Updating Breakpoints in Antimicrobial Susceptibility Testing

Author: Andrea Prinzi, PhD, MPH, SM(ASCP), Medical Science Liaison at bioMérieux

In a recent American Society for Microbiology article, Dr. Andrea Prinzi provides background on the antimicrobial susceptibility testing (AST) breakpoint update process and details the steps clinical laboratories must take to maintain compliance and provide accurate data for optimal patient care. The following content is a summary of Dr. Prinzi’s article, which can be read in its entirety here.

Clinical labs play a crucial role in AST

Antimicrobial resistance (AMR) is on the rise globally and is responsible for significant morbidity and mortality each year. Clinical microbiology laboratories play a crucial role in organism identification and AST, which aids in the successful clinical management of patients and supports infection prevention and control. To effectively keep up with the development of antimicrobial resistance over time and respond appropriately, the interpretive criteria used for antimicrobial susceptibility testing (otherwise known as “breakpoints”) must be updated regularly to reflect changes in organism resistance patterns and guide treatment.

Manufacturers are required to use FDA-cleared breakpoints

In the United States, the regulatory process for updating breakpoints is complex. Three primary agencies are responsible for determining breakpoints: the Food and Drug Administration (FDA), Clinical and Laboratory Standards Institute (CLSI), and European Committee on Antimicrobial Susceptibility Testing (EUCAST). First, CLSI reviews data and determines if breakpoints for a given bug-drug combination must be updated. Then, the organization submits a rationale document to the FDA detailing why the breakpoints should change. If the FDA agrees with CLSI’s rationale, the new breakpoints will be posted on the FDA’s susceptibility test interpretive criteria website (STIC) and serve as the current breakpoints for that bug-drug combination. If the FDA disagrees with the rationale, the existing FDA breakpoints will remain on the STIC website, and CLSI will publish its updated breakpoints in the M100 document released annually.

AST device manufacturers are required to use only FDA-cleared breakpoints on their systems. If CLSI suggests breakpoint updates and the FDA disagrees with the rationale, manufacturers must continue using the FDA breakpoints on their systems. If CLSI proposes a change that the FDA acknowledges, manufacturers may then perform internal validation studies using the new breakpoints and submit the data to the FDA to receive clearance for the new breakpoints. The validation process performed to achieve FDA clearance takes considerable time and resources. Manufacturers may not always be immediately aware of when breakpoints are updated on the STIC website, and must balance competing priorities to determine when to seek clearance for new breakpoints. Even after validation data have been submitted, the FDA clearance process can take a very long time. In addition, clinical laboratories may be unaware of which drugs have received FDA clearance on their AST systems and which updates are needed.

CAP requires clinical labs use AST breakpoints for better patient care and AMR surveillance

The College of American Pathologists (CAP), a primary accrediting body for clinical laboratories, recently updated its inspection checklist to state that as of January 1, 2024, all clinical laboratories must use the most updated AST breakpoints for all susceptibility testing within three years of the most recent update. While this is a necessary action that will ultimately result in better patient care and AMR surveillance, it is a daunting process for most clinical laboratories. For example, suppose that a manufacturer does not have FDA clearance for the most recent breakpoints for a given drug-bug combination on their device. In that case, clinical laboratories must perform an in-house validation study for the new breakpoints since their use is considered an off-label use of the FDA-cleared device. These validation studies can be time-consuming and labor-intensive, and may need to be performed for multiple antibiotics. Even when new breakpoints are FDA-cleared on a device and a validation is not required, a verification study must still be performed. Per the Clinical Laboratory Improvement Amendments (CLIA), clinical laboratories must perform smaller verification studies to demonstrate the acceptable performance of new breakpoints in their laboratory before results can be released to patients.

Working together to improve the AST breakpoint process

All clinical microbiology laboratories should use the most up-to-date AST breakpoints to interpret minimum inhibitory concentrations and disk diffusion zones. While challenging, it is critical for quality patient care and public health. Coordination and collaboration between government and regulatory agencies, industry, and clinical microbiology laboratories are needed to improve the AST breakpoint process.

To learn more on this topic, read Dr. Prinzi’s article in its entirety on the American Society for Microbiology.

Updating Breakpoints in Antimicrobial Susceptibility Testing

Clinical labs play a crucial role in AST

Manufacturers are required to use FDA-cleared breakpoints

CAP requires clinical labs use AST breakpoints for better patient care and AMR surveillance

Working together to improve the AST breakpoint process

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