Polymyxins retain <i>in vitro</i> activity and <i>in vivo</i> efficacy against “resistant” <i>Acinetobacter baumannii</i> strains when tested in physiological conditions

The emergence of plasmid-mediated resistance threatens the efficacy of polymyxins as the last line of defense against pan-drug-resistant infections. However, we have found that using Mueller-Hinton II (MHII), the standard minimum inhibitory concentration (MIC) medium, results in MIC data that are disconnected from <i>in vivo</i> treatment outcomes. We found that culturing putative colistin-resistant <i>Acinetobacter baumannii</i> clinical isolates, as defined by MICs of >2 mg/L in standard MHII testing conditions, in bicarbonate-containing media reduced MICs to the susceptible range by preventing colistin resistance-conferring lipopolysaccharide modifications from occurring. Furthermore, the lower MICs in bicarbonate-containing media accurately predicted <i>in vivo</i> efficacy of a human-simulated dosing strategy of colistin and polymyxin B in a lethal murine infection model for some polymyxin-resistant <i>A. baumannii</i> strains. Thus, current polymyxin susceptibility testing methods overestimate the contribution of polymyxin resistance-conferring mutations and incorrectly predict antibiotic activity <i>in vivo</i>. Polymyxins may remain a viable therapeutic option against <i>Acinetobacter baumannii</i> strains heretofore determined to be "pan-resistant."