Quantitative pharmacodynamic characterization of resistance vs. heteroresistance of colistin in E. coli using a semi-mechanistic modelling of killing curves

Mead, Andrew; Toutain, Pierre-Louis; Richez, Pascal; Pelligand, Ludovic

Abstract

Heteroresistance correspond to the presence in a bacterial isolate of an initial small subpopulation of bacteria characterized by a significant reduction in their sensitivity to a given antibiotic. Mechanisms of heteroresistance vs. resistance are poorly understood. The aim of this study was to compare resistant and heteroresistant E. coli strains exposed to colistin by modeling killing curves with a semi-mechanistic model. We quantify for sensitive, heteroresistant and resistant bacteria a maximum killing rate (Emax) of colistin and the corresponding potency (EC50) i.e. the colistin concentrations corresponding to Emax/2. Heteroresistant subpopulations was identified in both mcr-negative and mcr-positive E. coli as around 0.06% of the starting population. Minority heteroresistant bacteria, both for mcr-negative and mcr-positive strains, differed from the corresponding dominant populations only by the maximum killing rate of colistin (differences for Emax by a factor of 12.66 and 3.76 for mcr-negative and mcr-positive strains respectively) and without alteration of their EC50. On the other hand, the resistant mcr-positive strains are distinguished from the mcr-negative strains by differences in their EC50 which can reach a factor of 44 for their dominant population and of 22 for their heteroresistant subpopulations. It is suggested that the underlying physiological mechanisms differ between resistance and heteroresistance, resistance being linked to a decrease in the affinity of colistin for its site of action, whereas heteroresistance would rather be linked to an alteration of the target which will be more difficult to be further changed or destroyed.

Citation

Mead, A., Toutain, P., Richez, P., & Pelligand, L. (2022). Quantitative pharmacodynamic characterization of resistance vs. heteroresistance of colistin in E. coli using a semi-mechanistic modelling of killing curves. Antimicrobial Agents and Chemotherapy, https://doi.org/10.1128/aac.00793-22

• Journal Article Type: Article
• Acceptance Date: Aug 1, 2022
• Publication Date: Aug 30, 2022
• Deposit Date: Aug 30, 2022
• Publicly Available Date: Aug 30, 2022
• Print ISSN: 0066-4804
• Publisher: American Society for Microbiology
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.1128/aac.00793-22
• Keywords: Colistin; Heteroresistance; Pharmacokinetics; Pharmacodynamics; PK/PD 10
• Additional Information: This work was supported by Dopharma, V.M.D./Inovet, and Virbac through TransPharm. The PhD stipend of AM was covered by a Bloomsbury studentship. AM joined the London Interdisciplinary Biosciences Consortium cohort (Doctoral Training Partnership) as an RVC contribution and supported by the Biotechnology and Biological Sciences Research Council (BBSRC).