Abstract
Carbapenem resistance is a major global health problem that seriously compromises the treatment of infections caused by nosocomial pathogens. Resistance to carbapenems mainly occurs via the production of carbapenemases, such as VIM, IMP, NDM, KPC and OXA, among others. Preclinical and clinical trials are currently underway to test a new generation of promising inhibitors, together with the recently approved avibactam, relebactam and vaborbactam. This review summarizes the main, most promising carbapenemase inhibitors synthesized to date, as well as their spectrum of activity and current stage of development. We particularly focus on β-lactam/β-lactamase inhibitor combinations that could potentially be used to treat infections caused by carbapenemase-producer pathogens of critical priority. The emergence of these new combinations represents a step forward in the fight against antimicrobial resistance, especially in regard to metallo-β-lactamases and carbapenem-hydrolysing class D β-lactamases, not currently inhibited by any clinically approved inhibitor.
Highlights
Carbapenem resistance is a major global health problem that seriously compromises the treatment of infections caused by nosocomial pathogens
The KPC group is the most widely distributed worldwide and the constituents are predominantly found in Klebsiella pneumoniae, they have been identified in Enterobacter spp., Salmonella spp., P. aeruginosa and A. baumannii [8,9,10]; (ii) class B carbapenemases are usually found in pathogens such as P. aeruginosa, A. baumannii and Enterobacterales, and their prevalence has increased in recent years [8,11]
One of the main strategies used to restore the effectiveness of β-lactam antibiotics is to use β-lactamase inhibitors to prevent the antibiotic being hydrolyzed by the enzyme [20,21]
Summary
Efforts made in the last decade to develop new β-lactamase inhibitors able to protect β-lactams from the action of carbapenemases have led to the introduction in the clinical setting of three new, recently approved β-lactam/β-lactamase inhibitors: ceftazidime/avibactam, imipenem/relebactam and meropenem/vaborbactam. These three new combinations should be considered by clinicians as a real alternative treatment for infections caused by carbapenem-resistant pathogens, with demonstrated safety and efficacy.
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