A unified anti-mutant dosing strategy

Area of Science:

• Microbiology
• Pharmacology
• Infectious Diseases

Background:

• Antimicrobial resistance is a growing global health concern.
• Current antimicrobial dosing strategies have limitations in preventing resistance.
• Existing methods fail to adequately address pre-existing or therapy-induced resistant mutant subpopulations.

Purpose of the Study:

• To evaluate the shortcomings of current antimicrobial dosing strategies.
• To propose and explore the utility of mutant prevention concentration (MPC)-based pharmacokinetic/pharmacodynamic (PK/PD) thresholds.
• To demonstrate how MPC-based thresholds can restrict resistant subpopulation enrichment and amplification.

Main Methods:

• Analysis of existing antimicrobial dosing strategies (killing susceptible cells, maintaining drug concentration above mutant prevention concentration (MPC), dosage escalation modeling).
• Comparison of Minimum Inhibitory Concentration (MIC) and MPC values across multiple pathogen isolates.
• Conceptualization of MPC-based PK/PD thresholds (e.g., AUC(24)/MPC, t > MPC).

Main Results:

• Focusing solely on susceptible cell killing overlooks resistant subpopulations.
• Maintaining concentrations above MPC may be excessively stringent.
• Dosage escalation modeling relies on indirect susceptibility estimates, differing from direct MPC measurements, which are critical as MIC and MPC can be discordant.

Conclusions:

• Combining antimicrobial dosing strategies with MPC-based PK/PD thresholds is essential for restricting resistant subpopulation growth.
• Development of comprehensive databases with MPC values for diverse isolates is necessary for effective dosing regimen modeling.
• MPC-based dosing represents a critical advancement in antimicrobial stewardship to combat resistance.