Updating breakpoints in the United States: a summary from the ASM Clinical Microbiology Open 2022

ABSTRACT

Accurate antimicrobial susceptibility testing (AST) and reporting are essential for guiding appropriate therapy for patients and direction for public health prevention and control actions. A critical feature of AST reporting is the interpretation of AST results using clinical breakpoints for reporting as susceptible, susceptible-dose dependent, intermediate, or resistant. Breakpoints are subject to continuous adjustment and updating to best reflect current clinical data. These breakpoint changes can benefit patients and public health only if adopted in a timely manner. A recent survey identified that up to 70% of College of American Pathologists (CAP)-accredited U.S. laboratories and 45% of CAP-accredited laboratories outside the U.S. use various obsolete clinical breakpoints to interpret AST results to guide patient care. The reason for the ongoing use of obsolete breakpoints is multifactorial, including barriers encountered by laboratories, commercial AST device manufacturers, standards development organizations, and regulatory bodies alike. To begin to address this important patient safety issue, CAP implemented checklist requirements for CAP-accredited laboratories to ensure up-to-date clinical breakpoint use. Furthermore, the topic was discussed at the June 2022 American Society for Microbiology Clinical Microbiology Open (CMO) with various stakeholders to identify potential solutions. This minireview summarizes the breakpoint setting process in the U.S. and highlights solutions to close the gap between breakpoint revisions and implementation in clinical and public health laboratories. Solutions discussed include clarification of data requirements and minimum inhibitory concentration only reporting for regulatory clearance of AST devices, clinical data generation to close breakpoints gaps, advocacy, education, and greater dialogue between stakeholders.

INTRODUCTION

Antimicrobial resistance (AMR) is an urgent global health threat that is recognized by many international bodies, including the World Health Organization and the U.S. Centers for Disease Control and Prevention (CDC) (1, 2). In 2019, bacterial infections ranked second as the leading cause of deaths globally (3). It was estimated that 4.95 million deaths were associated with AMR, including 1.27 million deaths attributed to AMR worldwide (4). Accurate antimicrobial susceptibility testing (AST) and reporting are essential for guiding appropriate therapy for patients and for collecting antimicrobial resistance data that are used for local, regional, and global prevention and control actions. As such, AST is an integral tool for addressing this global public health threat.

A critical feature of AST reporting is the interpretation of minimum inhibitory concentration (MIC) or disk zone diameter (mm) results using clinical breakpoints. These breakpoints categorize MIC values or zone diameters as susceptible (S), susceptible-dose dependent (SDD), intermediate (I), or resistant (R) (5 – 7). These designations (S, SDD, I, or R) are reported for each antimicrobial agent, providing guidance to the clinician on antimicrobial treatment selection. Aggregated, cumulative AST data are used to surveil for AMR threats significant to public health. However, the accuracy of AST data depends upon whether the breakpoints applied to interpret AST results are updated and accurately reflect clinical utility of the antimicrobial.

Breakpoints are subject to continuous adjustment and updating to best reflect current clinical outcome data. An example of an important breakpoint change is the Clinical and Laboratory Standards Institute (CLSI) revision of the meropenem breakpoint against Enterobacterales. Prior to 2010, an MIC of ≤4 µg/mL was considered susceptible, but after 2010, the susceptible breakpoint revised to ≤1 µg/mL. This decision was made because clinical data demonstrated poor outcomes for patients treated with meropenem for Enterobacterales with MICs of 2–4 µg/mL (5, 8). The revised carbapenem breakpoints also simplified testing. The lower breakpoints appropriately classified carbapenemase-producing isolates as not susceptible (i.e., intermediate or resistant), whereas the obsolete breakpoints required testing for carbapenemase production when the MIC was ≥1 µg/mL (9). At that time, the recommended carbapenemase detection test, the modified Hodge test, had sensitivity and specificity issues (10) leading to both false susceptibility and false resistance that impacted patient care and public health estimates in the transmission of carbapenem-resistant Enterobacterales (CRE).

Breakpoint changes can benefit patients and public health only if adopted in a timely manner by clinical and public health laboratories that perform AST. A recent survey identified that up to 70% of College of American Pathologists (CAP)-accredited U.S laboratories and up to 45% of CAP-accredited laboratories outside the U.S. use various obsolete clinical breakpoints to interpret AST results to guide patient care. Furthermore, some laboratories indicated that they were unaware of breakpoint changes or the need to update breakpoints (9). This results in serious patient safety concerns and hampers the ability to track and contain the worldwide threat of AMR.

Use of obsolete breakpoints limits the global public health response to AMR, as pathogens of serious or urgent concern can go undetected and spread to additional patients and across healthcare systems and communities (1). For example, one study published in 2016 simulated the impact of delayed implementation of the current carbapenem breakpoints on the spread of CRE. This study found that use of updated instead of obsolete carbapenem breakpoints led to identification of almost 2,000 additional carriers per year in Orange County, CA, alone (11). Roughly 30% of CAP-accredited U.S. laboratories continued to apply obsolete carbapenem breakpoints in 2019, nearly a decade after revisions were published (9), indicating a need for improved awareness of updated breakpoints and incentives for implementation.

The reason for the ongoing use of obsolete breakpoints by U.S. laboratories is multifactorial. To increase awareness of this important issue, the American Society for Microbiology (ASM) Clin Micro Open (CMO) steering committee decided to discuss this important topic with various stakeholders at the June 2022 CMO meeting. The CMO is a forum that brings together laboratory and industry leaders to discuss current and potential issues affecting the future of diagnostic clinical microbiology. The goal of the CMO session on breakpoints was to bring together the stakeholders to identify areas to improve application of current breakpoints for better patient care.

This minireview summarizes the breakpoint setting process in the U.S. and highlights potential solutions to close the gap between breakpoint revisions and implementation in clinical and public health laboratories that was discussed at the ASM CMO meeting.

BREAKPOINT BASICS

Many breakpoints were updated in the last 20 years because of changes in the types of data used to establish breakpoints. Originally, decisions were based upon MIC distribution data for organism groups and patient outcome data by MIC. These data provided limited decision-making information. In vitro MIC data do not consider human response factors contributing to therapeutic efficacy nor do they consider variable dosing and site of infection which can determine the amount of antimicrobial that accumulates at the site of infection (i.e., antimicrobial exposure), which is also a key factor for therapeutic success. Similarly, clinical data can be limited because registrational clinical trials may not enroll patients with resistant infections as they may not be encountered during the conduct of a trial due to the lower incidence of resistance to newer antimicrobial agents. To solve some of these problems, pharmacokinetic (PK) data (i.e., the drug distribution in and elimination out of the body) and pharmacodynamic (PD) data (i.e., the antimicrobial activity) were introduced in the early 2000s to help guide breakpoint decisions. These data, collected in healthy individuals and animal models, are used to model the percentage of a population which are likely to achieve a therapeutic target (e.g., time-dependent agents require that the drug concentrations be above the MIC for a certain percentage of the dosing interval) per MIC of an infectious agent like a species of Enterobacterales (12). This mathematical model is assembled using principles of a Monte Carlo simulation (13). The model may be further informed by PK data from patients or special populations (i.e., patients with specific infection types or complications that effect drug exposure like renal insufficiency). Information from this model can fill in knowledge gaps created by limited clinical study outcomes and drive more accurate breakpoints. A complete summary of data used to guide breakpoint decisions can be found in CLSI document M23 (12).

