Volume 38 Number 6 | December 2024
Kristen L. Smith, PhD, D(ABMM)
Amanda Suchanek, PhD
Our role as medical laboratory science professionals is to provide information that clinicians can use to guide treatment of their patients. This directive is intimately tied to patient safety. From developing the test menu to the final interpretation of test results, it is our responsibility to ensure accuracy and reliability of our assays. Clinical microbiology is a unique microcosm of the lab, as it is the only discipline dealing with living organisms with a great propensity for change. Consequently, there are unique considerations needed to create a culture of safety in this setting.
The primary objectives in clinical microbiology are to confirm if an infectious etiology is present, identify the pathogen, and determine what antimicrobials are effective against the organism. To ensure patient safety, laboratories must be vigilant in their review of guidance documents and regulatory changes. While each step is important, one could argue that the most impactful step to patient safety is antimicrobial susceptibility testing.
“It is our responsibility to keep informed of the changes that impact our testing, because it is essential to patient safety.”
Antimicrobial therapies must be approved by the Federal Drug Administration (FDA) prior to use in patients. For new antimicrobials, the manufacturer submits a New Drug Application to the FDA Center for Drug Evaluation and Research (CDER) utilizing data from clinical trials to show that the drug is safe and effective. The proposed labeling, including indications for use, is also provided at this time. FDA-CDER then evaluates the application and uses the data to establish Minimum Inhibitory Concentrations (MICs), also referred to as breakpoints, for the new drug. These breakpoints are then published on the FDA-CDER Susceptibility Test Interpretive Criteria (STIC) website. In general, organisms are classified as susceptible, intermediate, or resistant to antimicrobials based on several factors, including pharmacokinetics, pharmacodynamics, and clinical data.
Manufacturers of devices that provide MIC data must also submit their data to the FDA to obtain 510k clearance for their products. They are required to utilize STIC breakpoints for the submission and in their package insert/instructions for use (PI/IFU) documents. If the manufacturer makes changes or updates, such as reformulating a new antimicrobial within their device, the breakpoint interpretations or organism coverage may change compared to the original FDA submission.
Breakpoints are dynamic and can change over time. This is because more data associated with patient outcomes is generated and microorganisms constantly evolve. Antimicrobials that may work well in urinary infections may have poor efficacy in systemic infections, necessitating site and/or source-specific breakpoints. Treatment failures associated with certain organisms/drug combinations could lead to lowering or complete removal of breakpoints to discourage that treatment. Or a new drug that could be found effective against organisms not initially studied could lead to the creation of new breakpoints.
To further complicate the issue, there are several entities in addition to the FDA that evaluate breakpoints. Many US laboratories recognize breakpoints established by the Clinical and Laboratory Standards Institute (CLSI). Additionally, the European Committee on Antimicrobial Susceptibility Testing (EUCAST) also provides interpretive criteria. Both CLSI and EUCAST provide regular updates to their guidance documents to incorporate new data (including clinical and technical) into their breakpoint considerations.
Unlike the manufacturers, laboratories have more flexibility in what breakpoints they would like to report. If they want to utilize FDA breakpoints, they will need to verify the breakpoints to ensure the device is working as stated in the PI/IFU. Alternatively, if laboratories choose to follow breakpoints published by CLSI or EUCAST (e.g., those that are not currently recognized by FDA on the STIC website), they will need to generate additional data in the form of a comprehensive verification or validation, according to CLSI M52 guidance for use of commercial AST systems. Manufacturers are beholden to breakpoints published on the FDA STIC website, thus, when laboratories choose to utilize breakpoints not listed on the FDA STIC site, it is considered “off-label” use, necessitating the additional data to demonstrate that the commercial AST system is performing as expected off-label.
The College of American Pathologists (CAP) found through a proficiency testing review in 2019 that labs were not consistently updating their breakpoints with approximately 30-70 percent utilizing outdated breakpoints. As this could lead to inappropriate antimicrobial therapy in patients and increased risk of significant patient harm, CAP added checklist items to require annual review of breakpoints, as well as a requirement to update breakpoints within three years of any changes.
Just as breakpoints change, so can regulatory oversight. In April of this year, the FDA announced a final rule on laboratory-developed tests (LDTs) with the intent to improve patient safety. There is still much to understand regarding the operationalization and impact of these changes to clinical laboratories, including how this will affect future updates to breakpoints. While the FDA and CLSI are in agreement for many breakpoints, there are several exceptions.
If non-FDA breakpoints are utilized in a clinical laboratory, this ruling may lead to more documentation requirements and submissions to the FDA prior to implementation. This would increase laboratory costs due to FDA submissions and additional staffing needs. Laboratories are already resource limited, and this could delay access to breakpoints based on the most up-to-date literature. Ultimately, patient care could be negatively impacted through breakpoint classification as LDTs.
As medical laboratory science professionals, we know that patient safety is the key priority in our laboratories. Another constant in our field is change. Changes in methods, clinical outcome data, guidelines, and regulations. It is our responsibility to keep informed of the changes that impact our testing, because it is essential to patient safety.
References
- Prinzi AM, Moore NM. Change of Plans: Overview of Bacterial Taxonomy, Recent Changes of Medical Importance, and Potential Areas of Impact. Open Forum Infect Dis. 2023;10(7):ofad269. Published 2023 May 17. doi:10.1093/ofid/ofad269
- Simner PJ, Rauch CA, Martin IW, et al. Raising the Bar: Improving Antimicrobial Resistance Detection by Clinical Laboratories by Ensuring Use of Current Breakpoints. Open Forum Infect Dis. 2022;9(3):ofac007. Published 2022 Feb 7. doi:10.1093/ofid/ofac007
- Patel JB, Alby K, Humphries R, et al. Updating breakpoints in the United States: a summary from the ASM Clinical Microbiology Open 2022. J Clin Microbiol. 2023;61(10):e0115422. doi:10.1128/jcm.01154-22
- Regulatory hurdles for updating breakpoints: What to know | ASM.org. ASM.org. https://asm.org/articles/2024/march/regulatory-hurdles-for-updating-breakpoints-what-t
- CLSI. Performance Standards for Antimicrobial Susceptibility Testing. 34th ed. CLSI supplement M100. Clinical and Laboratory Standards Institute; 2024.
- The European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for interpretation of MICs and zone diameters. Version 14.0, 2024. http://www.eucast.org.
Kristen L. Smith (Kristen.smith1@biomerieux.com) is a Medical Advisor at bioMérieux in Salt Lake City, Utah.
Amanda Suchanek (Amanda.suchanek@biomerieux.com) is a Medical Advisor at bioMérieux in Salt Lake City, Utah.