Bacterial Mixology: Combining Pharmacodynamic Models to Predict In Vitro Competition of MCR-1-Harboring <i>E. coli</i>

• Published in: Antibiotics
• Main Authors: Nicholas M. Smith, Arthur Chan, Thomas D. Nguyen, Jacob T. Dumbleton
• Format: Article
• Language: English
• Published: MDPI AG 2021-12-01
• Subjects: <i>mcr</i>; antimicrobial resistance; Gram-negative bacteria; polymyxin resistance; <i>Escherichia coli</i>
• Online Access: https://www.mdpi.com/2079-6382/11/1/34

The emergence of mobile colistin resistance (<i>mcr</i>)-mediated polymyxin resistance has resulted in a significant detriment to the utility of the polymyxins in the clinical setting. Though the risk for horizontal transfer of an <i>mcr</i>-containing plasmid is a major component of the transmissibility, selection of polymyxin resistant subpopulations is still a major risk factor for developing polymyxin-resistant infections. Using static time-kills over 24 h (h), we performed competition studies by mixing known inocula of isogenic <i>Escherichia coli</i> strains (wildtype [WT] and <i>mcr-1</i>-harboring) and treating with a concentration array of polymyxin B. These results were then compared to a priori predictions of bacterial-killing effects by polymyxin B on a mixed population of <i>E. coli</i> cells using a previously published mechanism-based model. The data showed that both selective pressure between WT and <i>mcr-1</i>-harboring strains as well as underlying polymyxin B heteroresistance within each of the two strains contributed to bacterial regrowth despite treatment with high concentration polymyxin B. Moreover, the simulations showed that when <i>mcr-1</i>-harboring cells were 1% or 10% of the total population, regrowth by 24 h was still observed in ≥50% of the simulated subjects for both a 10⁶ and 10⁸ inoculum. These results indicate that at lower inoculums with a low proportion of <i>mcr-1</i>-harboring cells, selective pressure from a pharmacokinetic-optimized regimen of polymyxin B still results in regrowth and selection of polymyxin-resistant cells.