Horcajada JP; Gales A; Isler B; Kaye KS; Kwa AL; Landersdorfer CB; Montero MM; Oliver A; Pogue JM; Shields RK; Villegas MV; Yahav D; Paterson DL

Abstract: Pseudomonas aeruginosa has a remarkable ability to develop resistance to antimicrobials in vivo, often leaving very limited therapeutic options and making treatment particularly challenging. In fact, P. aeruginosa infections with "difficult-to-treat resistance" are one of the most concerning contemporary bacterial infections. Many are hospital-acquired and frequently affect immunocompromised patients with high mortality risk. In the absence of head-to-head clinical trials, we have conducted a narrative review of the current therapeutic options for these infections, addressing five key management questions. Pubmed, Scopus, Web od Sicence and reference lists of key articles. Ceftolozane-tazobactam, ceftazidime-avibactam, imipenem-cilastatin-relebactam, and cefiderocol are newer options, but resistance and lack of relevant data from randomized clinical trials hamper knowledge of the best way to use them. Ceftolozane-tazobactam and ceftazidime-avibactam are initially preferred when susceptible because they enter the market first, and there is more published evidence about them. Ceftolozane-tazobactam is preferred in P. aeruginosa pneumonia instead of ceftazidime-avibactam. Both can be equally used in other P. aeruginosa infection types. Imipenem-relebactam and cefiderocol may retain susceptibility when there is resistance to ceftolozane-tazobactam and ceftazidime-avibactam, and when metallo-beta-lactamases are not present. However, there are no head-to-head comparative studies to support a preference for one over the other. In the presence of metallo-beta-lactamases, cefiderocol is the preferred agent. Other options in this situation are aztreonam-avibactam, ceftazidime-avibactam combined with aztreonam, and polymyxins combined with meropenem, but evidence is limited. In difficult-to-treat P. aeruginosa infections, combination therapy could be an option. However, despite demonstrations of in vitro synergy and of enhanced activity in hollow fibre or animal models, there is no clinical evidence to support using combination therapy in these infections, and it is not currently recommended as a general option. The role of older antibiotics such as fosfomycin, polymyxin B, or colistin is also reviewed. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases: 2025 doi: 10.1016/j.cmi.2025.08.018 https://pubmed.ncbi.nlm.nih.gov/40854462