Rationale for a Neisseria gonorrhoeae Susceptible-only Interpretive Breakpoint for Azithromycin

Abstract

Background: Azithromycin (AZI) is recommended with ceftriaxone (CRO) for treatment of uncomplicated gonococcal urethritis and cervicitis in the United States, and an AZI-susceptibility breakpoint is needed. Neither the Food and Drug Administration (FDA) nor the Clinical and Laboratory Standards Institute (CLSI) has set interpretive breakpoints for AZI susceptibility. As a result, AZI antimicrobial susceptibility testing (AST) cannot be interpreted using recognized standards. This has contributed to increasingly unavailable clinical laboratory AST, although gonorrhea is on the rise with >550 000 US gonorrhea cases reported to the Centers for Disease Control and Prevention in 2017, the highest number of cases since 1991.

Methods: This article summarizes the rationale data reviewed by the CLSI in June 2018.

Results: The CLSI decided to set a susceptible-only interpretive breakpoint at the minimum inhibitory concentration of ≤1 µg/mL. This is also the epidemiological cutoff value (ECV) (ie, the end of the wild-type susceptibility distribution). This breakpoint presumes that AZI (1-g single dose) is used in an approved regimen that includes an additional antimicrobial agent (ie, CRO 250 mg, intramuscular single dose).

Conclusions: Having a breakpoint can improve patient care and surveillance and allow future development and FDA regulatory approval of modernized AST to guide treatment. The breakpoint coincides with a European Committee on AST decision to remove previously established, differing AZI breakpoints and use the ECV as guidance for testing. The CLSI breakpoint is now the recognized standard that defines AZI susceptibility for gonococcal infections.

Keywords: Neisseria gonorrhoeae; antimicrobial resistance; breakpoints; interpretive criteria.

Fig. 1

A: AZI susceptibilities of 15,496 GISP GC isolates from the US national surveillance project GISP 2014 – 2016, as determined by the agar dilution method. The dotted line represents previous and current ECV determinations. The x-axis reflects the range of dilutions in the current GISP protocol. B: AZI susceptibilities of GISP GC isolates from 1992 – 2004 (dark grey), 2005 – 2012 (black), and 1992 – 2012 (light grey), as determined by agar dilution and previously reviewed by CLSI. The circle at 0.5 and 1 μg/ml highlights isolates at the CLSI breakpoint before and after 2005 when a media change took place. The shift in MICs by one dilution was likely due to a change in commercial media formulation. It occurred in all participating reference laboratories for AZI only in 2005. This prompted the CDC to change its alert criteria upwards by one dilution as a single event in 2006. Except for this occurrence, no substantial shift in the modal MIC has occurred in GISP.

Fig 2:

GC genetic marker association with AZI MICs. A previously sequenced convenience sample of 732 GISP isolates from 2013 – 2015 underwent genetic marker analysis at CDC. Analyses of the 23S rRNA C2611T (A) and A2059G (B) mutations are shown. The wild-type base at position 2611 is C, and is A at position 2059. The circle at ≥16 μg/ml highlights the three isolates with the A2059G mutation.