OXA-48-Like β-Lactamases: Global Epidemiology, Treatment Options, and Development Pipeline

Abstract

Modern medicine is threatened by the rising tide of antimicrobial resistance, especially among Gram-negative bacteria, where resistance to β-lactams is most often mediated by β-lactamases. The penicillin and cephalosporin ascendancies were, in their turn, ended by the proliferation of TEM penicillinases and CTX-M extended-spectrum β-lactamases. These class A β-lactamases have long been considered the most important. For carbapenems, however, the threat is increasingly from the insidious rise of a class D carbapenemase, OXA-48, and its close relatives. Over the past 20 years, OXA-48 and "OXA-48-like" enzymes have proliferated to become the most prevalent enterobacterial carbapenemases across much of Europe, Northern Africa, and the Middle East. OXA-48-like enzymes are notoriously difficult to detect because they often cause only low-level in vitro resistance to carbapenems, meaning that the true burden is likely underestimated. Despite this, they are associated with carbapenem treatment failures. A highly conserved incompatibility complex IncL plasmid scaffold often carries bla_OXA-48 and may carry other antimicrobial resistance genes, leaving limited treatment options. High conjugation efficiency means that this plasmid is sometimes carried by multiple Enterobacterales in a single patient. Producers evade most β-lactam-β-lactamase inhibitor combinations, though promising agents have recently been licensed, notably ceftazidime-avibactam and cefiderocol. The molecular machinery enabling global spread, current treatment options, and the development pipeline of potential new therapies for Enterobacterales that produce OXA-48-like β-lactamases form the focus of this review.

Keywords: OXA-48; OXA-48 β-lactamase; beta-lactamases; drug development; epidemiology; pharmacology; treatment.

FIG 1

MIC distribution of meropenem for Enterobacterales. MIC distributions of meropenem for Enterobacterales that were submitted to United Kingdom Health Security Agency (previously Public Health England) Antimicrobial Resistance and Healthcare Associated Infection Reference Unit from July 2015 to July 2016 are shown. (Reproduced from reference with permission of the Infectious Diseases Society of America.)

FIG 2

Global distribution of acquired OXA-48-like β-lactamases among Enterobacterales. (A) OXA-48; (B) prevalent OXA-48-like variants. Full-tone color is used to indicate where OXA-48-like enzymes are reported as the most prevalent carbapenemases in the country. Lighter-tone color is used to indicate countries where OXA-48-like enzymes are reported in outbreaks but where other carbapenemases (KPC or metalloenzymes) are more prevalent or the most prevalent carbapenemase is unclear.