期刊
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
卷 55, 期 1, 页码 82-85出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.01198-10
关键词
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资金
- National Institutes of Health [RO1 AI063517]
- Veterans Affairs Merit Review Program
- Geriatric Research Education and Clinical Center [VISN 10]
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI063517] Funding Source: NIH RePORTER
We evaluated the efficacy of NXL104, a novel beta-lactamase inhibitor, in combination with ceftazidime (CAZ) in two murine infection models (septicemia and thigh infection). We chose two KPC-producing Klebsiella pneumoniae strains (VA-361 and VA-406) showing MICs of CAZ of >= 256 mu g/ml. Septicemia was induced by the intraperitoneal injection of KPC-producing K. pneumoniae followed 30 min later by a single subcutaneous treatment with CAZ alone or CAZ-NXL104 in ratios of 2:1, 4:1, 8:1, and 16:1. In this model, the median effective doses for 50% (ED50) of the animals for CAZ alone versus VA-361 and VA-406 were 1,578 and 709 mg/kg of body weight, respectively. When combined with NXL104 at 2:1, 4:1, 8:1, and 16:1 ratios, the CAZ ED(50)s for VA-361 and VA-406 were reduced to 8.1 and 3.5 mg/kg, 15.1 and 3.8 mg/kg, 16.9 and 7.2 mg/kg, and 29.5 and 12.1 mg/kg, respectively. For thigh infection, neutropenia was induced by the intraperitoneal injection of cyclophosphamide at days -4 and -1 preinfection. Infection was established by the intramuscular injection of KPC-producing K. pneumoniae into the right thigh. Mice were treated 1.5 h postinfection with either CAZ alone or CAZ-NXL104 at constant ratios of 4:1. When thighs were removed at 24 h postinfection, a >2-log CFU reduction was observed for mice treated with CAZ-NXL104 at doses of >= 128:32 mg/kg. In contrast, CAZ doses of >= 1,024 mg/kg were unable to reduce the numbers of CFU. Despite resistance to CAZ and possessing a complex beta-lactamase background, NXL104 combined with CAZ proved to be very effective in murine models of infection due to contemporary highly resistant KPC-producing K. pneumoniae isolates.
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