therapy*; D008826:Microbial Sensitivity Tests; D010397:Penicillanic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010878:Piperacillin / Q000008:administration & dosage / Q000627:therapeutic use*; D011817:Rabbits; D000078142:Tazobactam; D065093:beta-Lactamase Inhibitors
D000900:Anti-Bacterial Agents; D004338:Drug Combinations; D065093:beta-Lactamase Inhibitors; D010397:Penicillanic Acid; D000078142:Tazobactam; D010878:Piperacillin