Antimicrobial Properties and Combination for management of Pseudomonas aeruginosa with Difficult-to-Treat Resistance

Abstract

Pseudomonas aeruginosa is a highly adaptable pathogen recognized for its intrinsic resistance and ability to develop difficult-to-treat resistance (DTR) against multiple antibiotic classes, posing significant challenges in clinical management. This review focuses on the antimicrobial properties of fosfomycin, rifampicin, and azithromycin, and their potential in combination therapies to manage DTR P. aeruginosa infections. These agents, although not traditionally first-line treatments for P. aeruginosa, have demonstrated promising synergistic effects when used in combination, particularly against biofilm-associated infections. Fosfomycin, with its ability to inhibit bacterial cell wall synthesis, has shown activity against certain resistant P. aeruginosa strains, especially when combined with other agents to overcome efflux-mediated resistance. Rifampicin, an RNA polymerase inhibitor, has limited standalone efficacy against Gram-negative bacteria but exhibits synergistic effects in combination therapies, enhancing bacterial killing. Azithromycin, a macrolide, targets protein synthesis and demonstrates immunomodulatory and anti-biofilm properties, making it a valuable adjunct in treating chronic P. aeruginosa infections. This review also explores the mechanisms underpinning the synergistic interactions of these agents and their role in enhancing antibiotic penetration, disrupting biofilms, and reducing the bacterial load. In vitro and in vivo studies indicate that combinations of these drugs can effectively target DTR P. aeruginosa by exploiting complementary mechanisms of action and minimizing the development of resistance. Emphasizing the need for innovative therapeutic strategies, this review highlights the clinical potential of fosfomycin, rifampicin, and azithromycin as part of combination regimens. By addressing the challenges posed by DTR P. aeruginosa, this article aims to provide insights into optimizing treatment approaches for one of the most challenging pathogens in modern healthcare.