New Antimicrobial Breakpoint Requirements from CLSI and FDA

What do they mean for Canadian Medical Microbiology Laboratories.

R.P. Rennie, Professor Emeritus, University of Alberta, Faculty of Medicine and Dentistry.

In the past few months, The FDA and CLSI have created a requirement for testing laboratories accredited by United States accreditation bodies that they follow either CLSI or FDA breakpoints for reporting of antimicrobial susceptibility test results. For some Canadian laboratories that are accredited by the College of American Pathologists (CAP) as well as their provincial laboratory accreditation bodies, this could mean an accreditation requirement to follow only those antimicrobial breakpoints that are defined by one or both of FDA or CLSI.

This article is the opinion of the author but it is hoped to provide an outcome for Canadian medical microbiology laboratories that provide the most up to date and accurate antimicrobial – micro-organism breakpoints for clinicians who treat patients infected with bacterial pathogens.

First, this was the statement issued by CLSI in January of this year:

Effective January 2024, clinical laboratories performing antimicrobial susceptibility testing (AST) will be required to use breakpoints currently recognized by Clinical and Laboratory Standards Institute (CLSI) or US Food and Drug Administration (FDA).

The following link to a toolkit developed by several groups in the United States is found below:

This toolkit identifies how laboratories can validate or verify if their breakpoints match current CLSI or FDA breakpoints for various antimicrobial agents. If one looks at the comparison between the two breakpoint organizations there are many of these that are different both for MIC and disc diffusion methods. It is unknown which of the two systems are most accurate in defining susceptibility or resistance from a test result. The presumption appears to be, for accreditation purposes, that laboratories will be required to perform validation and/or verification studies to satisfy CAP accreditation (if they are CAP accredited) that conform to one or the other system.

This would be considered an onerous and likely unnecessary activity for most of our laboratories. The breakpoint organizations (and there are more than just CLSI and FDA) have already done validation studies when new and/or older agents came to the marketplace. Further, other organizations such as EUCAST, and USCAST (a North American node of EUCAST), have done extensive work over many years using updated methodologies to validate the accuracy of many existing breakpoints.

In these latter cases, the breakpoints for many antimicrobial- micro-organism combinations have been subjected to pharmacokinetic, pharmacodynamic, target attainment and Monte-Carlo simulations of patient infections that coincide with dosing regimens, effects of impairment to various body systems, etc., to identify with greater clinical accuracy that original breakpoints established by organizations such as FDA and CLSI were too high. Many of these have been lowered significantly to either identify more reasonable degrees of susceptibility, where testing methodology needs to respond, and what clinical resistance should look like.  Comparisons (for which CLSI has responded to some) developed by EUCAST (https://www/eucast/org) and USCAST (https:// using more recent methodologies show that many agents have lower breakpoints. In addition, many EUCAST breakpoints have limited intermediate MICs (e.g.,Ceftolazane-tazobactam: ≤4mg/L -S, >4 mg/L -R) or disc zone diameters ( >22mm-S, ≤22mm-R) for Enterobacterales, whereas CLSI breakpoints for the same agent and Enterobacterales are (≤4mg/L -S, ≥16mg/L -R and disc zone diameters (≥21mm -S, ≤17mm -R). This is just one example. It is beyond the scope of this presentation to provide more specific information for all agent- organism combinations.

In the author’s opinion, medical microbiology laboratories in Canada should be permitted to determine which breakpoints are considered to be most accurate and fit their clinical reporting structure. It would be extremely difficult to validate or verify any agent-micro-organism group from one system to another since many different criteria have been used for primary validation, and these systems are subject to regular investigation regarding susceptibility or resistance.

It is worthwhile for Canadian laboratories to have knowledge of each of the breakpoint  systems available, and in general terms to be consistent in use of one of those currently available. If a specific breakpoint using a different system is reported by a local laboratory where resistance is significant, that should be indicated on a test report so that clinicians are aware of susceptible or resistant differences in that particular test. It may be epidemiological important to control usage of an agent in such an instance. 

For Canadian laboratories that are also accredited by CAP, it may be useful to contact CAP to request a variance in this regard, similar to that done in other disciplines such as haematology for certain aspects that are also standardized and in use in Canada that differ from U.S.A. requirements.

Almost all Canadian medical microbiology laboratories are accredited in Canada by provincial regulatory bodies (e.g. Colleges of Physicians and Surgeons, Accreditation Canada, etc.). Those accreditation bodies use ISO 15189:2022 as the standard guidance document for laboratory accreditation.  With respect to utilization of a standard method in the laboratory, the only requirements are that the laboratory shall use standard methods that have been validated for intended use, that their use should be based on clinical risk, and that there is a mechanism to regularly update those methods. These components would apply equally to the use of breakpoint methods. For Canadian laboratories that are also accredited by CAP, it may be useful to contact CAP to request a variance in this regard, similar to that done in other disciplines such as haematology for certain aspects that are also standardized and in use in Canada that differ from U.S.A. requirements.

Finally, it is important to remember that antimicrobial breakpoints, while significant and contributory, are only one consideration medical teams must take into account when treating infections.   Factors such as robustness of immune response impacted by underlying disease or medications, or age, or wound chronicity or presence of indwelling medical devices can impair the effectiveness of antimicrobial therapy.  Breakpoint results, while important, are only one guide.

It is hoped that this brief summary of these U.S. based rules and accreditation frameworks in Canada will assist Canadian medical microbiology laboratories to provide updated and accurate antimicrobial breakpoint results that are global in their structure and use.

Labs wishing to discuss this further with the author are welcomed to contact CMPT so we can put you in touch.

Posted in Clinical Microbiology