TY - JOUR
T1 - In vivo efficacy of meropenem with a novel non--lactam–-lactamase inhibitor, nacubactam, against gram-negative organisms exhibiting various resistance mechanisms in a murine complicated urinary tract infection model
AU - Monogue, Marguerite L.
AU - Giovagnoli, Sara
AU - Bissantz, Caterina
AU - Zampaloni, Claudia
AU - Nicolau, David P.
N1 - Funding Information:
This study was conducted using funding from F. Hoffmann-La Roche (Basel, Switzerland). D.P.N. has received research funding from F. Hoffmann-La Roche (Basel, Switzerland). C.B. and C.Z. are employees of F. Hoffmann-La Roche (Basel, Switzerland). This project has been funded in whole or in part with federal funds from the Department of Health and Human Services, the Office of the Assistant Secretary for Preparedness and Response, the Biomedical Advanced Research and Development Authority, under OT number HHS0100201600038C. The rest of us have no conflicts of interest to disclose.
Funding Information:
We thank Jennifer Tabor-Rennie, Debora Santini, Elizabeth Cyr, Christina Sutherland, Kimelyn Greenwood, Sean Stainton, Safa Abuhussain, Kamilia Abdelraouf, and Morde-chai Grupper from the Center for Anti-Infective Research and Development, Hartford, CT, for their assistance in conducting the study. This study was conducted using funding from F. Hoffmann-La Roche (Basel, Switzerland). D.P.N. has received research funding from F. Hoffmann-La Roche (Basel, Switzerland). C.B. and C.Z. are employees of F. Hoffmann-La Roche (Basel, Switzerland). This project has been funded in whole or in part with federal funds from the Department of Health and Human Services, the Office of the Assistant Secretary for Preparedness and Response, the Biomedical Advanced Research and Development Authority, under OT number HHS0100201600038C. The rest of us have no conflicts of interest to disclose.
Publisher Copyright:
Copyright © 2018 American Society for Microbiology. All Rights Reserved.
PY - 2018/9
Y1 - 2018/9
N2 - 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--lactam--lactamase inhibitor with in vitro activity against class A and class C -lactamases. Nacubactam is being developed in combination with meropenem, providing broad-spectrum activity in addition to improved stability against common -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 g/ 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.
AB - 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--lactam--lactamase inhibitor with in vitro activity against class A and class C -lactamases. Nacubactam is being developed in combination with meropenem, providing broad-spectrum activity in addition to improved stability against common -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 g/ 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.
KW - Ceftazidime-avibactam
KW - Gram-negative bacteria
KW - Meropenem
KW - Meropenem-nacubactam
KW - Nacubactam
KW - RG6080
KW - Urinary tract infection
UR - http://www.scopus.com/inward/record.url?scp=85052238832&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85052238832&partnerID=8YFLogxK
U2 - 10.1128/AAC.02596-17
DO - 10.1128/AAC.02596-17
M3 - Article
C2 - 30012751
AN - SCOPUS:85052238832
SN - 0066-4804
VL - 62
JO - Antimicrobial agents and chemotherapy
JF - Antimicrobial agents and chemotherapy
IS - 9
M1 - e02596-17
ER -