Abstract
Pseudomonas aeruginosa frequently causes respiratory tract infections in immunocompromised patient lungs as well as bloodstream, urinary tract, skin and soft tissue infections. The increasing prevalence of multi-drug-resistant P. aeruginosa strains poses a significant clinical challenge. Cephalosporin antibiotics from the β-lactam class are commonly prescribed to treat infections due to their broad spectrum of activity and generally low host toxicity. However, P. aeruginosa utilises four classes of β-lactamase enzymes to break down cephalosporins, efflux pumps that expel antibiotics from the cell and mutations in outer membrane porins/transporters and target proteins, all of which confer resistance. This review categorizes resistance mechanism 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 towards inhibitors via the accumulation of mutations within the targeted β-lactamase enzyme or increased activity of efflux pumps, as covered herein. 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.