2011
DOI: 10.1128/aac.01198-10
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Evaluation of Ceftazidime and NXL104 in Two Murine Models of Infection Due to KPC-Producing Klebsiella pneumoniae

Abstract: We evaluated the efficacy of NXL104, a novel ␤-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 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 med… Show more

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Cited by 76 publications
(59 citation statements)
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“…Therefore, the antibodies were tested in an acutely lethal K. pneumoniae pneumonia model, with a very narrow therapeutic window for successful treatment. mAbs were delivered either 24 hours prior to bacterial challenge or 1 hour after bacterial challenge, a time by which we expected LPS to have activated the TLR4 pathway, which is not so late that even standard-ofcare antibiotics cannot rescue the animals (16,17). Administration of the nonneutralizing mAb KPE33 24 hours prior to infection significantly increased survival as compared with prophylaxis with either 54H7 (P < 0.0001) or control IgG (c-IgG) (P < 0.0001), while both KPE33 and 54H7 protected to a similar degree when delivered 1 hour after infection ( Figure 1, B and D).…”
Section: Resultsmentioning
confidence: 99%
“…Therefore, the antibodies were tested in an acutely lethal K. pneumoniae pneumonia model, with a very narrow therapeutic window for successful treatment. mAbs were delivered either 24 hours prior to bacterial challenge or 1 hour after bacterial challenge, a time by which we expected LPS to have activated the TLR4 pathway, which is not so late that even standard-ofcare antibiotics cannot rescue the animals (16,17). Administration of the nonneutralizing mAb KPE33 24 hours prior to infection significantly increased survival as compared with prophylaxis with either 54H7 (P < 0.0001) or control IgG (c-IgG) (P < 0.0001), while both KPE33 and 54H7 protected to a similar degree when delivered 1 hour after infection ( Figure 1, B and D).…”
Section: Resultsmentioning
confidence: 99%
“…Avibactam, combined with ceftaroline or ceftazidime, has shown efficacy in preclinical animal models and also in phase II clinical trials of patients with Gram-negative infections (35)(36)(37)(38). The increased understanding of the mechanism of avibactam inhibition described in the present work may provide insight into the PK-PD relationship for β-lactam/avibactam combination therapies.…”
Section: Discussionmentioning
confidence: 99%
“…Although weakly inhibited by beta-lactamase inhibitors in vitro, the current Food and Drug Administration (FDA)-approved beta-lactambeta-lactamase inhibitor (BLBLI) combinations are not considered to be clinically effective against carbapenemase-producing organisms. 2 However, avibactam, a novel BLI, has broader inhibitory activity, and the combination agent ceftazidime/avibactam, the newest BLBLI, is promising against oxacillin-hydrolyzing (OXA-48) carbapenemases and Klebsiella pneumoniae carbapenemases (KPCs), [9][10][11] which are the most prevalent carbapenemases in North America and will be the primary subject of this article. Although all carbapenemases have the capacity to hydrolyze carbapenems, the rate and extent of hydrolysis vary, resulting in a range of susceptibilities from a fully susceptible to a highly resistant isolate.…”
Section: Microbiology and Epidemiologymentioning
confidence: 99%