In vitro activity of the new -lactamase inhibitors relebactam and vaborbactam in combination with -lactams against mycobacterium abscessus complex clinical isolates

Amit Kaushik, Nicole Ammerman, Jin Lee, Olumide Martins, Barry N. Kreiswirth, Gyanu Lamichhane, Nicole M Parrish, Eric Nuermberger

Research output: Contribution to journalArticle

Abstract

Pulmonary disease due to infection with Mycobacterium abscessus complex (MABC) is notoriously difficult to treat, in large part due to the intrinsic resistance of MABC strains to most antibiotics, including -lactams. MABC organisms express a broad-spectrum -lactamase that is resistant to traditional -lactam-based -lactamase inhibitors but inhibited by a newer non-lactam-based -lactamase inhibitor, avibactam. Consequently, the susceptibility of MABC members to some -lactams is increased in the presence of avibactam. Therefore, we hypothesized that two new non-lactam-based -lactamase inhibitors, relebactam and vaborbactam, would also increase the susceptibility of MABC organisms to -lactams. The objective of the present study was to evaluate the in vitro activity of various marketed -lactams alone and in combination with either relebactam or vaborbactam against multidrug-resistant MABC clinical isolates. Our data demonstrate that both -lactamase inhibitors significantly improved the anti-MABC activity of many carbapenems (including imipenem and meropenem) and cephalosporins (including cefepime, ceftaroline, and cefuroxime). As a meropenem-vaborbactam combination is now marketed and an imipenem-relebactam combination is currently in phase III trials, these fixed combinations may become the -lactams of choice for the treatment of MABC infections. Furthermore, given the evolving interest in dual -lactam regimens, our results identify select cephalosporins, such as cefuroxime, with superior activity in the presence of a -lactamase inhibitor that are deserving of further evaluation in combination with these carbapenem–-lactamase inhibitor products.

Original languageEnglish (US)
Article numbere02623-18
JournalAntimicrobial agents and chemotherapy
DOIs
StatePublished - Mar 1 2019

Fingerprint

Lactams
Mycobacterium
meropenem
Cefuroxime
Carbapenems
Imipenem
Cephalosporins
Mycobacterium Infections
MK-7655
In Vitro Techniques
Lung Diseases
Anti-Bacterial Agents
Infection

Keywords

  • Carbapenems
  • Cephalosporins
  • Lactamase inhibitors
  • Lactams
  • Mycobacterium abscessus
  • Relebactam
  • Vaborbactam

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

@article{0a6a6c4a3a434e1397e926b9ecaff80a,
title = "In vitro activity of the new -lactamase inhibitors relebactam and vaborbactam in combination with -lactams against mycobacterium abscessus complex clinical isolates",
abstract = "Pulmonary disease due to infection with Mycobacterium abscessus complex (MABC) is notoriously difficult to treat, in large part due to the intrinsic resistance of MABC strains to most antibiotics, including -lactams. MABC organisms express a broad-spectrum -lactamase that is resistant to traditional -lactam-based -lactamase inhibitors but inhibited by a newer non-lactam-based -lactamase inhibitor, avibactam. Consequently, the susceptibility of MABC members to some -lactams is increased in the presence of avibactam. Therefore, we hypothesized that two new non-lactam-based -lactamase inhibitors, relebactam and vaborbactam, would also increase the susceptibility of MABC organisms to -lactams. The objective of the present study was to evaluate the in vitro activity of various marketed -lactams alone and in combination with either relebactam or vaborbactam against multidrug-resistant MABC clinical isolates. Our data demonstrate that both -lactamase inhibitors significantly improved the anti-MABC activity of many carbapenems (including imipenem and meropenem) and cephalosporins (including cefepime, ceftaroline, and cefuroxime). As a meropenem-vaborbactam combination is now marketed and an imipenem-relebactam combination is currently in phase III trials, these fixed combinations may become the -lactams of choice for the treatment of MABC infections. Furthermore, given the evolving interest in dual -lactam regimens, our results identify select cephalosporins, such as cefuroxime, with superior activity in the presence of a -lactamase inhibitor that are deserving of further evaluation in combination with these carbapenem–-lactamase inhibitor products.",
keywords = "Carbapenems, Cephalosporins, Lactamase inhibitors, Lactams, Mycobacterium abscessus, Relebactam, Vaborbactam",
author = "Amit Kaushik and Nicole Ammerman and Jin Lee and Olumide Martins and Kreiswirth, {Barry N.} and Gyanu Lamichhane and Parrish, {Nicole M} and Eric Nuermberger",
year = "2019",
month = "3",
day = "1",
doi = "10.1128/AAC.02623-18",
language = "English (US)",
journal = "Antimicrobial Agents and Chemotherapy",
issn = "0066-4804",
publisher = "American Society for Microbiology",

