Evaluation of Ceftazidime and NXL104 in Two Murine Models of Infection Due to KPC-Producing Klebsiella pneumoniae

摘要: We evaluated the efficacy of NXL104, a novel β-lactamase inhibitor, in combination with ceftazidime (CAZ) two murine infection models (septicemia and thigh infection). chose KPC-producing Klebsiella pneumoniae strains (VA-361 VA-406) showing MICs CAZ ≥256 μg/ml. Septicemia was induced by intraperitoneal injection K. followed 30 min later single subcutaneous treatment alone or CAZ-NXL104 ratios 2:1, 4:1, 8:1, 16:1. In this model, median effective doses for 50% (ED(50)) animals versus VA-361 VA-406 were 1,578 709 mg/kg body weight, respectively. When combined NXL104 at 16:1 ratios, ED(50)s reduced to 8.1 3.5 mg/kg, 15.1 3.8 16.9 7.2 29.5 12.1 For infection, neutropenia cyclophosphamide days -4 -1 preinfection. Infection established intramuscular into right thigh. Mice treated 1.5 h postinfection either constant 4:1. thighs removed 24 postinfection, >2-log CFU reduction observed mice ≥128:32 mg/kg. contrast, ≥1,024 unable reduce numbers CFU. Despite resistance possessing complex background, proved be very due contemporary highly resistant isolates.