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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

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Abstract

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.

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Funding

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.

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Authors and Affiliations

  1. Department of Pathology & Immunology, Division of Laboratory and Genomic Medicine, Washington University in St. Louis School of Medicine, 660 S. Euclid Ave, Campus Box 8118, St. Louis, MO, 63110, USA

    Melanie L. Yarbrough, Meghan A. Wallace, Gautam Dantas & Carey-Ann D. Burnham

  2. The Edison Family Center for Genome Sciences and Systems Biology, Washington University in St. Louis School of Medicine, St. Louis, MO, USA

    Robert F. Potter, Alaric W. D’Souza & Gautam Dantas

  3. Department of Molecular Microbiology, Washington University in St. Louis School of Medicine, St. Louis, MO, USA

    Gautam Dantas & Carey-Ann D. Burnham

  4. Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, USA

    Gautam Dantas

  5. Department of Medicine, Washington University in St. Louis School of Medicine, St. Louis, MO, USA

    Carey-Ann D. Burnham

  6. Department of Pediatrics, Washington University in St. Louis School of Medicine, St. Louis, MO, USA

    Carey-Ann D. Burnham

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  1. Melanie L. Yarbrough
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Correspondence to Melanie L. Yarbrough.

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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.

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Yarbrough, M.L., Wallace, M.A., Potter, R.F. et al. 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. Eur J Clin Microbiol Infect Dis 39, 187–195 (2020). https://doi.org/10.1007/s10096-019-03711-y

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