Reviewing novel treatment options for carbapenem-resistant Enterobacterales

ABSTRACT

Introduction

Carbapenem resistant Enterobacterales (CRE) are a major threat to global health and hospital-onset CRE infections have risen during the COVID-19 pandemic. Novel antimicrobials are now available for the treatment of CRE infections. There remains an urgent need for new antimicrobials for CRE, especially for those producing metallo-β-lactamases.

Areas covered

This article discusses previously published research supporting currently available novel antimicrobials for the treatment of CRE infections. Newer compounds currently being evaluated in clinical trials are covered. A literature search was conducted in PubMed over all available dates for relevant published papers and conference abstracts with the search terms, ‘CRE,’ ‘carbapenem-resistant Enterobacterales,’ ‘β-lactam-β-lactamase inhibitor,’ ‘KPC,’ ‘NDM,’ ‘metallo-β-lactamase,’ ‘ceftazidime-avibactam,’ ‘meropenem-vaborbactam,’ ‘imipenem-cilastatin-relebactam,’ ‘cefiderocol,’ ‘eravacycline,’ ‘plazomicin,’ ‘taniborbactam,’ ‘zidebactam,’ and ‘nacubactam.’

Expert opinion

Novel antimicrobials for CRE infections have been developed, most notably the β-lactam-β-lactamase inhibitor combinations, though treatment options for infections with metallo-β-lactamase producing Enterobacterales remain few and have limitations. Development of antibiotics with activity against metallo-β-lactamase producing Enterobacterales is eagerly awaited, and there are promising new compounds in clinical trials. Finally, more clinical research is needed to optimize and individualize treatment approaches, which will help guide antimicrobial stewardship initiatives aimed at reducing the spread of CRE and development of further resistance.

KEYWORDS:

• Antimicrobial resistance
• AMR
• β-lactam-β-lactamase inhibitor
• CRE
• carbapenem-resistant Enterobacterales

Article highlights

• Ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-cilastatin-relebactam are the currently available, preferred empirical agents for treating CRE infections outside the urinary tract system in geographic areas with low prevalence of metallo-β-lactamase-production, when susceptibility testing results are not yet available (2023 Infectious Diseases Society of America guidance) (Table 1).

• Meropenem-vaborbactam is slightly favored over ceftazidime-avibactam for KPC-producing CRE infections.

• Ceftazidime-avibactam is the only β-lactam-β-lactamase inhibitor active against OXA-48-like producing CRE.

• There are no European Society of Clinical Microbiology and Infectious Diseases (ECSMID) recommendations for the use of imipenem-cilastatin-relebactam for CRE infections due to insufficient clinical data.

• Ceftazidime-avibactam plus aztreonam or cefiderocol are options for treatment of metallo-β-lactamase producing isolates and preferred empiric CRE treatment when susceptibility testing is pending and the prevalence of metallo-β-lactamase is high.

• Eravacycline may be an alternative treatment option for CRE infections regardless of the presence or type of carbapenemase, though should not be used for bloodstream or urinary tract infections due to rapid tissue uptake.

• Due to a difference in structure, plazomicin may have more activity against carbapenem-resistant and ESBL-producing enterobacterales compared with other aminoglycosides and may be used for infections of the urinary tract including acute pyelonephritis, if risk for nephrotoxicity is considered acceptable. However, this drug is not readily available.

• The novel compounds taniborbactam, zidebactam, and nacubactam as well as the combination of aztreonam-avibactam, are promising in combination with other β-lactams and are currently being evaluated in phase 3 clinical trials (Table 2). However, resistance has already been reported to some of these agents.

• There is an urgent need for drug development to address the global health threat of CRE.

Declaration of interest

David van Duin reports grants and contracts from the NIH, Merck, and Shinogi, paid to his institution, outside of the published work; consultancy for Actavis, Tetraphase. Sanofi-Pasteur. MedImmune, Astellas, Merck, Allergan, T2Biosystems, Roche, Achaogen, Neumedicine, Shionogi, Pfizer, Entasis, Qpex, Wellspring, Karius, and Utility paid directly to him; honoraria from Pfizer; and an editor’s stipend from the British Society for Antimicrobial Chemotherapy (BSAC).

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

Natalie A. Mackow was supported by an Antibacterial Resistance Leadership Group fellowship [National Institute of Allergy and Infectious Diseases UM1AI104681]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.