Reliance on Historic Breakpoints May Lead to False Antimicrobial Susceptibility Reports

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Failure to adopt updated antimicrobial susceptibility testing breakpoints may lead to reports of false susceptibility for antimicrobials commonly used to treat Gram-negative infections and preclude recognition of CRE.

Failure to adopt updated antimicrobial susceptibility testing (AST) breakpoints may lead to false reports of susceptibility for antimicrobials commonly used in the treatment of Gram-negative infections and preclude recognition of carbapenem-resistant Enterobacteriaceae (CRE), according to data published in the European Journal of Clinical Microbiology & Infectious Diseases.

Zone sizes from risk diffusion AST for 10,183 Enterobacteriaceae isolates recovered from clinical cultures over a 1-year period and CRE from 342 clinical and environmental sources from the United States and Pakistan were evaluated to measure the effect of breakpoint changes on AST interpretation for CRE. The results were interpreted using current (CLSI M100-S29) and historic (CLSI M100-S19) breakpoints and interpretive errors calculated according to US Food and Drug Administration definitions.

Using current breakpoints as the reference standard, 56 very major errors (false susceptibility) occurred for cefepime. Using historic breakpoints in clinical isolates of Enterobacteriaceae, 13 very major errors for meropenem interpretation occurred, corresponding to 12 carbapenemase-producing CRE that would have been missed during the 1-year period.

Of the 342 clinical and environmental CRE, 251 isolates were interrogated further for carbapenemase production and mechanism of resistance. Of these strains, 149 were characterized as encoding blaKPC. The very major error rate for the 149 confirmed blaKPC carbapenemase-producing CRE using historic breakpoints were 8%, 30%, 63%, and 0% for cefepime, meropenem, imipenem, and ertapenem, respectively. The use of historic breakpoints for blaKPC isolates would, therefore, have led to 42 reports of false susceptibility to meropenem.

The number of unique patients represented by the isolates in the dataset was unknown and was one of several study limitations. Also, categoric AST interpretations were based on zone sizes measured by Kirby Bauer disk diffusion, which is not commonly used by US clinical laboratories. However, laboratories are being encouraged to implement alternative methods to automated AST as a means of testing novel antimicrobials and to facilitate more rapid adoption of the latest Clinical and Laboratory Standards Institute interpretation criteria and the analysis of the accuracy of the disk diffusion method is increasingly important.

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Investigators concluded that delays in adopting the most up-to-date interpretative criteria may result not only in incorrect interpretations of susceptibility profiles for Enterobacteriaceae but also missed opportunities for the detection of carbapenemase-producing CRE. They further concluded that, “this has important implications for patient therapy and initiation of appropriate isolation precautions to prevent further spread of these multidrug-resistant organisms.”


Yarbrough ML, Wallace MA, Potter RF, D’Souza AW, Dantas G, Burnham CD. 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 [published online November 2, 2019]. Eur J Clin Microbiol Infect Dis. doi:10.1007/s10096-019-03711-y