Application of a mathematical model to prevent in vivo amplification of antibiotic-resistant bacterial populations during therapy

Abstract

Development and owns stock and stock options. James B. Kahn is an employee of OrthoMcNeil Pharmaceutical and owns stock and stock options. Nonstandard abbreviations used: minimum inhibitory concentration (MIC); Mueller-Hinton II broth (MHB); minimum bactericidal concentration (MBC); area under the concentration time curve (AUC); nonparametric expectation maximization 2 (NPEM2); maximum a posteriori probability (MAP); quinolone resistance-determining region (QRDR).caused by antibiotic-resistant bacteria are more difficult to treat, resulting in excess morbidity and mortality as well as higher health care costs. Therefore, it is imperative to identify ways of suppressing the emergence of antibiotic-resistant mutants.Current preclinical methods for assessing the efficacy of an antimicrobial agent most often evaluate the effect of selected dosages of the compound on the reduction in the total bacterial population at an infection site. The impact of drug pressure on the amplification of the drug-resistant subpopulation is ignored (1-3).For some antibiotic dosages, the drug-susceptible population may be completely replaced with resistant mutants over time. Clinically, this may manifest as the failure of an infection to respond to therapy or a relapse of infection with drug-resistant mutants shortly after a prescribed course of antibiotic therapy is completed.The probability that a resistant subpopulation exists within a predominantly drug-susceptible wildtype population is dependent on the number of organisms at the infection site (total population burden) and the mutational frequency to resistance to 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 m...

Low or High Doses of Cefquinome Targeting Low or High Bacterial Inocula Cure Klebsiella pneumoniae Lung Infections but Differentially Impact the Levels of Antibiotic Resistance in Fecal Flora

“…A. Ferran, M. Z. Lacroix, P. L. Toutain, and A. BousquetMélou, submitted for publication). In addition, a set of published works on the influence of inoculum size on the in vivo efficacy of fluoroquinolones or beta-lactams against various Gram-positive or Gram-negative pathogens (11,15,17,19,23) supports the hypothesis that efficacious doses can be lower in early than in later interventions. In particular, Mizunaga et al (11) determined that the 50% effective doses (ED 50 s) of 3 carbapenems were 12 to 50 times lower in Pseudomonas aeruginosa-infected mice when the initial bacterial inoculum was 100-fold lower.…”

Antimicrobial Effects of β-Lactams on Imipenem-Resistant Ceftazidime-Susceptible Pseudomonas aeruginosa

“…Other factors, such as quorum sensing, decreasing expression of selected penicillin-binding proteins, and expression of autolysins, have been reported to be related to the inoculum effect (11-13); these factors were not explored in the present study. In addition, Jumbe et al (14) showed that a substantially higher drug exposure was required to suppress resistance for high-CFU inocula, as the high CFU exceeded the inverse of the mutation frequency. However, we did not evaluate the mutation frequency in time-kill studies.…”

Suppression of Emergence of Resistance in Pathogenic Bacteria: Keeping Our Powder Dry, Part 1

“…Finally, also in line with the previous study, the first 48 h of the experiment did not demonstrate any mutations in the target site. All organisms mediated resistance through efflux pump upregulation, as seen previously (11).…”

“…The first demonstration of resistance suppression in vivo or in vitro was performed in a murine thigh infection model (11) and an in vitro pharmacodynamic model (8). Pseudomonas aeruginosa was the challenge strain and levofloxacin the drug employed in the animal model (11) and moxifloxacin the drug employed in the in vitro model (8).…”

“…Pseudomonas aeruginosa was the challenge strain and levofloxacin the drug employed in the animal model (11) and moxifloxacin the drug employed in the in vitro model (8). In contrast to other studies conducted in mice in that time frame, the animals were nonneutropenic.…”