Since PK/PD data were a significant source of new information, many breakpoints were re-evaluated to consider these new data. These revisions include breakpoint adjustments for dose options (i.e., different dosing strategies based on the AST results to achieve levels that are like to be clinically effective) and the establishment of site-specific breakpoints (e.g., cerebrospinal fluid- or urine-specific breakpoints) (5).

Breakpoint Setting Organizations

There are three major breakpoint setting organizations/bodies: the CLSI, the U.S. Food and Drug Administration (FDA), and the European Committee for Antimicrobial Susceptibility Testing (EUCAST) (5 – 7, 14). CLSI is a not-for-profit standards development organization (SDO) that sets laboratory standards for a wide range of medical laboratory practices (https://clsi.org/). FDA has federal authority to regulate drugs and devices used in medical practice, including antimicrobials and AST devices (www.fda.gov). The FDA Center for Drug Evaluation and Research (CDER) regulates antimicrobials and breakpoints, while the FDA Center for Devices and Radiological Health (CDRH) regulates AST devices, including breakpoint implementation on these devices, based upon CDER recognized breakpoints at the time of device clearance. EUCAST establishes guidelines for AST methods and breakpoints (www.eucast.org). EUCAST breakpoints are recognized by the European Medicines Agency (ww.ema.org). For this review, we will focus on differences in breakpoints between FDA and CLSI. CLSI is an SDO that meets standards of the American National Standards Institute (ANSI) (www.ansi.org) and is recognized by the FDA as a breakpoint SDO (7). Recognition as an SDO by ANSI and U.S. federal agencies means that the organization meets tenets of transparency, openness to participation by interested stakeholders, balance of representation, and due process, among other principles (https://www.fda.gov/medical-devices/premarket-submissions-selecting-and-preparing-correct-submission/standards-and-conformity-assessment-program). Several CLSI documents are recognized as voluntary standards by the FDA. Voluntary standards are recognized standards that the FDA has reviewed and recognized conformity with FDA standards (https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfStandards/search.cfm).

Establishing and Updating Breakpoints by FDA-CDER and CLSI

The process for setting breakpoints for new antimicrobial drugs is different from revising or updating breakpoints for an on market antimicrobial (Fig. 1). Breakpoints for a new drug are usually established by FDA-CDER when a new drug application (NDA) is reviewed (i.e., at the time of initial FDA-approval of a drug). Data used to establish these breakpoints are collected by a pharmaceutical company during drug development and the registrational clinical trials which evaluate drug efficacy. Previously, FDA-recognized breakpoints were published in drug labels but, as mandated in the 21st Century Cures Act (https://www.congress.gov/114/plaws/publ255/PLAW-114publ255.pdf), breakpoints were moved to a website entitled Antibacterial Susceptibility Test Interpretive Criteria (STIC) (7). Placement of breakpoints on this website allows the FDA to update breakpoints more easily when a clinical need exists and provides a single location for all FDA-recognized breakpoints rather than locating these in various drug labels.

Fig 1.

Breakpoint setting process in the U.S. Breakpoint differences for new drugs may occur because FDA tends to rely more on clinical trial data than CLSI does when there are significant differences between the clinical trial cutoff and the PK/PD cutoff. This is the usual process, but exceptions can occur. Conditions for considering a breakpoint revision are outlined in CLSI document M23. Briefly, these include the emergence of new types of antimicrobial resistance, new clinical and PK/PD data indicating that the current breakpoints may be wrong, and a shift in dosing practices that significantly differs from original dosing recommendations [see CLSI M23 for a complete list (12)].

If a pharmaceutical company chooses to publish breakpoints for the first time in CLSI documents, it submits data to the CLSI AST subcommittee for consideration. These data are usually for new antimicrobials and are usually the same data that were presented to the FDA as part of the NDA. The subcommittee reviews the data and makes an independent decision from the FDA for breakpoints. If the breakpoints decided by CLSI differ from those recommended by FDA, then CLSI will ask FDA to consider this change by drafting a rationale document and submitting it to the FDA. This step is necessary because the FDA only allows a commercial AST device to report FDA-recognized breakpoints. If the FDA recognizes the CLSI breakpoint, a commercial AST device can submit data to the FDA for clearance and, if successful, report the new FDA-recognized breakpoint. If a pharmaceutical company does not initiate the process of submitting data to the CLSI AST subcommittee for consideration, then CLSI recognized breakpoints will not exist. For example, tigecycline data were never presented to the CLSI AST subcommittee for review and the reason why there are no CLSI breakpoints for this drug. However, the FDA recognizes breakpoints for tigecycline; data on the agent can be submitted to the FDA for clearance and reporting of the FDA-recognized breakpoints for commercial AST devices.

CLSI may also decide to revise an existing breakpoint in the CLSI document for a previously approved antimicrobial agent (Fig. 1). Reasons for considering a breakpoint revision are outlined in CLSI document M23. Briefly, these include the emergence of new types of antimicrobial resistance; new clinical and PK/PD data indicating that the current breakpoints may be wrong and a shift in dosing practices that significantly differs from original dosing recommendations [see CLSI M23 for a complete list (12)]. The data used to evaluate a breakpoint revision usually rely on peer-reviewed published data and, for the most part, are not as robust as the clinical trials required by the FDA as part of the NDA process for initial FDA breakpoint establishment. However, these data may better reflect current clinical practice and outcomes. After the data are reviewed, CLSI may decide to revise the breakpoint. When this occurs, CLSI writes a rationale document and submits to FDA for consideration for inclusion on FDA’s STIC website so that these revised breakpoints can be used with FDA-cleared AST devices. In this case, manufacturers of AST devices with FDA clearance using the old breakpoints can submit data for FDA-cleared reporting of AST results using the revised breakpoints. The submission can be a re-evaluation of existing clinical trial data if no new types of antimicrobial-resistant bacteria have emerged since the original clearance. Otherwise, new data are generated and included in the submission. The revised CLSI breakpoints can be implemented without delay in countries outside of the U.S. that recognize ISO 20776–2 guidance for determining performance of a commercial AST device. This is because these ISO performance standards are independent of breakpoints and instead ensure quality reporting by assessing essential agreement (EA) and bias for the reporting range of an AST device (15, 16). Within the U.S., AST device manufacturers must comply with FDA regulations as detailed further below under FDA-CDRH Clearance of AST Devices for Updated Breakpoints.

