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 (t(0)), 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 (beta, 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