Bacterial Mixology: Combining Pharmacodynamic Models to Predict In Vitro Competition of MCR-1-Harboring .

The emergence of mobile colistin resistance ()-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 -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 strains (wildtype [WT] and -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 cells using a previously published mechanism-based model. The data showed that both selective pressure between WT and -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 -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 10 and 10 inoculum. These results indicate that at lower inoculums with a low proportion of -harboring cells, selective pressure from a pharmacokinetic-optimized regimen of polymyxin B still results in regrowth and selection of polymyxin-resistant cells.