FDA-CDER reviews CLSI rationale documents and considers whether a new or revised breakpoint can be recognized on the STIC website. The FDA recognizes many of the CLSI breakpoints published in various documents (e.g., M45, M27, M44S, M62, and M100); it does not recognize all breakpoints (5, 17 – 19). The data used by FDA-CDER to recognize a breakpoint are similar to data used by CLSI, and several of the CLSI rationale documents have resulted in breakpoint changes on the STIC website, but others have not ((12) see examples below). The FDA may not recognize a breakpoint if it finds the data supporting the breakpoint insufficient. In general, the FDA has based its breakpoint determinations on FDA-approved dosing regimens. This differs from CLSI, which is more flexible in adjusting breakpoints based upon current clinical needs and practices. This difference in practice has resulted in breakpoint differences and gaps on the STIC website compared to those published in CLSI M100 (Table 1) (5). This also results in the lack of FDA-cleared AST devices for antimicrobial agent/organism combinations where the FDA does not recognize a CLSI breakpoint.

TABLE 1.

Breakpoint differences for drugs listed on the FDA STIC website compared to CLSI breakpoints

Drug name	Organism/organism group	Comments
Colistin	Acinetobacter species	No FDA STIC breakpoints
Imipenem-relebactam	Acinetobacter species	No CLSI breakpoints
Cefepime	Acinetobacter species	No FDA STIC breakpoints
Cefiderocol	Acinetobacter species	FDA STIC breakpoints differ
Cefotaxime	Acinetobacter species	FDA STIC breakpoints differ
Ceftriaxone	Acinetobacter species	No FDA STIC breakpoints
Ciprofloxacin	Acinetobacter species	No FDA STIC breakpoints
Gatifloxacin	Acinetobacter species	No FDA STIC breakpoints
Gentamicin	Acinetobacter species	No FDA STIC breakpoints
Levofloxacin	Acinetobacter species	No FDA STIC breakpoints
Polymyxin B	Acinetobacter species	No FDA STIC breakpoints
Ticarcillin-clavulanate	Acinetobacter species	No FDA STIC breakpoints
Tobramycin	Acinetobacter species	No FDA STIC breakpoints
Trimethoprim-sulfamethoxazole	Acinetobacter species	No FDA STIC breakpoints
Azithromycin	Beta-hemolytic Streptococcus	No FDA STIC breakpoints
Chloramphenicol	Beta-hemolytic Streptococcus	No FDA STIC breakpoints
Tigecycline	Beta-hemolytic Streptococcus	No CLSI breakpoints
Chloramphenicol	Burkholderia cepacia complex	No FDA STIC breakpoints
Levofloxacin	Burkholderia cepacia complex	No FDA STIC breakpoints
Meropenem	Burkholderia cepacia complex	No FDA STIC breakpoints
Minocycline	Burkholderia cepacia complex	No FDA STIC breakpoints
Ticarcillin-clavulanate	Burkholderia cepacia complex	No FDA STIC breakpoints
Trimethoprim-sulfamethoxazole	Burkholderia cepacia complex	No FDA STIC breakpoints
Cefaclor	Enterobacterales	No FDA STIC breakpoints
Cefazolin—uncomplicated urinary tract infections (UTIs)	Enterobacterales	No FDA STIC breakpoints for UTIs
Cefdinir	Enterobacterales	No FDA STIC breakpoints
Cefoperazone	Enterobacterales	FDA STIC breakpoints differ
Cefotetan	Enterobacterales	FDA STIC breakpoints differ
Cefoxitin	Enterobacterales	FDA STIC breakpoints differ
Cefprozil	Enterobacterales	No FDA STIC breakpoints
Ceftibuten	Enterobacterales	FDA STIC breakpoints are for oral only, no parenteral breakpoints
Cefuroxime (parenteral)	Enterobacterales
Colistin	Enterobacterales	No FDA STIC breakpoints
Moxifloxacin	Enterobacterales	No CLSI breakpoints
Polymyxin B	Enterobacterales	No FDA STIC breakpoints
Tigecycline	Enterobacterales	No CLSI breakpoints
Eravacycline	Enterobacterales: Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae only	No CLSI breakpoints
Delafloxacin	Enterobacterales: Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae only	No CLSI breakpoints
Azithromycin	Enterobacterales: Salmonella enterica ser. Typhi only	No FDA STIC breakpoints
Azithromycin	Enterobacterales: Shigella species only	No FDA STIC breakpoints
Chloramphenicol	Enterococcus species	No FDA STIC breakpoints
Daptomycin	Enterococcus species: Enterococcus faecalis only	No FDA STIC breakpoints for E. faecium
Doxycycline	Enterococcus species	No FDA STIC breakpoints
Minocycline	Enterococcus species	No FDA STIC breakpoints
Rifampin	Enterococcus species	No FDA STIC breakpoints
Moxifloxacin	Enterococcus species: Enterococcus faecalis only	No FDA STIC breakpoints for Enterococcus species other than E. faecalis
Tigecycline	Enterococcus species: Vancomycin susceptible Enterococcus faecalis only	No CLSI breakpoints. No FDA breakpoints for vancomycin-resistant Enterococcus species
Aztreonam	Other non-Enterobacterales	No FDA STIC breakpoints
Cefepime	Other non-Enterobacterales	No FDA STIC breakpoints
Cefoperazone	Other non-Enterobacterales	FDA STIC breakpoints differ
Cefotaxime	Other non-Enterobacterales	FDA STIC breakpoints differ
Ceftazidime	Other non-Enterobacterales	No FDA STIC breakpoints
Ceftriaxone	Other non-Enterobacterales	No FDA STIC breakpoints
Chloramphenicol	Other non-Enterobacterales	No FDA STIC breakpoints
Ciprofloxacin	Other non-Enterobacterales	No FDA STIC breakpoints
Doxycycline	Other non-Enterobacterales	No FDA STIC breakpoints
Gentamicin	Other non-Enterobacterales	No FDA STIC breakpoints
Imipenem	Other non-Enterobacterales	No FDA STIC breakpoints
Levofloxacin	Other non-Enterobacterales	No FDA STIC breakpoints
Meropenem	Other non-Enterobacterales	No FDA STIC breakpoints
Minocycline	Other non-Enterobacterales	No FDA STIC breakpoints
Ofloxacin	Other non-Enterobacterales	No FDA STIC breakpoints
Piperacillin-tazobactam	Other non-Enterobacterales	No FDA STIC breakpoints
Tetracycline	Other non-Enterobacterales	No FDA STIC breakpoints
Ticarcillin-clavulanate	Other non-Enterobacterales	No FDA STIC breakpoints
Tobramycin	Other non-Enterobacterales	No FDA STIC breakpoints
Trimethoprim-sulfamethoxazole	Other non-Enterobacterales	No FDA STIC breakpoints
Cefepime	Pseudomonas aeruginosa
Cefiderocol	Pseudomonas aeruginosa	FDA STIC breakpoints differ
Ceftazidime	Pseudomonas aeruginosa
Colistin	Pseudomonas aeruginosa	No FDA STIC breakpoints
Delafloxacin	Pseudomonas aeruginosa	No CLSI breakpoints
