Quantitative assessment of combination antimicrobial therapy against multidrug-resistant bacteria in a murine
Zhe Yuan1, Kimberly R Ledesma, Renu Singh
1Department of Clinical Sciences and Administration, University of Houston College of Pharmacy, Houston, Texas, USA.
Background:
Combination antimicrobial therapy is clinically used as a last-resort strategy to control multidrug-resistant bacterial infections. However, selection of antibiotics is often empirical, and conventional assessment of combined drug effect has not been correlated to clinical outcomes. Here, we report a quantitative method to assess combined killing of antimicrobial agents against 2 multidrug-resistant bacteria.
Methods:
Combined time-kill studies were performed using clinically achievable concentrations for each 2-agent combination against clinical isolates of Acinetobacter baumannii and Pseudomonas aeruginosa. Bacterial burden observed at 24 h was mathematically modeled using a 3-dimensional response surface. Subsequently, a neutropenic murine pneumonia model with simulated clinical dosing exposures was used to validate our quantitative assessment of combined killing.
Results:
Different antimicrobial combinations were found to have varying efficacy against the multidrug-resistant bacteria. As predicted by our quantitative method, cefepime plus amikacin was found to be the most superior combination, which was evidenced by a reduction in tissue bacterial burden and prolonged survival of infected animals.
Conclusions:
The consistency between the predictions of the mathematical model and in vivo observations substantiated the robustness of our quantitative method. These data highlighted a novel and promising method to guide rational selection of antimicrobial combination in the clinical setting.
