Bacterial-population responses to drug-selective pressure: examination of garenoxacin's effect on Pseudomonas aeruginosa.
The emergence of resistance to antibiotics is a serious problem often related to suboptimal drug dosing; such suboptimal dosing results in the preferential killing of drug-susceptible microbial subpopulations, allowing amplification of drug-resistant microbial subpopulations. We determined the effect that fluctuating concentrations of quinolone drugs have on both the total population and the resistant subpopulation of Pseudomonas aeruginosa, by employing, over a 48-h period, human pharmacokinetics and multiple regimens in an in vitro-infection model. All data were simultaneously modeled by use of 3 parallel inhomogeneous differential equations. Model parameters were used to derive the minimal, or breakpoint, drug exposure necessary to suppress amplification of the resistant subpopulation. In a prospective-validation study, we found that a drug exposure near to but below the calculated breakpoint amplified the resistant subpopulation, whereas a drug exposure at the breakpoint suppressed it. This approach allows delineation of target drug exposures (area under the concentration/time curve for 24 h : minimal inhibitory concentration [AUC(24) : MIC] = 190) that will suppress amplification of the antibiotic-resistant subpopulation, thereby preserving the susceptibility of target pathogens.
Tam
Vincent H
VH
Emerging Infections and Host Defense Theme, Ordway Research Institute, Albany, NY 12208, USA.
Louie
Arnold
A
Deziel
Mark R
MR
Liu
Weiguo
W
Leary
Robert
R
Drusano
George L
GL
D019540:Area Under Curve; D001798:Blood Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D024841:Fluoroquinolones / Q000097:blood / Q000494:pharmacology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000235:genetics*
D001798:Blood Proteins; D024841:Fluoroquinolones; C419689:garenoxacin