Polymyxin B	Pseudomonas aeruginosa	No FDA STIC breakpoints
Chloramphenicol	Staphylococcus species	No FDA STIC breakpoints
Dirithromycin	Staphylococcus species	Dirithromycin not listed on FDA STIC website
Doxycycline	Staphylococcus species	No FDA STIC breakpoints
Levofloxacin	Staphylococcus species	No FDA STIC breakpoints for methicillin-resistant Staphylococcus sp.
Norfloxacin	Staphylococcus species	Norfloxacin not listed on FDA STIC website; CLSI BPs removed in 2019, reinstated in 2020
Ofloxacin	Staphylococcus species	*FDA STIC website lists BPs as 2/4/8 for MSSA only
Rifampin	Staphylococcus species	No FDA STIC breakpoints
Trimethoprim-sulfamethoxazole	Staphylococcus species	No FDA STIC breakpoints
Amikacin	Staphylococcus species: Staphylococcus aureus only	No CLSI breakpoints
Ceftaroline	Staphylococcus species: Staphylococcus aureus only	FDA STIC breakpoints differ
Tigecycline	Staphylococcus species: Staphylococcus aureus only	No CLSI breakpoints
Cefiderocol	Stenotrophomonas maltophilia	No FDA STIC breakpoints
Chloramphenicol	Stenotrophomonas maltophilia	No FDA STIC breakpoints
Levofloxacin	Stenotrophomonas maltophilia	No FDA STIC breakpoints
Minocycline	Stenotrophomonas maltophilia	No FDA STIC breakpoints
Ticarcillin-clavulanate	Stenotrophomonas maltophilia	No FDA STIC breakpoints
Trimethoprim-sulfamethoxazole	Stenotrophomonas maltophilia	No FDA STIC breakpoints
Cefepime (meningitis)	Streptococcus pneumoniae	No FDA STIC breakpoints for meningitis
Cefprozil	Streptococcus pneumoniae	FDA STIC breakpoints differ
Chloramphenicol	Streptococcus pneumoniae	No FDA STIC breakpoints
Loracarbef	Streptococcus pneumoniae	No FDA STIC breakpoints
Quinupristin-dalfopristin	Streptococcus pneumoniae	No FDA STIC breakpoints
Rifampin	Streptococcus pneumoniae	No FDA STIC breakpoints
Tigecycline	Streptococcus pneumoniae	No CLSI breakpoints
Vancomycin	Streptococcus pneumoniae	No FDA STIC breakpoints
Azithromycin	Streptococcus viridans group	No FDA STIC breakpoints
Chloramphenicol	Streptococcus viridans group	No FDA STIC breakpoints
Clarithromycin	Streptococcus viridans group	No FDA STIC breakpoints
Daptomycin	Streptococcus viridans group	FDA STIC website does not list BPs for Streptococcus sp. viridans group
Levofloxacin	Streptococcus viridans group	No FDA STIC breakpoints
Ofloxacin	Streptococcus viridans group	No FDA STIC breakpoints
Tetracycline	Streptococcus viridans group	No FDA STIC breakpoints
Tigecycline	Streptococcus viridans group	No CLSI breakpoints
Amoxicillin-clavulanate	Haemophilus influenzae and Haemophilus parainfluenzae	FDA STIC breakpoints differ
Cefotaxime	Haemophilus influenzae and H. parainfluenzae	FDA STIC breakpoints differ
Cefonicid	Haemophilus influenzae and H. parainfluenzae	No FDA STIC breakpoints
Cefamandole	Haemophilus influenzae and H. parainfluenzae	No FDA STIC breakpoints
Cefepime	Haemophilus influenzae and H. parainfluenzae	No FDA STIC breakpoints
Ceftizoxime	Haemophilus influenzae and H. parainfluenzae	No FDA STIC breakpoints
Cefaclor	Haemophilus influenzae and H. parainfluenzae	No FDA STIC breakpoints
Cefprozil	Haemophilus influenzae and H. parainfluenzae	No FDA STIC breakpoints
Cefdinir	Haemophilus influenzae and H. parainfluenzae	No FDA STIC breakpoints
Loracarbef	Haemophilus influenzae and H. parainfluenzae	No FDA STIC breakpoints
Ceftibuten	Haemophilus influenzae and H. parainfluenzae	No FDA STIC breakpoints
Cefetamet	Haemophilus influenzae and H. parainfluenzae	No FDA STIC breakpoints
Doripenem	Haemophilus influenzae and H. parainfluenzae	No FDA STIC breakpoints
Gatifloxacin	Haemophilus influenzae and H. parainfluenzae	No FDA STIC breakpoints
Grepafloxacin	Haemophilus influenzae and H. parainfluenzae	No FDA STIC breakpoints
Lomefloxacin	Haemophilus influenzae and H. parainfluenzae	No FDA STIC breakpoints
Sparfloxacin	Haemophilus influenzae and H. parainfluenzae	No FDA STIC breakpoints
Trovafloxacin	Haemophilus influenzae and H. parainfluenzae	No FDA STIC breakpoints
Fleroxacin	Haemophilus influenzae and H. parainfluenzae	No FDA STIC breakpoints
Rifampin	Haemophilus influenzae and H. parainfluenzae	No FDA STIC breakpoints
Cefepime	Neisseria gonorrhoeae	No FDA STIC breakpoints
Ceftizoxime	Neisseria gonorrhoeae	No FDA STIC breakpoints
Azithromycin	Neisseria gonorrhoeae	No FDA STIC breakpoints
Penicillin	Neisseria meningitidis	No FDA STIC breakpoints
Azithromycin	Neisseria meningitidis	No FDA STIC breakpoints
Ciprofloxacin	Neisseria meningitidis	No FDA STIC breakpoints
Levofloxacin	Neisseria meningitidis	No FDA STIC breakpoints
Sulfisoxazole	Neisseria meningitidis	No FDA STIC breakpoints
Trimethoprim-sulfamethoxazole	Neisseria meningitidis	No FDA STIC breakpoints
Chloramphenicol	Neisseria meningitidis	No FDA STIC breakpoints
Ampicillin	Anaerobes	No FDA STIC breakpoints
Penicillin	Anaerobes	No FDA STIC breakpoints
Amoxicillin-clavulanate	Anaerobes	No FDA STIC breakpoints
Ampicillin-sulbactam	Anaerobes	No FDA STIC breakpoints
Cefotetan	Anaerobes	FDA STIC breakpoints differ
Cefoxitin	Anaerobes	FDA STIC breakpoints differ
Ceftizoxime	Anaerobes	No FDA STIC breakpoints
Ceftriaxone	Anaerobes	FDA STIC breakpoints differ
Cefmetazole	Anaerobes	No FDA STIC breakpoints
Cefoperazone	Anaerobes	FDA STIC breakpoints differ
Cefotaxime	Anaerobes	FDA STIC breakpoints differ
Doripenem	Anaerobes	FDA STIC breakpoints differ
Chloramphenicol	Anaerobes	No FDA STIC breakpoints

Differences in breakpoints between CLSI and FDA occur for various reasons. These include

1. FDA-rejected breakpoints recommended in a CLSI rationale document because the CLSI breakpoints reflect doses used in clinical practice but differ for those in the FDA-approved drug labeling. An example is the daptomycin breakpoints for Enterococcus faecium based on 8–12 mg/kg/day (https://www.fda.gov/drugs/development-resources/fda-rationale-recognition-decision-daptomycin) and ceftaroline breakpoints for Staphylococcus aureus where the susceptible breakpoint is based on 600 mg/12 h or SDD breakpoint based on 600 mg/8 h administered over 2 h as intravenous infusion (https://www.fda.gov/drugs/development-resources/fda-rationale-recognition-decision-ceftaroline-fosamil).

