The current study represents, to our knowledge, the first national surveillance on trends of susceptibility of N. gonorrhoeae to azithromycin and ceftriaxone over time in China. In addition, associations between susceptibility data and demographic and clinical characteristics of study participants were examined. Our findings indicate that the rate of dual RTA and DSC increased between 2013 and 2016. The prevalences of N. gonorrhoeae RTA and DSC found in this study in China were higher than those reported in many countries, including in Europe and the Americas (Table 3). A high prevalence of RTA or DSC has also been reported in Japan, although the sample size of the available study was relatively small (less than 700 isolates in total over 3 years). It is unclear whether circulating gonococcal strains with altered susceptibility to the key antibiotic agents in China acquired these mutations through domestic selective pressure or whether the strains have been imported. Antimicrobial resistant gonorrhea was documented first in Asia, then emerged in other areas in the world. Although azithromycin monotherapy is not recommended for gonorrhea treatment in China, this antibiotic is widely used for treatment of chlamydial infection according to the national STD treatment guidelines. The prevalence of chlamydial infection is much higher than that of gonorrhea both among high-risk groups, such as female sex workers and men who have sex with men, and in the general population in China. Overuse of macrolides for chlamydia and other infections could facilitate emergence of resistance in N. gonorrhoeae. Studies in China have reported that a high percentage (>50%) of outpatient visits result in prescription of antibiotics.

WHO and many countries have recommended dual antimicrobial therapy with ceftriaxone plus azithromycin for people with symptomatic and asymptomatic gonorrhea. However, despite the high prevalence of DSC (more than 10%) in the current study, treatment failure of ceftriaxone has not been documented in China. It is important that clinicians be on high alert to recognize gonorrhea treatment failures so that they can be reported promptly to public health officials. The high and increasing prevalence of RTA/DSC found in the current study suggests the need for further consideration and validation of an appropriate regimen for treatment of gonorrhea in China.

Socioeconomic, behavioral, and clinical factors associated with antimicrobial resistance have been investigated by previous studies in China and other countries. Interestingly, the factors independently associated with RTA and DSC were not the same in our study. Female patients had a higher risk of infection with an azithromycin-resistant strain than males. This finding was consistent with that reported in Amsterdam but different from that reported in Shanghai, where male sex was a significant predictor of tetracycline resistance. Our finding of an association of younger age with RTA is different from that reported in Shanghai, where probable resistance to ceftriaxone was most common among those in older age groups. In addition, in our study, DSC was more likely to occur in areas along the coast, but RTA/DSC was more prevalent in other areas. These associations may be related to transmission dynamics linked to the sexual networks of different populations or in different areas. In addition, the resistance patterns are also dependent on the population seeking care in the sentinel clinics. Further studies on genomic epidemiology and sexual networks among people infected with resistant strains are needed. In contrast to the expected association between previous gonorrhea infection-linked to potential exposure to the antibiotics-and antimicrobial resistance, our study indicated that previous infection with gonorrhea was not associated with risk of RTA or DSC.

There are some potential limitations to this study. First, although the current study was a national surveillance survey with a large number of isolates collected from 7 provinces in China, the sample accounts for roughly only 1% of reported cases of gonorrhea during the study period in the country. Geographically, less than a quarter of the 31 provinces in the country participated in the study, and most of them were located in the economically developed areas along the coast. Moreover, the majority of male participants provided urethral specimens (99.4% of men), and the majority of female participants provided cervical or urethral specimens (96.2% of women). Our sample overrepresents men because men are usually symptomatic and easy to identify for specimen collection. Another concern is that most pharyngeal and anal gonorrhea is asymptomatic, and repeat infections or repeat visits of anonymized patients to clinics during the study period may result in the true number of individuals sampled being smaller than the number of “patients” described here, although this difference is likely to be relatively small. In addition, only a small proportion of the study participants were homosexual or bisexual, and therefore the majority of men did not report any anal or pharyngeal sexual intercourse. All of these potential biases may limit the generalizability of the current study to all people infected with gonorrhea in China. Second, those isolates with MIC > 0.5 mg/l for azithromycin or MIC > 0.125 mg/l for ceftriaxone were not further categorized for susceptibility analysis to identify high-level RTA and/or resistance to ceftriaxone. Third, although molecular typing of N. gonorrhoeae was carried out in a few areas and reported previously, it was not performed in the present survey. Future studies should include molecular and genomic analyses to investigate gonorrhea transmission and to track the spread of antimicrobial resistance. With regard to the treatment of gonorrhea in China, the national STD guidelines have not yet been updated to include dual therapy with ceftriaxone plus azithromycin for gonorrhea but recommend the use of azithromycin for treating potential infection with chlamydia among patients infected with gonorrhea. Further studies are needed to look into appropriate doses of ceftriaxone and azithromycin as well as use of other antibiotics in China.

In conclusion, the current study was a national study on the susceptibility of N. gonorrhoeae to azithromycin and ceftriaxone with implications for antibiotic choice for treatment of gonorrhea in China. An increasing trend of isolates with simultaneous RTA and DSC will likely impede the introduction of the currently WHO-recommended dual therapy in China. Therefore, evaluation of the efficacy of the dual therapy and the development of novel treatment strategies are urgently warranted in China. In addition, future resources should be dedicated to enhancing antimicrobial resistance surveillance by increasing both the number of laboratories performing susceptibility testing and the quality of susceptibility tests. The development of rapid diagnostics to promptly detect gonococcal infections and identify antimicrobial resistance is also urgently needed.