A review of recently discovered mechanisms of cephalosporin resistance in Pseudomonas aeruginosa

Abstract

• Novel mutations are linked to cephalosporin resistance in Pseudomonas aeruginosa . • Efflux pumps and ß-lactamases drive multidrug resistance in P. aeruginosa . • Emerging resistance mechanisms to cefiderocol in P. aeruginosa . • ß-Lactamase inhibitors extend cephalosporin efficacy against resistant P. aeruginosa . • Understanding regulation and pathways crucial to tackling cephalosporin resistance. Pseudomonas aeruginosa frequently causes respiratory tract infections in immunocompromised patients as well as bloodstream, urinary tract, skin, and soft tissue infections. The increasing prevalence of multidrug-resistant P. aeruginosa strains poses a significant clinical challenge. Cephalosporin antibiotics from the β-lactam class are commonly prescribed to treat infections owing to their broad spectrum of activity and generally low host toxicity. P. aeruginosa utilizes β-lactamase enzymes, efflux pumps, and mutations in outer membrane porins/transporters and target proteins, all of which confer resistance to cephalosporin antibiotics. This review categorizes resistance mechanisms into (i) well-characterized pathways, such as AmpC β-lactamase and Mex efflux pumps, (ii) recently described mutations linked to cephalosporin resistance (e.g., ygfB, sltB1, pbp3, galU, pmrAB, fusA1 , and gyrA ), and (iii) hypothetical β-lactamases and other mechanisms requiring further validation. A variety of β-lactamase inhibitors have been developed to overcome β-lactamase-mediated resistance, but resistance has already been observed toward inhibitors via the accumulation of mutations within the targeted β-lactamase enzyme or increased activity of efflux pumps. Understanding the regulation and pathways that lead to resistance is crucial in developing effective strategies to combat P. aeruginosa infections and extending the therapeutic lifespan of cephalosporin antibiotics.

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