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

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

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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.