2. FDA-rejected breakpoints recommended by CLSI for insufficient data. For example, FDA rejected the cefazolin breakpoint for Enterobacterales (surrogate test for oral cephalosporins and uncomplicated urinary tract infections) because of insufficient data to establish a urine-specific breakpoint (https://www.fda.gov/drugs/development-resources/rationale-fdas-position-use-cefazolin-breakpoints-surrogate-determining-breakpoints-oral).

3. CLSI does not submit a rationale document supporting a previously established breakpoint to FDA as the data are not robust enough to meet current breakpoint standards and there is no M23 condition indicating a possible need for breakpoint revision. This most often occurs when the breakpoints were established years ago (e.g., trimethoprim-sulfamethoxazole breakpoints for S. aureus) or for less common bacterial species (e.g., species that are included in the non-Enterobacterales reporting group).

In an era of increasing AMR and a limited antimicrobial pipeline, clinicians are forced to identify uses of drugs outside of the evidence collected in a prospective clinical trial. This gap between initial labeling and actual clinical practice needs to be closed so that breakpoints applied in the laboratory reflect current clinical practice. Similarly, breakpoints are needed for the range of pathogens that can cause infection and not just the most common pathogens.

FDA-CDRH clearance of AST devices for updated breakpoints

Before manufacturers can legally sell or distribute an AST device in the U.S., they must obtain clearance for their device by the FDA. To obtain such clearance, manufacturers must submit a 510K submission packet showing that the device is safe and effective (see reference (20) data required in 510K submission). FDA regulations established in 2007 significantly changed the breakpoint reporting landscape for cleared AST devices in the U.S. Prior to 2007, an AST device could report both CLSI and FDA breakpoints. The regulations were changed to allow AST devices to only report FDA breakpoints; reporting of CLSI breakpoints was “grandfathered” in for devices with pre-2007 510K submissions, and reporting of CLSI breakpoints occurred often because of gaps in FDA breakpoints. A list of breakpoint gaps between CLSI and FDA can be found in Table 1. FDA-CDRH limits for breakpoint reporting requirements apply to all class II devices including MIC tests and antimicrobial disks for disk diffusion testing. Any AST device that has come to market after 2007 is not allowed any claims by FDA for reporting breakpoints where FDA breakpoint gaps occur (i.e., where a CLSI breakpoint may exist, but the FDA does not recognize it) or where the FDA has recognized breakpoints other than CLSI breakpoints.

Currently, when an AST device manufacturer updates a breakpoint, they submit data to the FDA demonstrating that the test performance continues to meet FDA guidance for category agreement (CA) and error rates (i.e., agreement of interpretive criteria categories like S, I, and R and the type of error). Comparison between the commercial AST device and the CLSI reference method, frozen broth microdilution (BMD), may be necessary, but this depends on multiple factors (21). Below are the most common scenarios for updating breakpoints on a commercial AST device.

1. The updated breakpoints can be implemented on the device without the need to redesign (e.g., reformulate) the test, and a Breakpoint Change Protocol (i.e., a streamlined data submission to FDA) was included in the last FDA 510K submission. In this case, a submission that is limited to the breakpoint change only is required.

2. The updated breakpoints can be implemented on the device without the need for re-design, but the last submission of this test occurred before a Breakpoint Change Protocol option was allowed (the FDA first allowed this in 2019). A 510K submission is required.

3. The updated breakpoints can be implemented on the device without the need for re-design, but new types of resistant bacteria emerged since the last submission of this test. A 510K submission is required.

4. The test needs to be re-designed for accurate implementation of the new breakpoints. A 510K submission is required.

An important difference between the Breakpoint Change Protocol and 510K submission options is the extent of decision making that FDA will apply for a breakpoint update. The Breakpoint Change Protocol limits FDA decision making to the breakpoint change only because that is the only data submitted. For a 510K submission, the manufacturer must provide all data for all reporting options of a drug, and the FDA will consider all claims for a drug. If, for example, the 510K submission is to update a commercial device’s meropenem breakpoints for Enterobacterales to reflect the 2010 CLSI change, then the FDA will consider all claims for meropenem reporting for the device, not just the claims associated with the organism group requiring a breakpoint change. This occurs because the FDA is required to implement all current regulatory requirements within the scope of the submission. A 510K submission for updated meropenem breakpoints for the Enterobacterales reporting group will result in removal of claims for all organism groups where FDA has a breakpoint gap (if the device was previously cleared for those organisms). For meropenem, this means that reporting for non-Enterobacterales and Burkholderia cepacia complex would no longer be allowed. In other words, removal of claims means there is no more grandfathered reporting of CLSI breakpoints for this device cleared prior to 2007. This may disincentivize AST device manufacturers from wanting to update the breakpoints. Users of the device will benefit from updated Enterobacterales breakpoints, but other reporting is now considered off-label testing. The end user is faced with either the regulatory burden of implementing an off-label test, the logistical and cost burden of implementing multiple tests to fill in all breakpoint reporting gaps, or the clinical burden of not being able to produce sufficient data to drive therapeutic decisions, which might affect patient management and outcomes. The problem of off-label testing is greater for AST devices that have recently come to market because no grandfathered reporting of CLSI breakpoints is permitted. These practices create an environment where claims allowed on a device are based upon the date that a test on an AST device was most recently FDA-cleared and not upon test performance.

Updating breakpoints in the microbiology laboratory

Keeping up to date with AST breakpoints is a challenging but critically important task for the clinical laboratory that impacts the quality of patient care and patient safety. Until recently, there was no obligation of laboratories to keep up to date with evolving AST breakpoints. To address this, CAP implemented requirements for CAP-accredited laboratories (i) to list what breakpoints they are applying to interpret AST results and (ii) to implement use of up-to-date breakpoints for patient care (22).

