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Rationale for FDA’s Position on the Cefazolin Breakpoints for Enterobacterales

FDA has completed their review of the rationale document submitted by the Clinical Laboratory and Standards Institute (CLSI) to STIC Docket# FDA-2017-N-5925-023, entitled, “Cefazolin Breakpoints for Enterobacterales (systemic infections) – CLSI Rationale Document MR07.”

Cefazolin is a first-generation cephalosporin for parenteral administration and is indicated for the treatment of a variety of infections ranging in severity from mild to severe and life-threatening using dosing regimens that range from 250 mg every 8 hours to 1.5 grams every 6 hours. Additionally, the cefazolin labeling allows for doses up to 12 g per day in rare instances. 1

In 2010, CLSI updated the cefazolin breakpoints for the Enterobacterales (previously known as Enterobacteriaceae) based on probability of target attainment for an FDA-approved dosing regimen of cefazolin (1 g every 8 hours); these were recognized by FDA. 2 In 2011, CLSI revised the cefazolin breakpoints a second time, primarily due to the recognition that the dose of cefazolin used most often clinically (2 g every 8 hours) supports a higher susceptible breakpoint than with the FDA-approved dose. 3

The microbiology data regarding the MIC distribution of Enterobacterales, show that the susceptible breakpoint of 2 mcg/mL, covers the majority of wild-type isolates. From a clinical standpoint, the limited clinical data suggest that the 2 g every 8 hours cefazolin dosing regimen appears to be effective in the treatment of severe infections due to Enterobacterales with MIC ≤2 mcg/mL. Although 2 gram every 8 hours is not a labeled dose, the pharmacokinetic profile of this regimen provides probability of target attainment outcomes comparable to the approved 1.5 g every 6 hours dosing regimen. Also, the cefazolin labeling allows for doses up to 12 g per day. Hence, it was considered acceptable to set the breakpoints using a dosing regimen of 2 gram every 8 hours.

Based on the available clinical and microbiology information, FDA concurs with the revised CLSI breakpoints for Enterobacterales. The STIC, including MIC and zone diameters, are shown in Table 1 below.

Table 1. Recognized Susceptibility Interpretive Criteria for Cefazolin

Organism Group

Minimum Inhibitory Concentration


Zone Diameters









≤ 2a


≥ 8

≥ 23

20 - 22

≤ 19

Abbreviations: I, Intermediate; R, Resistant; S, Susceptible.
a Interpretive criteria are based on dose of 2 g every 8 hours

1 U.S. Food and Drug Administration. Ancef Prescribing Information. (https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/50461slr139_ancef_lbl.pdf)
2 Humphries RM, Abbott AN, Hindler JA. Understanding and Addressing CLSI Breakpoint Revisions: a Primer for Clinical Laboratories. Journal of Clinical Microbiology 2019; 57(6): e00203-19.
3 CLSI. Performance Standards of Antimicrobial Susceptibility Testing. CLSI Supplement M100. Wayne, PA: Clinical and Laboratory Standards Institute, 2011.

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