A long journey from minimum inhibitory concentration testing to clinically predictive breakpoints: deterministic and...

Area of Science:

• Clinical Microbiology
• Pharmacology
• Infectious Diseases

Background:

• Standardization of antimicrobial susceptibility testing (AST) has progressed since 1971.
• Discrepancies in AST results arose due to a lack of consensus on methods and interpretive criteria.
• The European Committee on Antimicrobial Susceptibility Testing (EUCAST) now harmonizes methods and coordinates breakpoint setting.

Purpose of the Study:

• To explain the evolution of breakpoint setting methodologies in antimicrobial susceptibility testing.
• To highlight the limitations of the deterministic approach in breakpoint determination.
• To introduce and advocate for the probabilistic approach in defining antimicrobial breakpoints.

Main Methods:

• Review of historical approaches to breakpoint setting.
• Explanation of the deterministic approach using mean pharmacokinetic parameters and MIC values.
• Description of the probabilistic approach integrating pharmacokinetic/pharmacodynamic (PK/PD) principles and clinical isolate MIC data through probability density functions.

Main Results:

• Deterministic breakpoint setting can result in overly high values, potentially classifying resistant bacteria as susceptible.
• This inadequacy in drug exposure can lead to increased resistance development and clinical failure.
• The probabilistic approach yields lower breakpoints by modeling the full range of drug exposures, thereby reducing resistance amplification.

Conclusions:

• The probabilistic approach, utilizing PK/PD integration, provides a more robust method for defining antimicrobial breakpoints.
• This method accounts for variability in drug exposure and pathogen susceptibility, minimizing resistance development.
• The ongoing evolution of breakpoint setting reflects advancements in understanding antimicrobial pharmacodynamics.