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FDA Rationale for Breakpoints Recognition Decision: Azithromycin and Neisseria gonorrhoeae

Summary

FDA has reevaluated the rationale document submitted by the Clinical and Laboratory Standards Institute (CLSI) to susceptibility test interpretive criteria docket #FDA-2017-N-5925-017, entitled, “Azithromycin Breakpoint for Neisseria gonorrhoeae – CLSI Rationale Document MR04”. The initial review was completed by FDA in October 2021.1 At that time, the Agency did not recognize the CLSI susceptible breakpoint for azithromycin of ≤1 mcg/mL, which presumed that azithromycin (1 gram single dose) is used in a regimen that includes an additional antimicrobial agent (i.e., ceftriaxone 250 mg IM single dose). FDA understands that information regarding the MIC for azithromycin of a clinical Neisseria gonorrhoeae isolate is important for clinicians managing drug-resistant gonorrhea infections and public health agencies conducting surveillance. Based on our re-evaluation, FDA stands by its October 2021 review, but identifies alternative breakpoints for azithromycin and Neisseria gonorrhoeae shown in the table below:

FDA and CLSI Azithromycin Breakpoints for Neisseria gonorrhoeae

 

Minimum Inhibitory Concentrations
(mcg/mL)

S

I

R

FDA

-

≤ 1

≥ 2

CLSI

≤ 1

-

-

Abbreviations: S, susceptible; I, intermediate; R, resistant;

Rationale 

At present, the only CDC-recommended treatment of uncomplicated urogenital, anorectal, and pharyngeal gonorrhea is monotherapy with a single intramuscular dose of ceftriaxone 500 mg.2 Reporting and consultation with CDC is encouraged in the event of suspected gonorrhea cephalosporin treatment failure or any N. gonorrhoeae specimen with decreased cephalosporin susceptibility.3 Azithromycin may be recommended by CDC consultants for the management of drug-resistant gonorrhea as part of a treatment regimen on a case by case basis. Information regarding the MIC for azithromycin of a clinical Neisseria gonorrhoeae isolate may be helpful in the management of drug-resistant gonorrhea and for public health surveillance purposes.

FDA agrees with CLSI’s assessment of surveillance data that < 1 mcg/mL is the end of the natural wild-type distribution and there are few isolates with MICs > 1 mcg/mL. FDA is not aware of pharmacokinetic/pharmacodynamic data that would inform breakpoints. With respect to clinical outcome data, it is FDA’s assessment that published reports are not supportive of establishing a susceptible breakpoint. In a series from public sexually transmitted disease clinics in the U.S. published in the early 1990s, a high treatment success rate was reported for monotherapy with a single oral 2-gram azithromycin dose.4 However, in a clinical trial evaluating a single 2 gram oral dose of azithromycin with extended release formulation, failures of eradication were reported for subjects with isolates with MIC as low as 0.5 mcg/mL.5

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. However, it is FDA’s assessment that the use of a Susceptible interpretive category is not adequately supported by the data, would not be consistent with FDA’s definition of this category, and may result in inappropriate treatment if experts are not consulted. Considering the public health need for a breakpoint recognition and the limitations of the data available, it is FDA’s conclusion that the breakpoint identification of Intermediate and Resistant categories only is the most appropriate for use of azithromycin in ceftriaxone-resistant N. gonorrhoeae.

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