Polymyxins retain in vitro activity and in vivo efficacy against "resistant" Acinetobacter baumannii strains when tested in physiological conditions

Antimicrob Agents Chemother. 2024 Oct 8;68(10):e0072524. doi: 10.1128/aac.00725-24. Epub 2024 Sep 6.

Abstract

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 in vivo treatment outcomes. We found that culturing putative colistin-resistant Acinetobacter baumannii 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 in vivo efficacy of a human-simulated dosing strategy of colistin and polymyxin B in a lethal murine infection model for some polymyxin-resistant A. baumannii strains. Thus, current polymyxin susceptibility testing methods overestimate the contribution of polymyxin resistance-conferring mutations and incorrectly predict antibiotic activity in vivo. Polymyxins may remain a viable therapeutic option against Acinetobacter baumannii strains heretofore determined to be "pan-resistant."

Keywords: Acinetobacter; antibiotic resistance; colistin; polymyxins.

MeSH terms

  • Acinetobacter Infections* / drug therapy
  • Acinetobacter Infections* / microbiology
  • Acinetobacter baumannii* / drug effects
  • Animals
  • Anti-Bacterial Agents* / pharmacology
  • Colistin* / pharmacology
  • Drug Resistance, Bacterial / genetics
  • Drug Resistance, Multiple, Bacterial / genetics
  • Humans
  • Mice
  • Microbial Sensitivity Tests*
  • Polymyxin B* / pharmacology
  • Polymyxins* / pharmacology

Substances

  • Anti-Bacterial Agents
  • Polymyxins
  • Colistin
  • Polymyxin B