For the first item, the revised CAP checklist MIC.11380 (previously MIC.21930) requires laboratories to understand and have a record of which breakpoints are applied on AST methods used in their laboratory. Many laboratories assume that if their device is FDA-cleared, they are applying the most up-to-date breakpoints. However, this assumption is not always correct and needs to be verified by the users of the system as the breakpoints applied can vary based on the date of device clearance vs the breakpoint update, the panel, software, and reporting structure applied. Although AST devices marketed in the U.S. must apply the most up-to-date FDA-recognized breakpoints at the time of initial clearance, there is currently no FDA regulatory requirement that the manufacturer update their system as breakpoints change outside of the provided recommendation in the 2009 FDA-CDER/CDRH guidance (20). As such, devices that were cleared >10 years ago may continue to apply obsolete, pre-2010 breakpoints, and some manufacturers have continued to market panels that apply obsolete breakpoints. Furthermore, application of breakpoint interpretations can occur at multiple points in the process, whether that be by manual interpretation of results, an automated AST system middleware, in the laboratory information system (LIS), or the electronic health care (EHR) record. Thus, laboratories should know and record where the final interpretation of results occur during the process. For some laboratories, there might be different scenarios requiring different reporting structures. For example, many laboratories apply AST interpretations in the middleware of their automated system; those interpretations are carried through to the LIS and on to the EHR. However, some interpretations may be at the LIS level or even at the EHR level. As an example, SDD interpretations may not cross from the AST device middleware into the LIS and may require application at the EHR level instead. Thus, laboratories need to understand where breakpoint interpretations are applied to ensure that the current breakpoints and interpretations are utilized. The CAP Microbiology and CLSI’s ad hoc working group on Breakpoint Implementation committees have assembled an Excel template, along with instructions to assess compliance with currently accepted breakpoints (https://clsi.org/standards/products/microbiology/companion/bpiu/). Completion of the template will likely require the laboratory to contact its commercial AST system manufacturer (if appropriate) to understand what breakpoints are being applied based on the panel, software, and expert rules utilized. Based on this exercise, laboratories will gain an understanding of breakpoints utilized and can identify the use of obsolete breakpoints that will help address the new checklist item, MIC.11385. The template should be reviewed on an annual basis to remain in compliance with MIC.11380.

The second checklist item, MIC.11385, is new and goes into effect on 1 January 2024. This item requires laboratories to use current breakpoints for MIC and disk diffusion tests within 3 years of the date of official publication by the FDA, for laboratories in the U.S. Outside the U.S., laboratories should follow local regulatory requirements and may choose to apply EUCAST, CLSI, or FDA breakpoints, but again within 3 years of their publication by the SDO in use by the laboratory. There are instances when CLSI or other SDOs may update breakpoints, but it is not immediately recognized by the FDA. In those scenarios, laboratories in the U.S. may wait to update the breakpoint within 3 years of the FDA recognition of the updated breakpoint. If the FDA update does not occur with the breakpoint, or it is different from the SDO, the laboratory may choose to use current SDO or FDA breakpoints. The implementation path (including verification or validation of the revised breakpoints) will depend on whether the device manufacturer has updated labeling to incorporate the new breakpoints. A list of updated CLSI breakpoints can be found in the M100, and the FDA breakpoints are found on the FDA STIC website (5 – 7). The “Breakpoint in Use Template” provides the current CLSI and FDA breakpoints for comparison and evaluation of compliance (https://clsi.org/meetings/ast/breakpoints-in-use-toolkit/; See Part A Breakpoints in Use). The laboratory may choose to apply CLSI, EUCAST, or FDA breakpoints (depending on location), but they must review the breakpoints applied on an annual basis.

Once laboratories have established what breakpoints are applied in their laboratory (MIC.11380), they need to identify which breakpoints are obsolete and need to be updated for compliance with the new checklist item by 1 January 2024. If significant discrepancies exist, the laboratory should work with the antimicrobial stewardship team and clinical colleagues to prioritize the updates required. Alternatively, they may want to evaluate different panels for their current automated AST systems or evaluate a different system altogether to address multiple breakpoint updates at once. Laboratories may adopt a methodology that is up to date, discontinue testing, send out to a reference laboratory, or validate their current AST systems off-label for updated breakpoints. For U.S. laboratories, CLIA regulations allow laboratories to make such modifications to AST devices, provided the laboratory performs analytical studies to validate the modification prior to implementation. However, many laboratories lack the guidance and resources required to do so. As such, various stakeholders, CLSI, ASM, the Association of Public Health Laboratories, and CDC have created tools and resources for laboratories to validate off-label testing to comply with the new checklist items. Table 2 summarizes the current resources available to laboratories to address breakpoint updates. Although this new CAP oversight is a step in the right direction, only 40% of Clinical Laboratory Improvement Amendments (CLIA)-licensed laboratories in the U.S. are CAP accredited. Thus, additional oversight for all CLIA-licensed laboratories should be pursued by regulatory bodies. Ideally, additional regulation would extend in some capacity internationally as AMR is a global public health threat.

TABLE 2.

Resources created by various communities to support updated breakpoint applications by clinical and public health laboratories

Resource	Description	Location of resource
Breakpoint in Use Template	An Excel template, instructions, and demo data to assess breakpoint application and compliance with CAP MIC.11380	CLSI: https://clsi.org/standards/products/microbiology/companion/bpiu/ https://clsi.org/meetings/ast/breakpoints-in-use-toolkit/; See Part A Breakpoints in Use. CAP: Checklist Resources section of eLabs Solution Suite (ELSS)
Summary of breakpoint additions/revisions	A list of new and revised breakpoints	CLSI: M100 – CLSI Breakpoint Additions/Revisions since 2010 Table (5) FDA: FDA STIC website under “Notice of Updates” (7)
Frequently asked questions on new CAP checklist items	FAQ with answers provided to address the most common questions in regard to the CAP checklist items addressing breakpoints	CAP: Checklist Resources section of ELSS
CDC and FDA Antimicrobial Resistance (AR) Isolate Bank	The bank can be used to obtain isolates to assist with breakpoint verifications/validations. The MIC data were generated by reference BMD method and repeatedly tested to obtain a mode that can be used as the comparator result for verification/validation studies.	https://www.cdc.gov/drugresistance/resistance-bank/index.html
Breakpoint Implementation Toolkits	Toolkits to guide laboratories through verification/validation studies required to implement updated clinical breakpoints. These toolkits include instructions, recommended CDC & FDA AR Isolate Bank isolates, an outline of a verification/validation plan, worksheets for data input and analysis, and example verification/validation summaries.	APHL CRO Breakpoint Implementation Toolkit (aphl.org) CLSI Breakpoint Implementation Toolkit: https://clsi.org/all-free-resources/ https://clsi.org/meetings/ast/breakpoints-in-use-toolkit/
Educational Webinars	Freely available webinars to understand the need for updating clinical breakpoints and how to address updating clinical breakpoints in the laboratory	CLSI and CAP: Breakpoints Matter: Understanding CLSI Efforts and New CAP Requirements to Ensure Appropriate Antimicrobial Treatment for All Patients (https://clsi.org/standards/products/microbiology/education/astcap22wr/) CAP: Introduction to Microbiology: Breakpoints by Dr. Romney Humphries (https://documents-cloud.cap.org/appdocs/learning/LAP/FFoC/MicroBreakpoints/index.html#/) CLSI: Update Breakpoints – Challenges and Solutions for Various Stakeholders (https://clsi.org/standards/products/microbiology/education/astedujune22wr/)
Identifying breakpoints applied by your automated AST device	Resources available through commercial, automated AST devices manufacturers to identify breakpoints applied by your system	Contact your commercial device manufacturer for further guidance

POTENTIAL SOLUTIONS: ASSEMBLING STAKEHOLDERS AT THE CLINICAL MICROBIOLOGY OPEN

Broader application of updated breakpoints requires action from AST device manufacturers, regulatory agencies, laboratories, laboratory accreditation groups, and SDOs. At the CMO, each stakeholder (e.g., AST device manufacturers, clinical laboratory directors, FDA-CDER and CDRH, CDC, CAP, and CLSI) presented their perspective, identified barriers, and provided potential solutions towards a combined objective to improve patient care and public health. These are detailed in Table 3. In addition to hearing from the individual stakeholders, a panel discussion took place where the attendees and stakeholders discussed potential solutions. There were various potential solutions woven into the discussion, including both short-term and long-terms efforts. Selected discussions of potential solutions are highlighted in further detail below.

