The Challenge of Treating Infections Caused by Metallo-β-Lactamase-Producing Gram-Negative Bacteria: A Narrative Review.

Gram-negative multidrug-resistant (MDR) bacteria, including Enterobacterales, Acinetobacter baumannii, and Pseudomonas aeruginosa, pose a significant challenge in clinical practice. Infections caused by metallo-β-lactamase (MBL)-producing Gram-negative organisms, in particular, require careful consideration due to their complexity and varied prevalence, given that the microbiological diagnosis of these pathogens is intricate and compounded by challenges in assessing the efficacy of anti-MBL antimicrobials. We discuss both established and new approaches in the treatment of MBL-producing Gram-negative infections, focusing on 3 strategies: colistin; the recently approved combination of aztreonam with avibactam (or with ceftazidime/avibactam); and cefiderocol. Despite its significant activity against various Gram-negative pathogens, the efficacy of colistin is limited by resistance mechanisms, while nephrotoxicity and acute renal injury call for careful dosing and monitoring in clinical practice. Aztreonam combined with avibactam (or with avibactam/ceftazidime if aztreonam plus avibactam is not available) exhibits potent activity against MBL-producing Gram-negative pathogens. Cefiderocol in monotherapy is effective against a wide range of multidrug-resistant organisms, including MBL producers, and favorable clinical outcomes have been observed in various clinical trials and case series. After examining scientific evidence in the management of infections caused by MBL-producing Gram-negative bacteria, we have developed a comprehensive clinical algorithm to guide therapeutic decision making. We recommend reserving colistin as a last-resort option for MDR Gram-negative infections. Cefiderocol and aztreonam/avibactam represent favorable options against MBL-producing pathogens. In the case of P. aeruginosa with MBL-producing enzymes and with difficult-to-treat resistance, cefiderocol is the preferred option. Further research is needed to optimize treatment strategies and minimize resistance.
Competing Interests: Declarations. Funding: The publication of this article was supported by Shionogi, Spain. Conflict of Interests: CH-T has conducted consulting work for Shionogi, Angellini, Advanz, ViiV, Gilead Sciences, Janssen, and Merck Sharp & Dohme. CH-T has received research grants from Gilead Sciences and ViiV, as well as financial compensation for presentations from Shionogi, Gilead Sciences, Janssen, Merck Sharp & Dohme, and ViiV Healthcare. LM-M has been a consultant for MSD, Shionogi and Advanz, has served as a speaker for MSD, Pfizer and Shionogi and has received research grants from Pfizer, MSD and Shionogi. MR-A has conducted consulting work for Shionogi and Viatris. MR-A has served as a speaker for Pfizer, Gilead Sciences and Shionogi. AO has received research grants and speakers fees from Shionogi, Pfizer and MSD. GB has been a consultant for Pfizer, Astellas, Roche, MSD, Shionogi and Advanz, has served as a speaker for MSD, Pfizer, Roche, Advanz and Shionogi and has received research grants from Pfizer, Advanz and MSD. MSL has received remuneration for lectures and advisory boards (Advanz Pharma, Angelini Pharma, Janssen, Menarini, MSD, Pfizer, Shionogi, Viatris) and educational grants (Gilead, Tedec-Meiji). Author Contributions: All authors have contributed to the conception of the work. All authors wrote the original draft and performed substantial contributions to the final manuscript. All authors reviewed and approved the final manuscript for submission. All authors agreed to be accountable for all aspects of the work. Ethics Approval, Informed Consent, and Data Availability: Not applicable for this review.
(© 2024. The Author(s).)