Breakpoint beware: reliance on historical breakpoints for Enterobacteriaceae leads to discrepancies in interpretation of susceptibility testing for carbapenems and cephalosporins and gaps in detection of carbapenem-resistant organisms

  • Melanie L. YarbroughEmail author
  • Meghan A. Wallace
  • Robert F. Potter
  • Alaric W. D’Souza
  • Gautam Dantas
  • Carey-Ann D. Burnham
Original Article


Carbapenem-resistant Enterobacteriaceae (CRE) are an important public health and infection prevention threat. CRE are typically detected via phenotypic antimicrobial susceptibility testing (AST), for which interpretive standards were modified in recent years. Our objective was to measure the impact of breakpoint changes on AST interpretation for CRE. Zone sizes from disk diffusion AST for Enterobacteriaceae isolates recovered from clinical cultures over a 1-year period (n = 10,183) and CRE from clinical and environmental sources from the USA and Pakistan (n = 342) were evaluated. Results were interpreted according to historical (CLSI M100-S19) and current (CLSI M100-S29) breakpoints. Interpretive errors were calculated according to the FDA definitions. Using current breakpoints as the reference standard, 56 (17%) very major (false susceptibility) errors occurred for cefepime and 13 (45%) very major errors for meropenem interpretation using historical breakpoints in clinical isolates of Enterobacteriaceae, corresponding to 12 carbapenemase-producing CRE that would have been missed during the 1-year period. For confirmed blaKPC CP-CRE clinical and environmental isolates (n = 149), the very major error rate for historic breakpoints was 8%, 30%, 63%, and 0% for cefepime, meropenem, imipenem, and ertapenem, respectively. For blaKPC isolates, the use of historical breakpoints would have led to 42 (28%) reports of false susceptibility to meropenem. Failure to adopt updated AST breakpoints may lead to reports of false susceptibility for antimicrobials commonly used to treat Gram-negative infections and preclude recognition of CRE. Such errors could negatively impact patient care and hamper infection control and public health efforts.


Carbapenemase-producing CRE KPC Breakpoint Enterobacteriaceae 


Funding information

This work is supported in part by awards to G.D. through the National Institute of Allergy and Infectious Diseases and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, of the National Institutes of Health under award numbers R01AI123394 and R01HD092414, respectively. R.F.P. was supported by a National Institute of General Medical Sciences training grant through award T32 GM007067 and the Monsanto/Bayer Excellence Fund graduate fellowship. A.W.D. was supported by the Institutional Program Unifying Population and Laboratory-Based Sciences Burroughs Welcome Fund grant to Washington University.

Compliance with ethical standards

Conflict of interest

M.L.Y., M.A.W., R.F.P., A.W.D., and G.D. have nothing to disclose. C-A.D.B. serves as an advisor on the Clinical and Laboratory Standards Institute subcommittee on Antimicrobial Susceptibility Testing.

Informed consent

No informed consent was needed for this study since no personal data were involved.

Ethical approval

Approval by the institutional review board was not required for this study.


The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pathology & Immunology, Division of Laboratory and Genomic MedicineWashington University in St. Louis School of MedicineSt. LouisUSA
  2. 2.The Edison Family Center for Genome Sciences and Systems BiologyWashington University in St. Louis School of MedicineSt. LouisUSA
  3. 3.Department of Molecular MicrobiologyWashington University in St. Louis School of MedicineSt. LouisUSA
  4. 4.Department of Biomedical EngineeringWashington University in St. LouisSt. LouisUSA
  5. 5.Department of MedicineWashington University in St. Louis School of MedicineSt. LouisUSA
  6. 6.Department of PediatricsWashington University in St. Louis School of MedicineSt. LouisUSA

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