TABLE 3.

High-level summary of challenges/barriers and potential solutions from various stakeholders discussed at the ASM Clin Micro Open in June 2022 ^a

Stakeholder	Challenges/barriers	Potential solutions
Commercial AST device manufacturers	Legacy devices (i.e., AST devices or panels cleared prior to 2007) and AST device tests approved after implementation of the FDA STIC website are not able to report AST results for CLSI breakpoints not recognized by FDA. This reporting limitation applies to any drug-specific 510K submissions to the FDA. Devices are limited to reporting FDA breakpoints. This removes the ability to test and report many important antimicrobial agent/organism combinations for which CLSI breakpoints are available, but FDA STIC does not have a breakpoint (e.g., trimethoprim-sulfamethoxazole and Stenotrophomonas maltophilia). FDA AST Special Control Document does not reflect current guidance since its last publication, for example, updates to disk diffusion requirements and the addition of the Breakpoint Change Protocol. The regulations surrounding current guidance changes are in previous decision documents for AST devices which are not easy to locate without the knowledge of these decisions.	Allow for Breakpoint Change Protocol to be applicable for legacy AST devices. Implement a MIC-only reporting structure following ISO 20776–2, which is independent of breakpoints. The requirements would be essential agreement and bias assessment across the reportable MIC range. Permit use of a recognized SDO (e.g., CLSI) or FDA breakpoints at the time of FDA clearance/approval of a device. FDA should consider revisions of the AST Special Control document to reflect current requirement and updated decisions by the FDA.
FDA-CDRH	Need to follow current regulation and law surrounding AST devices. Although significant changes have occurred, current laws and regulations do not support further changes to facilitate breakpoint updates for commercial AST device manufacturers in the absence of FDA-recognized breakpoints.	Continued interaction among stakeholders and FDA-CDRH. Formation of a collaborative community initiated by various stakeholders to address the challenge in partnership with the FDA.
CDC	The National Healthcare Safety Network annual survey found higher breakpoint compliance than the CAP-accredited laboratory survey. The survey respondent may be an infection preventionist, and thus, these results may demonstrate a lack of awareness of the use of outdated breakpoints by staff outside of the laboratory. Current estimates of AMR rates used to create the CDC Antibiotic Resistance Threats report may rely on data obtained from outdated breakpoints, which may underestimate AMR rates as breakpoint updates for the most part result in lowered breakpoints (1). CDC-FDA AR Isolate Bank isolates are an excellent resource and an interim solution to help laboratories verify on-label breakpoints or validate commercial AST devices off-label to update breakpoints, although panels are not currently available for all breakpoint revisions (see Table 2).	Create awareness within and outside the laboratory on the impact of applying outdated breakpoints for both patient care and public health. Encourage more interaction between the laboratory and infection prevention and control and antibiotic stewardship teams. Encourage the use of current breakpoints to more accurately detect AMR for patient care and public health prevention efforts.
CAP	Lack of consensus on proficiency testing challenges because of variable breakpoint application among laboratories. False susceptibility reporting because of laboratory use of outdated breakpoints.	Mandate that CAP-accredited laboratories understand what breakpoints are applied in their laboratory and that current breakpoints be applied within 3 years of recognition by the FDA in the U.S. or an SDO outside the US [CAP Checklist items; MIC.11380 and MIC.11385; see reference (22)]
CLSI	Not all CLSI breakpoints are currently recognized by the FDA (e.g., FDA will not recognize breakpoints for trimethoprim-sulfamethoxazole and Stenotrophomonas maltophilia, which is accepted as first-line therapy). Breakpoint revisions often reflect current clinical practice which may not reflect the dosing in the prescriber’s information as submitted with the initial approval of the agent. In these scenarios, the FDA has not recognized the breakpoint updates despite the revised breakpoints more accurately reflecting clinical practice and likely outcomes. For breakpoint revisions, the data are not being generated by funding put forward by pharmaceutical companies, and data considered by CLSI often rely on peer-reviewed publications which may not meet the stringency of FDA requirements set forth on initial breakpoint applications (i.e., there are no randomized clinical control studies).	Identify opportunities to use real-world data to generate the evidence required by the FDA to accept a revised breakpoint rather than needing an expensive randomized clinical trial to be executed.
Clinical and public health laboratories	Smaller laboratories do not have a dedicated doctoral-trained clinical microbiologist and operate with fewer technical resources to help perform verification of FDA-cleared breakpoints or validation of breakpoints off-label. Resources including time, staff and funds to perform verification/validation studies as required.	Create awareness about breakpoint updates and need to verify/validate updated breakpoints. Create resources for laboratories of all sizes to be able to update breakpoints (see Table 2). Create easily accessible isolate banks with −20°C to room temperature stability covering relevant breakpoints. validation gaps. Continue to promote timely “real-world” studies within the academic community regarding the performance of newly adopted CLSI breakpoints on commercial devices most likely to be used by clinical laboratories (CLSI breakpoint changes are based on studies using reference methodologies and not commercial devices). Advocate for additional resources and support from all levels within each individual hospital system, regionally and nationally. Encourage appropriate laboratory oversight by a doctoral-level trained clinical microbiologist. Simplify regulatory requirements and reduce the need for off-label validations.
Professional societies (e.g., ASM, IDSA, SIDP, PIDS, SHEA)	Advocacy needed to improve implementation of updated breakpoints	Include clinical microbiology on the antibiotic stewardship team so that the laboratory can better support improved antibiotic use. Organize a Collaborative Community meeting with FDA to promote dialogue on this topic.

^a ASM, American Society for Microbiology; IDSA, Infectious Diseases Society of America; PIDS, Pediatric Infectious Diseases Society; SHEA, Society for Healthcare Epidemiology of America; SIDP, Society of Infectious Diseases Pharmacists.