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T1 - In vitro activity of the new -lactamase inhibitors relebactam and vaborbactam in combination with -lactams against mycobacterium abscessus complex clinical isolates

AU - Kaushik, Amit

AU - Ammerman, Nicole

AU - Lee, Jin

AU - Martins, Olumide

AU - Kreiswirth, Barry N.

AU - Lamichhane, Gyanu

AU - Parrish, Nicole M

AU - Nuermberger, Eric

PY - 2019/3/1

Y1 - 2019/3/1

N2 - Pulmonary disease due to infection with Mycobacterium abscessus complex (MABC) is notoriously difficult to treat, in large part due to the intrinsic resistance of MABC strains to most antibiotics, including -lactams. MABC organisms express a broad-spectrum -lactamase that is resistant to traditional -lactam-based -lactamase inhibitors but inhibited by a newer non-lactam-based -lactamase inhibitor, avibactam. Consequently, the susceptibility of MABC members to some -lactams is increased in the presence of avibactam. Therefore, we hypothesized that two new non-lactam-based -lactamase inhibitors, relebactam and vaborbactam, would also increase the susceptibility of MABC organisms to -lactams. The objective of the present study was to evaluate the in vitro activity of various marketed -lactams alone and in combination with either relebactam or vaborbactam against multidrug-resistant MABC clinical isolates. Our data demonstrate that both -lactamase inhibitors significantly improved the anti-MABC activity of many carbapenems (including imipenem and meropenem) and cephalosporins (including cefepime, ceftaroline, and cefuroxime). As a meropenem-vaborbactam combination is now marketed and an imipenem-relebactam combination is currently in phase III trials, these fixed combinations may become the -lactams of choice for the treatment of MABC infections. Furthermore, given the evolving interest in dual -lactam regimens, our results identify select cephalosporins, such as cefuroxime, with superior activity in the presence of a -lactamase inhibitor that are deserving of further evaluation in combination with these carbapenem–-lactamase inhibitor products.

AB - Pulmonary disease due to infection with Mycobacterium abscessus complex (MABC) is notoriously difficult to treat, in large part due to the intrinsic resistance of MABC strains to most antibiotics, including -lactams. MABC organisms express a broad-spectrum -lactamase that is resistant to traditional -lactam-based -lactamase inhibitors but inhibited by a newer non-lactam-based -lactamase inhibitor, avibactam. Consequently, the susceptibility of MABC members to some -lactams is increased in the presence of avibactam. Therefore, we hypothesized that two new non-lactam-based -lactamase inhibitors, relebactam and vaborbactam, would also increase the susceptibility of MABC organisms to -lactams. The objective of the present study was to evaluate the in vitro activity of various marketed -lactams alone and in combination with either relebactam or vaborbactam against multidrug-resistant MABC clinical isolates. Our data demonstrate that both -lactamase inhibitors significantly improved the anti-MABC activity of many carbapenems (including imipenem and meropenem) and cephalosporins (including cefepime, ceftaroline, and cefuroxime). As a meropenem-vaborbactam combination is now marketed and an imipenem-relebactam combination is currently in phase III trials, these fixed combinations may become the -lactams of choice for the treatment of MABC infections. Furthermore, given the evolving interest in dual -lactam regimens, our results identify select cephalosporins, such as cefuroxime, with superior activity in the presence of a -lactamase inhibitor that are deserving of further evaluation in combination with these carbapenem–-lactamase inhibitor products.

KW - Carbapenems

KW - Cephalosporins

KW - Lactamase inhibitors

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KW - Mycobacterium abscessus

KW - Relebactam

KW - Vaborbactam

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