What are CLSI Guidelines?
The Clinical and Laboratory Standards Institute (CLSI) is a volunteer-led, multidisciplinary consensus organization that develops and publishes standards for antimicrobial susceptibility testing (AST) methods, interpretive breakpoints, and quality control ranges used by clinical microbiology laboratories in the United States and internationally. 1
Core Functions and Purpose
CLSI serves as the primary standards-setting body for antimicrobial susceptibility testing in the United States, with its recommendations recognized by the FDA and incorporated into commercial AST devices. 2 The organization's work directly impacts patient mortality and morbidity by ensuring laboratories can accurately predict whether antimicrobial therapy will succeed or fail for a given infection. 2
Key Operational Activities
Breakpoint Development: CLSI establishes the critical values (breakpoints) that laboratories use to classify bacterial isolates as susceptible, intermediate, or resistant to specific antimicrobials. 2 These breakpoints integrate microbiological data, pharmacokinetic-pharmacodynamic properties, and clinical outcome data. 2
Reference Method Standardization: CLSI designates broth microdilution (BMD) as the gold standard reference method for antimicrobial susceptibility testing, against which all commercial AST systems are validated. 3 The organization also recognizes agar dilution and disk diffusion as reference methods for specific applications. 3
Quality Control Standards: The organization sets quality control ranges and validates new testing methods to ensure consistency and accuracy across laboratories. 1
Annual Updates: CLSI publishes the Performance Standards for Antimicrobial Susceptibility Testing (M100) as an annual update, incorporating new breakpoints, revised testing recommendations, and emerging resistance mechanisms. 4, 1
Organizational Structure and Process
The CLSI Subcommittee on Antimicrobial Susceptibility Testing operates through a transparent, consensus-based approach with twice-yearly face-to-face meetings and active working groups throughout the year. 1 All meetings are open to the public, and participants include clinical microbiologists, infectious disease pharmacists, and physicians representing healthcare, government, and industry. 1
Critical conflict of interest policies prohibit individuals working for companies with primary financial dependency on drug sales from serving as voting members. 1
Clinical Impact on Patient Outcomes
Preventing Treatment Delays
Poor study design in AST evaluations has led to documented delays in implementing commercial AST systems for new antibiotics, directly limiting physicians' ability to treat life-threatening infections effectively. 3 For example, delays in implementing revised carbapenem breakpoints for Enterobacteriaceae in 2010 facilitated the spread of carbapenem-resistant organisms. 3
ESBL Testing Evolution
CLSI's 2010 updates eliminated the requirement for routine ESBL testing before reporting cephalosporin results when using newer interpretive criteria, though ESBL testing remains valuable for epidemiological and infection control purposes. 3, 5 However, the new ceftazidime (≤4 μg/mL) and cefepime (≤8 μg/mL) susceptible breakpoints fail to identify many ESBL-producing organisms, creating clinical uncertainty about treatment efficacy. 3
Carbapenem Breakpoint Revisions
The revised carbapenem breakpoints were designed to detect carbapenemase-producing Enterobacteriaceae without requiring modified Hodge testing for routine clinical purposes. 3 However, implementation of these breakpoints in regions like Taiwan resulted in significant reclassification of isolates—an additional 12% of ESBL-producing K. pneumoniae and 27% of E. cloacae became non-susceptible to ertapenem. 3
Common Pitfalls and Limitations
Geographic and Practical Considerations
CLSI guidelines are available for non-members at US $500 annually, which is prohibitive for laboratories in resource-poor settings, whereas EUCAST guidelines are freely available. 6 This cost barrier can delay implementation of updated standards in regions with limited resources.
Automated System Compatibility
Some automated AST systems (Vitek II, Phoenix) have MIC ranges that cannot detect susceptible or intermediate isolates when using newer CLSI breakpoints for certain drugs like cefazolin, ertapenem, and ceftriaxone. 3 Laboratories must verify their systems can accommodate updated breakpoints before implementation.
Study Design Requirements
CLSI has established minimum study design requirements for evaluating commercial AST systems because published evaluations often suffer from major design flaws that render results misleading. 3 The M52 guideline provides specific requirements for laboratory verification studies, which are smaller in scope than full performance evaluations. 3
Comparison with EUCAST
While CLSI dominates in the United States, the European Committee on Antimicrobial Susceptibility Testing (EUCAST) provides an alternative set of breakpoints used internationally. 6, 7 Agreement between CLSI and EUCAST interpretations varies by organism and antimicrobial, ranging from slight to almost perfect concordance. 6, 7 The choice of guideline can impact susceptibility categorization and potentially influence dosing decisions, particularly with EUCAST's redefined intermediate category that may indicate need for higher drug dosages. 7