Allow MIC-only reporting for FDA STIC breakpoint gaps

Performance characteristics required by the FDA for AST system clearance, includes both EA (i.e., MIC agreement within ±1 doubling dilution) and CA (i.e., agreement between interpretive categories) with a reference method. If the FDA does not recognize a breakpoint for an antimicrobial agent/organism combination, then clearance of AST devices for reporting MICs without interpretations from an AST device would allow a laboratory to apply a CLSI breakpoint. Category agreement is important for measuring AST device accuracy, but the FDA could use MIC bias standards across the MIC range to mitigate risks of category errors if MICs trend high or low compared to reference BMD for a particular method. This solution could be achieved by the FDA setting a new standard for reporting when FDA breakpoint gaps exist, or adoption of ISO 20776–2 (16), which is the data standard for AST devices outside of the U.S. This standard requires MIC EA and bias performance standards, but no CA performance standard as it is independent of defined breakpoints.

Clarify the data needed by FDA for breakpoint updates and streamline the submission pathway

The Antimicrobial Susceptibility Test Systems–Class II Special Controls Guidance for Industry and FDA (referred to as the AST Special Controls document hereafter) lists the studies and acceptability criteria required of AST device manufacturers prior to FDA regulation of a device and market availability (20). The current version of the document was revised and published in 2009. Since publication, there have been significant efforts and beneficial updates by the FDA that facilitated and streamlined AST device submission and data review. These changes include coordinated development to allow concurrent FDA reviews of a new antimicrobial with clearance of an AST device that enables testing of the new drug, clearance of disk diffusion devices as part of an NDA, streamlined review of updated breakpoints using the Breakpoint Change Protocol, decoupling of breakpoints from prescriber information on the STIC website, and the use of adjusted error rates for agents with no intermediate category emphasizing the role of essential agreement (https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm?ID=k161227). These updated approaches are not reflected or summarized in the current AST Special Controls document but may be available in other public sources. For example, the Breakpoint Change Protocol is summarized in the K183527 FDA decision summary, which is available in a searchable FDA database of 510K summary decisions if a user knows to look for it there (510(k) Premarket Notification (fda.gov)). Guidance is also needed for updating breakpoints for a disk diffusion test. It would be beneficial for FDA to make these modifications publicly available, preferably in the AST Special Controls document. The first step could be to make a list of these and future recommendations available on an FDA website for easy access by the public so they are easier for AST manufacturers to find.

FDA could consider measures so that claims allowed on a device are based upon test performance and and not upon the data that an AST device was first FDA-cleared. These measures could include the Breakpoint Change Protocol to be applicable for every AST device including legacy devices cleared prior to 2007. This will simplify the manufacturer’s ability to update breakpoints without the need to submit a new 510K packet for review. Other possibilities include consideration for grandfathered reporting of CLSI breakpoints for new AST devices and/or allowing both FDA and CLSI breakpoint reporting on all AST devices.

Close FDA breakpoint gaps

Closing the gap in breakpoints between values on the FDA STIC website and those revised by SDOs like CLSI will require multiple approaches. When dosing strategies in a drug label are not consistent with current clinical practices, there must be options for justifying use of the higher dose for safety and efficacy. This is usually done in a clinical trial, but repeating a clinical trial is a significant logistical and financial barrier. Instead, FDA review of real-world clinical data and publications could be used to expand the use and dosing options of an antimicrobial agent after market launch. In June 2023, the FDA decided to introduce an SDD interpretive category similar to CLSI to allow different dosing strategies be applied to FDA-recognized breakpoints (7). The addition of the SDD category by the FDA will allow for further alignment between CLSI and FDA breakpoints. As an example, the FDA now recognizes a cefepime SDD category (MIC: 4–8 µg/mL) for Enterobacterales at a dose a dose of 2 g every 8 h in patients with normal renal function (7).

Infection-specific breakpoints are a necessity to account for differences in drug distribution. This level of specificity improves the predictive value of breakpoints. When the drug concentration is high at the site of infection, a correctly set infection-specific breakpoint can ensure that the antimicrobial is not unnecessarily discarded. When the drug concentration is low at the site of infection, appropriately adjusted breakpoints and associated comments can ensure that a drug is used at a dose that is specific for the infection type and thereby improve efficacy. The FDA needs methods to set these breakpoints and is taking steps to collect data for this purpose (e.g., the FDA Broad Agency Agreement funding announcements, https://www.fda.gov/emergency-preparedness-and-response/mcm-issues/antimicrobial-resistance -information-fda).

Data are often limited for establishing breakpoints for infrequently isolated bacteria, but when these cause infections, AST results are needed to drive therapeutic decisions. For these pathogens, CLSI has adopted different requirements for data, and this is described in the CLSI M45 guideline (17). Unlike the organisms in the CLSI M100 Standard, extensive microbiological, clinical, and PK/PD data are not normally available for M45 organisms. FDA recognizes some CLSI M45 breakpoints on the STIC website (7). Expanding this practice of recognizing breakpoints with limited clinical outcome data to reporting groups like non-Enterobacterales, B. cepacia complex, and Stenotrophomonas maltophilia, among others, will significantly expand AST results available for these important pathogens.

Advocacy

Using updated breakpoints needs to be the standard of care and this requires more changes. The process for updating breakpoints needs to be faster and easier. Advocacy at multiple levels within the healthcare continuum and congress to help the FDA implement changes for faster and easier breakpoint updates is essential. It is also important that all laboratories reporting AST results understand that using updated breakpoints is essential for aligning with current clinical practices, improving patient care, patient safety, and antibiotic use. One may argue that the implementation and use of updated breakpoints are an antibiotic stewardship issue that could be added to the Joint Commission Standards for antibiotic stewardship programs (https://www.jointcommission.org/resources/patient-safety-topics/infection-prevention-and-control/antibiotic-stewardship/).

Greater dialogue

It was clear from the ASM CMO meeting that the barriers reported by the various constituencies present were poorly understood by others. No effort to implement updated breakpoints will be successful unless the community constituents understand the problems. The FDA-CDRH has a forum in place called “Collaborative Communities” that brings together stakeholders in the medical device ecosystem to achieve common outcomes, solve shared challenges and leverage collective opportunities (https://www.fda.gov/about-fda/cdrh-strategic-priorities-and-updates/collaborative-communities-addressing-health-care-challenges-together). This topic needs to be an ongoing dialogue between constituency partners with responsibility for breakpoint setting, for delivery of accurate AST devices and for the education of laboratory staff. This is one potential forum for discussion.

Summary

To ensure life-threatening infections are adequately treated and transmission of highly resistant organisms is prevented, it is imperative that clinical and public health laboratories perform susceptibility testing using updated clinical breakpoints that reflect current clinical practice and data. FDA-cleared breakpoints are the fastest and easiest way for a laboratory to implement susceptibility testing. Thus, it is important that FDA breakpoints are updated to reflect current clinical practice and data so updated breakpoints get incorporated into FDA-cleared AST devices. Many things need to change before broad-scale application of current breakpoint use becomes a reality in the U.S., but it should be taken up as a common goal and an area of concerted collaboration among healthcare-providers, regulators, public health authorities, industry partners, and standards development organizations. Clinical leaders representing multiple societies and organizations (ASM, IDSA, SHEA, CAP, and SIDP) are working along with the FDA-CDER and CDRH to discuss the issue and seek to identify the next steps. One proposal is to hold a public meeting or workshop with the FDA to begin to move the pendulum forward.