In June 2010, the Clinical and Laboratory Standards Institute (CLSI) published new MIC and disk diffusion interpretive criteria (i.e., breakpoints) for the Enterobacteriaceae for five cephalosporins, including:
- first-generation and third-generation (extended-spectrum) cephalosporins,
- and for three carbapenems (imipenem, meropenem, and ertapenem).
CLSI also published initial breakpoints for doripenem. The revised breakpoints are shown in Table I (PDF). The new MIC breakpoints are one to three doubling dilutions lower than the original breakpoints and the new disk diffusion criteria include larger zone diameters than those in previous guidelines. Thus, many organisms that would have been categorized previously as susceptible using the former breakpoints may now be considered intermediate or resistant.
The new CLSI breakpoints simplify susceptibility testing by obviating the need for extended-spectrum beta-lactamase (ESBL) testing, (i.e., testing isolates using cefotaxime and ceftazidime, with and without the beta-lactamase inhibitor, clavulanic acid) to enhance the detection of strains with low-level cephalosporin resistance.
The modified Hodge test (MHT), which was used to detect carbapenemase activity, also is no longer necessary to detect low-level carbapenem resistance, although both ESBL testing and the MHT may be performed to detect these specific resistance mechanisms for infection control purposes.
The decision to revise the CLSI breakpoints came after several years of intense discussion and debate and was ultimately based on:
- the analysis of the susceptibility test results of literally tens of thousands of organisms tested by disk diffusion and MIC methods;
- characterization of the resistance mechanisms of hundreds of those isolates;
- laboratory proficiency testing data from several sources;
- updated pharmacokinetic and pharmacodynamic (PK/PD) models and analyses;
- and a review of patient outcome data from clinical trials of antimicrobial agents and from the published medical literature.
- The revised disk diffusion breakpoints for cephalosporins and carbapenems can be implemented immediately. There are no regulatory barriers that prevent the use of the revised breakpoints for patient care.
- There are barriers to immediate implementation of the new MIC breakpoints, especially in laboratories that use FDA-cleared automated or other commercial MIC susceptibility testing systems. The manufacturers of these systems cannot ship instruments or software in the United States that have breakpoints installed other than those promulgated by the United States Food and Drug Administration. It may take several years before the FDA clears commercial susceptibility testing systems that include the revised CLSI breakpoints.
- However, laboratories that use FDA-cleared systems can implement the new MIC breakpoints after performing an appropriate validation study (see Appendix A (PDF)). Thus, Infectious Diseases physicians need to work with the Microbiology Laboratory (and vice versa) to determine the best way to implement the new breakpoints in their hospital or healthcare system. Microbiologists, pharmacists, and other IDSA members will also play key roles in the implementation process. The validation pathway allowing the use of alternate breakpoints is outlined in the Clinical Laboratory Improvement Amendment (CLIA) Interpretive Guidelines §493.1253(b)(2).
- Practical approaches for implementing MIC breakpoints:
- Ensure that the microbiology laboratory has the latest CLSI documents including M100 S-21 (2011 edition) or M100 S-20 (2010 edition) and the June 2010 M100 S20 update with the new breakpoints. (Note that the cefazolin breakpoints have changed since the June 2010 M100 update).
- Assess whether the MIC panels and cards for automated susceptibility testing devices have MIC ranges that include dilutions low enough to implement the new breakpoints. This may be an issue specifically for cefazolin and ertapenem (see Appendix B (PDF)).
- Ensure that the laboratory has access to a validation protocol, such as the example in Appendix A (PDF) of this Alert.
- Work with the laboratory to determine what makes most sense for patient care in your hospital in terms of implementing the new or revised breakpoints. Considerations include:
- Prevalence of ESBL- and carbapenemase-producing Enterobacteriaceae in your institution,
- antimicrobial agents available on your hospital formulary, laboratory budget, and availability of laboratory resources for validation testing
- and availability of an alternate method to detect carbapenem-resistant Enterobacteriaceae. This may include using the disk diffusion method with carbapenem disks and the revised (lower) disk breakpoints to test selected isolates of Enterobacteriaceae (e.g., Klebsiella species, E. coli, and Enterobacter species) that are resistant to extended-spectrum cephalosporins.
- Determine either how to phase in the new MIC breakpoints when the FDA-cleared susceptibility testing systems are eventually updated, or take a more pro-active approach by performing an in-house validation test of MIC panels that already have the lower antimicrobial dilutions available.
- ID specialists, Microbiologists, and Pharmacists need to work together with other hospital services to implement changes. This would include infection control, medicine, and surgery services.
- Some laboratory directors may have concerns about “off label” use of FDA-cleared antimicrobial susceptibility testing devices, i.e., using CLSI breakpoints instead of FDA breakpoints. However, according to Clinical Laboratory Improvement Amendments listed in CLIA Interpretive Guidelines §493.1253(b)(2); the CLSI breakpoints can be used and reported after an appropriate in-house validation study is performed and documented. The CLIA Guidelines state:
“Prior to reporting patient test results, the laboratory is responsible for establishing the performance specifications for each modified FDA-cleared or approved test system, each test system not subject to FDA clearance or approval, and each test system for which the manufacturer does not provide performance specifications. The establishment of method performance specifications should provide evidence that the accuracy, precision, analytical sensitivity, and analytical specificity of the procedure is adequate to meet the clients' needs as determined by the laboratory director and clinical consultant. “Modified by the laboratory,” means any change to the assay that could affect its performance specifications for sensitivity, specificity, accuracy, or precision, etc. Laboratory modification of the manufacturer's instructions that could affect performance specifications include but are not limited to:
- Change in specimen handling instructions;
- Change or elimination of a procedural step;
- Change or addition of detector (conjugate) or substrate;
- Change in the cutoff or method of calculating the cutoff for semi-quantitative assays;
- Change in the endpoint or calculation of the endpoint;
- Changing the calibrator/reference material.”
IDSA members are encouraged to review the new/revised CLSI breakpoints (PDF), assess their impact on patient management, and work with the laboratory to implement the breakpoints as appropriate to optimize treatment of infectious diseases in your institution.