Phage-first treatment results in subpopulation-driven collateral sensitivity to beta-lactams in an extensively drug-resistant Pseudomonas aeruginosa

作者：Claire Han, Karishma Patel, Hao-Ran Gao, Jacob T. Sanborn, Thomas D. Nguyen, Jack F. Klem, Brian M. Ho, Patrick O. Kenney, Ya-Nan Zhao, Troy D. Wood, Dwayne R. Roach, Liang Chen, Nicholas M. Smith · 发表于：Antimicrobial Agents and Chemotherapy · 年份：2026 · DOI：10.1128/aac.00048-26 · 研究领域：Medicine

ABSTRACT Nosocomial Pseudomonas aeruginosa infections are among the most challenging infections to treat, and resistance to last-line agents, including polymyxins and aztreonam-based therapies, risks a future with limited or no clinical treatment options. Bacteriophages (phages) have emerged as a promising therapeutic option, both in cocktails and when given in combination with antibiotics. In this study, we show that the synergy between a lipopolysaccharide (LPS)-specific phage and antibiotics is driven by clinically relevant increases in beta-lactam permeability due to the selection of phage-resistant subpopulations. First, in the Hollow Fiber Infection Model (HFIM), we show that the combination of phage LUZ19 (pili-targeted), phage E215 (LPS-specific), and aztreonam (ATM) eradicated the laboratory host PAO1, whereas monotherapy with neither phage nor ATM could eradicate PAO1. Static time-kill studies (STKS) evaluated the LPS-specific phage PYO2 in combination with either aztreonam/avibactam (ATM/AVI) or polymyxin B (PMB) against an extensively drug-resistant clinical isolate of P. aeruginosa (AR-0231). PYO2 combined with ATM/AVI was determined to be synergistic, with a mean excess-over-bliss (EOB) of 0.350 (P < 0.05), while PYO2 with PMB was also synergistic, with a mean EOB of 0.361 (P < 0.05). Linear regression of STKS using sequential administration showed that, compared to antibiotic-first treatment, phage-first treatment reduced bacterial concentrations at 24 h by −6....