The latest advances in β-lactam/β-lactamase inhibitor combinations for the treatment of Gram-negative bacterial infections

ABSTRACT

Introduction: Antimicrobial resistance in Gram-negative pathogens is a significant threat to global health. β-Lactams (BL) are one of the safest and most-prescribed classes of antibiotics on the market today. The acquisition of β-lactamases, especially those which hydrolyze carbapenems, is eroding the efficacy of BLs for the treatment of serious infections. During the past decade, significant advances were made in the development of novel BL-β-lactamase inhibitor (BLI) combinations to target β-lactamase-mediated resistant Gram-negatives.

Areas covered: The latest progress in 20 different approved, developing, and preclinical BL-BLI combinations to target serine β-lactamases produced by Gram-negatives are reviewed based on primary literature, conference abstracts (when available), and US clinical trial searches within the last 5 years. The majority of the compounds that are discussed are being evaluated as part of a BL-BLI combination.

Expert opinion: The current trajectory in BLI development is promising; however, a significant challenge resides in the selection of an appropriate BL partner as well as the development of resistance linked to the BL partner. In addition, dosing regimens for these BL-BLI combinations need to be critically evaluated. A revolution in bacterial diagnostics is essential to aid clinicians in the appropriate selection of novel BL-BLI combinations for the treatment of serious infections.

KEYWORDS:

• Antimicrobial resistance
• β-lactam
• β-lactamase
• β-lactamase inhibitor
• Gram-negative

Article highlights

• The development of novel BL-BLI combinations has escalated over the last decade.

• The spectrum of activity for 20 different novel BL-BLI combinations, including in vitro and in vivo studies, are presented; in addition, potential resistance mechanisms are described.

• The boronic acid- and diazabicyclooctane-based BLI scaffolds are likely the most outstanding advances in the field.

• The pursuit of novel ‘oral-stepdown’ BL-BLI combinations is fundamental necessity in the antibiotic arsenal.

• The greatest limitations in BL-BLI development are the selection of the BL partner, appropriate dosing strategies to obtain clinical cure, as well as rapid bacterial diagnostics to pinpoint the most suitable therapies.

This box summarizes key points contained in the article.

Declaration of interest

The author of this manuscript has or has had in the past two years research collaborations with Allecra, Entasis, Merck, VenatoRx, Wockhardt, Roche and Allergan. She has 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

One referee is an employee of JMI Laboratories. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

The author’s lab is supported in part by funds and/or facilities provided by the Cleveland Department of Veterans Affairs, the Veterans Affairs Merit Review Program BX002872 to KMP-W from the United States (U.S.) Department of Veterans Affairs Biomedical Laboratory Research and Development Service. The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.