Decreased Azithromycin Susceptibility of Neisseria Gonorrhoeae Isolates in Patients Recently Treated with Azithromycin.

Background:Increasing azithromycin usage and resistance in Neisseria gonorrhoeae threatens current dual treatment. Because antimicrobial exposure influences resistance, we analyzed the association between azithromycin exposure and decreased susceptibility of N. gonorrhoeae.Methods:We included N. gonorrhoeae isolates of patients who visited the Amsterdam STI Clinic between 1999 and 2013 (t0), with another clinic visit in the previous 60 days (t-1). Exposure was defined as the prescription of azithromycin at t-1. Using multivariable linear regression, we assessed the association between exposure and azithromycin minimum inhibitory concentration (MIC). Whole genome sequencing (WGS) was performed to produce a phylogeny and identify multilocus sequence types (MLST), N. gonorrhoeae multiantigen sequence types (NG-MAST), and molecular markers of azithromycin resistance.Results:We included 323 isolates; 212 were unexposed to azithromycin, 14 were exposed ≤30 days, and 97 were exposed between 31 and 60 days before isolation. Mean azithromycin MIC was 0.28 mg/L (range, <0.016-24 mg/L). Linear regression adjusted for age, ethnicity, infection site, and calendar year showed a significant association between azithromycin exposure ≤30 days and MIC (β, 1.00; 95% confidence interval, 0.44-1.56; P = .002). WGS was performed on 31 isolates: 14 unexposed, 14 exposed to azithromycin ≤30 days before isolation, and 3 t-1 isolates. Exposure to azithromycin was significantly associated with A39T or G45D mtrR mutations (P = .046) but not with MLST or NG-MAST types.Conclusions:The results suggest that frequent azithromycin use in populations at high risk of contracting N. gonorrhoeae induces an increase in MIC and may result in resistance.