AUTHOR=Lyons Nikita , Wu Weihui , Jin Yongxin , Lamont Iain L. , Pletzer Daniel 

TITLE=Using host-mimicking conditions and a murine cutaneous abscess model to identify synergistic antibiotic combinations effective against Pseudomonas aeruginosa

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=14

YEAR=2024

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2024.1352339

DOI=10.3389/fcimb.2024.1352339

ISSN=2235-2988

ABSTRACT=<p>Antibiotic drug combination therapy is critical for the successful treatment of infections caused by multidrug resistant pathogens. We investigated the efficacy of β-lactam and β-lactam/β-lactamase inhibitor combinations with other antibiotics, against the hypervirulent, ceftazidime/avibactam resistant <italic>Pseudomonas aeruginosa</italic> Liverpool epidemic strain (LES) B58. Although minimum inhibitory concentrations <italic>in vitro</italic> differed by up to eighty-fold between standard and host-mimicking media, combinatorial effects only marginally changed between conditions for some combinations. Effective combinations <italic>in vitro</italic> were further tested in a chronic, high-density murine infection model. Colistin and azithromycin demonstrated combinatorial effects with ceftazidime and ceftazidime/avibactam both <italic>in vitro</italic> and <italic>in vivo</italic>. Conversely, while tobramycin and tigecycline exhibited strong synergy <italic>in vitro</italic>, this effect was not observed <italic>in vivo</italic>. Our approach of using host-mimicking conditions and a sophisticated animal model to evaluate drug synergy against bacterial pathogens represents a promising approach. This methodology may offer insights into the prediction of combination therapy outcomes and the identification of potential treatment failures.</p>