Journal
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY
Volume 77, Issue 2, Pages 443-447Publisher
OXFORD UNIV PRESS
DOI: 10.1093/jac/dkab405
Keywords
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Funding
- Venatorx Pharmaceuticals, Inc. (Malvern, PA, USA)
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272201300019C]
- Wellcome Trust [360G-Wellcome-101999/Z/13/Z]
- Biomedical Advanced Research and Development Authority, Office of the Assistant Secretary for Preparedness and Response, Department of Health and Human Services [HHSO100201900007C]
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This study evaluated the efficacy of cefepime alone and the combination cefepime/taniborbactam in a neutropenic murine complicated urinary tract infection (cUTI) model. The results showed that cefepime/taniborbactam exhibited substantial killing of different types of bacteria with beta-lactamases, indicating its potential role in treating cUTI.
Objectives Complicated urinary tract infections (cUTIs) are frequently encountered in hospitals and ICUs. Increasingly, the causative pathogens harbour enzymatic resistance mechanisms. Taniborbactam is a novel beta-lactamase inhibitor with activity against Ambler class A, B, C and D beta-lactamases. Herein, we assessed the efficacy of cefepime alone and the combination cefepime/taniborbactam in a neutropenic murine cUTI model. Methods Eighteen cefepime-resistant clinical isolates (9 Enterobacterales, 3 Pseudomonas aeruginosa and 6 Stenotrophomonas maltophilia; cefepime MIC = 32 to >512 mg/L) were assessed. Cefepime/taniborbactam MICs ranged from 0.06 to 128 mg/L. Human-simulated plasma regimens (HSRs) of cefepime alone and in combination with taniborbactam were developed in the murine cUTI model. The efficacy of cefepime HSR and cefepime/taniborbactam HSR was determined as the change in log(10) cfu/kidney at 48 h compared with 48 h controls. Results Mean +/- SD initial bacterial burden was 5.66 +/- 0.56 log(10) cfu/kidney, which increased to 9.05 +/- 0.39 log(10) cfu/kidney at 48 h. The cefepime HSR was ineffective, as bacterial burden was similar to untreated controls (-0.14 +/- 0.40 change in log(10) cfu/kidney). In contrast, cefepime/taniborbactam exhibited substantial killing, with log(10) cfu/kidney changes of -5.48 +/- 1.3, -4.79 +/- 0.3 and -5.04 +/- 0.7 for ESBL/AmpC-, KPC- and OXA-48-harbouring Enterobacterales, respectively. Cefepime/taniborbactam also exhibited robust killing of P. aeruginosa (-6.5 +/- 0.26) and S. maltophilia (-5.66 +/- 0.71). Conclusions Humanized exposures of cefepime/taniborbactam achieved robust killing of Enterobacterales, P. aeruginosa and S. maltophilia harbouring ESBL, AmpC, KPC and/or OXA-48. These data support the role of cefepime/taniborbactam for cUTI treatment for cefepime/taniborbactam MICs up to 32 mg/L.
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