Abstract
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
Liverpool epidemic strain (LES) B58. Although minimum inhibitory concentrations
differed by up to eighty-fold between standard and host-mimicking media, combinatorial effects only marginally changed between conditions for some combinations. Effective combinations
were further tested in a chronic, high-density murine infection model. Colistin and azithromycin demonstrated combinatorial effects with ceftazidime and ceftazidime/avibactam both
and
. Conversely, while tobramycin and tigecycline exhibited strong synergy
, this effect was not observed
. 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.