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

Abstract

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.

Fig. 1

Flowchart of treatment options for infections caused by metallo-β-lactamase-producing Gram-negative bacteria. CRAB: carbapenem-resistant Acinetobacter baumannii; CRE: carbapenem-resistant Enterobacterales; HD: high doses; refers to the need to use loading doses of certain drugs and/or doses higher than those usually recommended by the technical sheet; MBL: metallo-β-lactamases. a Ideally the choice of treatment should be guided by appropriate susceptibility testing results. According to current trends of resistance to the novel β-lactams, this is particularly relevant in the case of ATM/AVI for NDM-producing Gram-negative bacilli and for all MBL–producing P. aeruginosa. b Aztreonam/avibactam, approved in April 2024, is not yet available for clinical use. Ceftazidime/avibactam plus aztreonam could be used as an alternative, although some limiting factors should be considered: (i) there is no evidence of clinical equivalence with aztreonam-avibactam, (ii) there is a risk of emergence of resistant mutants if dosing is not optimal, and (iii) there is a lack of standardized synergy testing methods. c Avibactam does not significantly contribute to increased aztreonam activity in aztreonam-resistant P. aeruginosa and is not usually an adequate option for PA-DTR. The CHMP positive opinion, highlights its utility in infections caused by MBL–producing Enterobacterales. d Combined: The combination could depend on the source of infection; recommended in hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP), bloodstream infections, cIAI and cUTI. The combined treatment option for colistin includes the possibility of its inhalation route through aerosol therapy in pneumonia, along with other systemic antibiotics. Combinations that increase nephrotoxicity or other adverse effects should be avoided." e Eravacycline is not yet (April 2024) available. f Combined with aminoglycosides in cUTI. g ATM/AVI is approved for the treatment of MBL–producing Enterobacterales and for the treatment of infections caused by aerobic Gram-negative organisms in adult patients with limited treatment options.