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  5. FDA Rationale for Breakpoints Recognition Decision: Polymyxins and Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter spp.
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FDA Rationale for Breakpoints Recognition Decision: Polymyxins and Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter spp.

FDA has reevaluated the rationale document submitted by the Clinical and Laboratory Standards Institute (CLSI) to susceptibility test interpretive criteria (STIC) docket #FDA-2017-N-5925 entitled, “Polymyxin Breakpoints for Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter spp.– CLSI Rationale Document MR01.” The initial review was completed by FDA in January 2023.1 At that time, the Agency did not recognize the CLSI established colistin and polymyxin B minimal inhibitory concentration (MIC) breakpoints:

  • For Pseudomonas aeruginosa, the intermediate and resistant breakpoints (BPs) were established as ≤ 2 mg/L and ≥ 4 mg/L, respectively. No susceptible BP was established.
  • For Acinetobacter spp., the intermediate and resistant BPs were established as ≤ 2 mg/L and ≥ 4 mg/L, respectively. No susceptible BP was established.
  • For Enterobacterales, the intermediate and resistant BPs of ≤ 2 mg/L and ≥ 4 mg/L, respectively, were established. No susceptible BP was established.

FDA stands by its January 2023 review conclusions that the available pharmacokinetic and pharmacodynamic data are limited and inconclusive, and that the available clinical data do not support an assessment of clinical outcomes in patients treated with polymyxins based on MIC.

FDA, in general, agrees with the MIC distribution data presented in CLSI Rationale Document MR01. While MIC distribution data are limited for polymyxin B, the data support epidemiological cutoff values for colistimethate of ≤ 2 mg/L for Enterobacterales, 4 mg/L for Pseudomonas aeruginosa, and 2 mg/L for Acinetobacter spp.

FDA recognizes that in the absence of breakpoint recognition or identification, susceptibility testing information may not be available to health care providers. Health care providers considering treatment with a polymyxin are likely caring for a patient with a difficult to treat life-threatening infection and are faced with a challenging benefit risk decision. Knowledge of the MIC of the isolate may be helpful in making the benefit risk decision regarding initiation of treatment with a polymyxin. The application of the Intermediate and Resistant interpretive categories in this situation is unconventional, with Resistant essentially denoting the end of the wild-type distribution. Based on reconsideration, FDA now concurs that this is the best decision considering clinical care needs and data limitations. FDA concurs that the use of a Susceptible interpretive category is not adequately supported by the data. FDA notes that it is expected that the circumstances leading to this unconventional recognition would be expected to occur very infrequently.

In conclusion, FDA recognizes the STIC standard for Polymyxins and Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter spp. published in: Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing. 34th ed. CLSI supplement M100; 2024.

1 Available at: https://www.fda.gov/drugs/development-resources/notice-updates

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