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

Marguerite L. Monogue, Sara Giovagnoli, Caterina Bissantz, Claudia Zampaloni, David P. Nicolau

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numbere02596-17
JournalAntimicrobial Agents and Chemotherapy
Volume62
Issue number9
DOIs
StatePublished - Sep 2018
Externally publishedYes

Fingerprint

meropenem
Lactams
Urinary Tract Infections
Enterobacter cloacae

Keywords

  • Ceftazidime-avibactam
  • Gram-negative bacteria
  • Meropenem
  • Meropenem-nacubactam
  • Nacubactam
  • RG6080
  • Urinary tract infection

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

@article{7cf672de8a6b4654a519299b8b37d724,
title = "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",
abstract = "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.",
keywords = "Ceftazidime-avibactam, Gram-negative bacteria, Meropenem, Meropenem-nacubactam, Nacubactam, RG6080, Urinary tract infection",
author = "Monogue, {Marguerite L.} and Sara Giovagnoli and Caterina Bissantz and Claudia Zampaloni and Nicolau, {David P.}",
year = "2018",
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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.

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.

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KW - Nacubactam

KW - RG6080

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