title: Assessment of two penicillins plus beta-lactamase inhibitors versus cefotaxime in treatment of murine Klebsiella pneumoniae infections.
abstract: The in vivo efficacies of piperacillin, piperacillin plus tazobactam, ticarcillin, ticarcillin plus clavulanic acid, piperacillin plus clavulanic acid, and cefotaxime were compared in a mouse model of pneumonia induced by the SHV-1 beta-lactamase-producer Klebsiella pneumoniae. Each antibiotic was injected either once intraperitoneally at 24 h postinfection or at repeated times during 24 h. The efficacies of the drugs and therapeutic protocols were assessed by counting viable bacteria recovered from the lungs of mice sacrificed at selected times. No emergence of beta-lactam-resistant organisms was detected. Ticarcillin at 300 mg/kg was ineffective. Repeated injections of piperacillin at 300 mg/kg, either alone or in combination with tazobactam (8:1), led to a significant decrease in bacterial counts, but this was followed by bacterial regrowth. The pharmacokinetic analysis demonstrated that this short-lasting antibacterial effect was not due to a failure of piperacillin and/or tazobactam to penetrate the lungs. The combinations of ticarcillin at 300 mg/kg plus clavulanic acid (15:1) and piperacillin at 300 mg/kg plus tazobactam (4:1) were proven to be effective in that they decreased the bacterial burden in the lungs from 10(5) to < 10(3) CFU. This dose effect of tazobactam can be explained by its dose-dependent penetration in the lungs. Cefotaxime at 100 mg/kg and the combination of piperacillin (slightly hydrolyzed by SHV-1) at 300 mg/kg plus clavulanic acid (15:1) led to the best efficacy. Both of these treatments induced a decrease in bacterial counts of nearly 4 log10 units. The survival rates correlated with the quantitative measurements of in vivo bacterial killing. These experimental results obtained from the restricted animal model used here may help in the design of further protocols for clinical trials.
authors.affiliation: Service de Bactériologie-Virologie, Université Paris-Nord, France.
authors.forename: J L
authors.initials: JL
authors.lastname: Fournier
authors.forename: F
authors.initials: F
authors.lastname: Ramisse
authors.forename: A C
authors.initials: AC
authors.lastname: Jacolot
authors.forename: M
authors.initials: M
authors.lastname: Szatanik
authors.forename: O J
authors.initials: OJ
authors.lastname: Petitjean
authors.forename: J M
authors.initials: JM
authors.lastname: Alonso
authors.forename: M R
authors.initials: MR
authors.lastname: Scavizzi
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D002439:Cefotaxime / Q000627:therapeutic use*; D002511:Cephalosporins / Q000627:therapeutic use*; D019818:Clavulanic Acid; D002969:Clavulanic Acids / Q000008:administration & dosage; D015169:Colony Count, Microbial; D004338:Drug Combinations; D004359:Drug Therapy, Combination / Q000627:therapeutic use*; D005260:Female; D007710:Klebsiella Infections / Q000188:drug therapy* / Q000382:microbiology; D007711:Klebsiella pneumoniae / Q000187:drug effects; D008168:Lung / Q000382:microbiology; D051379:Mice; D008826:Microbial Sensitivity Tests; D010397:Penicillanic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D010406:Penicillins / Q000008:administration & dosage*; D010878:Piperacillin / Q000008:administration & dosage / Q000493:pharmacokinetics; D018410:Pneumonia, Bacterial / Q000188:drug therapy* / Q000382:microbiology; D000078142:Tazobactam; D013982:Ticarcillin / Q000008:administration & dosage; D065093:beta-Lactamase Inhibitors
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D002969:Clavulanic Acids; D004338:Drug Combinations; D010406:Penicillins; D065093:beta-Lactamase Inhibitors; D019818:Clavulanic Acid; D010397:Penicillanic Acid; D013982:Ticarcillin; D002439:Cefotaxime; D000078142:Tazobactam; D010878:Piperacillin