Breakpoints for carbapenemase-producing Enterobacteriaceae: is the problem solved?

Area of Science:

• Clinical microbiology
• Antimicrobial resistance
• Pharmacokinetics/Pharmacodynamics

Background:

• Antimicrobial susceptibility testing breakpoints are crucial for guiding therapy.
• Discrepancies exist between Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints for carbapenems against Enterobacteriaceae.
• These differences stem from varied pharmacokinetic/pharmacodynamic (PK/PD) approaches.

Purpose of the Study:

• To analyze the reasons behind differing carbapenem breakpoints set by CLSI and EUCAST.
• To compare the impact of these differing breakpoints on the detection of carbapenemase-producing Enterobacteriaceae (CPE).

Main Methods:

• Comparison of CLSI and EUCAST breakpoint setting methodologies.
• Analysis of pharmacokinetic/pharmacodynamic (PK/PD) modeling, including Monte Carlo simulations and probability of target attainment (PTA).
• Evaluation of confidence intervals (CIs) and inclusion of "inflated variance" in PK parameter variability.

Main Results:

• CLSI breakpoints for imipenem and meropenem are lower than EUCAST's.
• CLSI's approach, incorporating "inflated variance," captures more carbapenemase-producing Enterobacteriaceae (CPE).
• EUCAST has introduced specific cut-off values for CPE screening.

Conclusions:

• Differences in PK/PD modeling significantly impact carbapenem breakpoints and CPE detection.
• Current recommendations favor reporting susceptibility "as tested," with carbapenemase production data for surveillance.
• Emerging clinical data may necessitate revised recommendations, especially regarding combination therapy for CPE infections.