In Vivo Efficacy of Meropenem with a Novel Non-β-Lactam–β-Lactamase Inhibitor, Nacubactam, against Gram-Negative Organisms Exhibiting Various Resistance Mechanisms in a Murine Complicated Urinary Tract Infection Model
| Autor: | Caterina Bissantz, Sara Giovagnoli, Marguerite L. Monogue, David P. Nicolau, Claudia Zampaloni |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Pharmacology Gram-negative bacteria Klebsiella pneumoniae 030106 microbiology biochemical phenomena metabolism and nutrition Biology bacterial infections and mycoses Antimicrobial Ceftazidime/avibactam biology.organism_classification Enterobacteriaceae Meropenem Microbiology 03 medical and health sciences 030104 developmental biology Infectious Diseases In vivo polycyclic compounds medicine Experimental Therapeutics Pharmacology (medical) Enterobacter cloacae medicine.drug |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 62 |
| ISSN: | 1098-6596 0066-4804 |
| Popis: | Urinary tract infections (UTIs) are a tremendous burden on the health care system due to the vast number of infections resulting in antibiotic therapy and/or hospitalization. Additionally, these infections are frequently caused by multidrug-resistant (MDR) organisms, limiting the availability of effective antimicrobials. Nacubactam is a novel non-β-lactam-β-lactamase inhibitor with in vitro activity against class A and class C β-lactamases. Nacubactam is being developed in combination with meropenem, providing broad-spectrum activity in addition to improved stability against common β-lactamases. Here, we utilized a neutropenic murine complicated UTI (cUTI) model to determine the potential clinical utility of meropenem-nacubactam compared with meropenem or nacubactam alone against 10 Klebsiella pneumoniae, Escherichia coli, and Enterobacter cloacae isolates with diverse genotypic and phenotypic profiles, including NDM, KPC, OXA, CTX-M, SHV, and TEM enzyme-producing isolates. Selected isolates had meropenem-nacubactam MICs between 1 and 8 μg/ml. Meropenem-nacubactam demonstrated the greatest in vivo efficacy against 9 of 10 isolates, achieving a ≥3 log reduction from the 48-h control in all isolates tested, including isolates prepared as high inoculums. Nacubactam alone confirmed antibacterial properties, achieving a >1 log reduction against the majority of isolates. The combination of meropenem-nacubactam further enhanced the activity of either agent alone, notably against meropenem-resistant isolates. Against ceftazidime-avibactam-resistant isolates, meropenem-nacubactam demonstrated increased antibacterial kill upwards of 6 log(10) CFU in comparison to the 48-h control. Our data support the potential clinical utility of meropenem-nacubactam for cUTI in humans against MDR Enterobacteriaceae, although further clinical data supporting meropenem-nacubactam efficacy are needed. |
| Databáze: | OpenAIRE |
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