Open AccessApplication of a mathematical model to prevent in vivo amplification of antibiotic-resistant bacterial populations during therapy
Author(s) -
Nelson L. ‘Shasha’ Jumbe,
Arnold Louie,
Robert Leary,
Weiguo Liu,
Mark R. Deziel,
Vincent H. Tam,
Reetu Bachhawat,
Christopher Freeman,
Jeff Kahn,
Karen Bush,
Michael N. Dudley,
Michael H. Miller,
George L. Drusano
Publication year - 2003
Publication title -
the journal of clinical investigation/the journal of clinical investigation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.278
H-Index - 488
eISSN - 1558-8238
pISSN - 0021-9738
DOI - 10.1172/jci200316814
Subject(s) - antibiotics , pseudomonas aeruginosa , biology , antimicrobial , population , drug resistance , antibiotic resistance , microbiology and biotechnology , efflux , in vivo , pathogen , quinolone , multiple drug resistance , bacteria , dosing , drug , pharmacology , medicine , genetics , environmental health
The worldwide increase in the prevalence of multi-antibiotic–resistant bacteria has threatened the physician’s ability to provide appropriate therapy for infections. The relationship between antimicrobial drug concentration and infecting pathogen population reduction is of primary interest. Using data derived from mice infected with the bacterium Pseudomonas aeruginosa and treated with a fluoroquinolone antibiotic, a mathematical model was developed that described relationships between antimicrobial drug exposures and changes in drug-susceptible and -resistant bacterial subpopulations at an infection site. Dosing regimens and consequent drug exposures that amplify or suppress the emergence of resistant bacterial subpopulations were identified and prospectively validated. Resistant clones selected in vivo by suboptimal regimens were characterized. No mutations were identified in the quinolone resistance–determining regions of gyrA/B or parC/E. However, all resistant clones demonstrated efflux pump overexpression. At base line, MexAB-OprM, MexCD-OprJ, and MexEF-OprN were represented in the drug-resistant population. After 28 hours of therapy, MexCD-OprJ became the predominant pump expressed in the resistant clones. The likelihood of achieving resistance-suppression exposure in humans with a clinically prescribed antibiotic dose was determined. The methods developed in this study provide insight regarding how mathematical models can be used to identify rational dosing regimens that suppress the amplification of the resistant mutant population