FDA has completed their review of the rationale document submitted by the Clinical and Laboratory Standards Institute (CLSI) to STIC Docket #FDA-2017-N-5925-017, entitled, “Azithromycin Breakpoint for Neisseria gonorrhoeae – CLSI Rationale Document MR04”.
CLSI added an azithromycin susceptible only breakpoint of ≤1 mcg/mL for Neisseria gonorrhoeae in the M100 standard (29th edition, January 2019) with the associated comment: “this breakpoint presumes that azithromycin (1 g single dose) is used in an approved regimen that includes an additional antimicrobial agent (i.e., ceftriaxone 250 mg IM single dose)”.1
The purpose of the Agency’s review was to assess the azithromycin susceptible only breakpoint of ≤1mcg/mL established by CLSI for N. gonorrhoeae. As noted, this breakpoint is based on azithromycin (1 g single dose) used in a regimen that includes a single dose of intramuscularly administered ceftriaxone 250 mg.
Based on the Agency’s evaluation of the literature from the 1990’s to 2000’s, a single dose of azithromycin 1 g was noted to be effective treatment for uncomplicated gonorrhea. However, the relevance of those data to the current treatment of gonorrhea is unclear. Limited data regarding the azithromycin 2 g dose were available from the literature from Japan where azithromycin 2 g sustained release has been in use. In these studies, it appears that treatment failure was reported with isolates of MICs ≥0.5 mcg/mL. In addition, given the geographic variation of N. gonorrhoeae isolates between countries and even within a country, the results of these studies may not be reflective of N. gonorrhoeae isolates in the US.
The Agency notes that the 2020 CDC update to the guidelines2 for the treatment of uncomplicated gonococcal infection recommends a single dose of 500 mg ceftriaxone intramuscular injection and no longer recommends use of combination therapy with azithromycin. One of the reasons provided for this recommendation is the observed increase in N. gonorrhoeae resistance to azithromycin associated with azithromycin’s use for the treatment of gonococcal and nongonococcal infections.
Because clinical treatment decision making for the treatment of gonorrhea mainly relies on NAAT testing instead of culture, there is a paucity of MIC data correlating treatment outcomes with azithromycin monotherapy in the US. There are insufficient data at this time to support the CLSI susceptible-only breakpoint for azithromycin of ≤1 mcg/mL with the associated comment: “this breakpoint presumes that azithromycin (1 g single dose) is used in an approved regimen that includes an additional antimicrobial agent (i.e., ceftriaxone 250 mg IM single dose)”.
Based on the information discussed above, at this time the Agency does not recognize the CLSI susceptible-only breakpoint for azithromycin of ≤1 mcg/mL. Currently, the Agency does not have recommended breakpoints for azithromycin for N. gonorrhoeae.
1 CLSI. Performance Standards for Antimicrobial Susceptibility Testing. 29th ed. CLSI supplement M100. Wayne, PA: Clinical and Laboratory Standards Institute; 2019.
2 Center for Disease Control and Prevention. Morbidity and Mortality Weekly Report (MMWR): Update to CDC’s Treatment Guidelines for Gonococcal Infection, 2020.
https://www.cdc.gov/mmwr/volumes/69/wr/mm6950a6.htm, accessed on January 23, 2021