Predicting bacterial resistance using the time inside the mutant selection window: possibilities and limitations

Area of Science:

• Microbiology
• Pharmacology
• Infectious Diseases

Background:

• The time inside the mutant selection window (TMSW) is often used to predict antibiotic resistance.
• However, the ratio of area under the concentration-time curve to minimum inhibitory concentration (AUC/MIC) has shown greater predictive power for fluoroquinolone resistance.

Purpose of the Study:

• To compare the predictive capabilities of TMSW and AUC/MIC in the selection of ciprofloxacin-resistant bacteria.
• To investigate the enrichment of resistant mutants under varying TMSW conditions in an in vitro dynamic model.

Main Methods:

• Four strains of Escherichia coli were exposed to ciprofloxacin twice daily for 3 days in a dynamic in vitro model.
• Simulated peak antibiotic concentrations were set at or above the mutant prevention concentration (MPC).
• Bacterial mutant enrichment was monitored by plating on antibiotic-containing media, with TMSW ranging from 0% to 100% of the dosing interval.

Main Results:

• Plots of the area under the bacterial mutant concentration-time curve (AUBCM) against TMSW showed a hysteresis loop for each organism.
• The AUBCM was greater at a given TMSW on the ascending portion of the curve (when time above MPC was zero) compared to the descending portion.
• A sigmoid function effectively fitted separate data sets (r(2)=0.81 and 0.92), outperforming a fit ignoring the AUC/MIC-resistance relationship (r(2)=0.61).

Conclusions:

• The study demonstrates that TMSW can be an appropriate predictor of bacterial resistance.
• The findings highlight the importance of considering the time above the mutant prevention concentration (T>MPC) when evaluating TMSW's predictive power.
• This research provides a more nuanced understanding of antibiotic resistance selection dynamics.