Antimicrobial resistant gonorrhoea is an increasing public health concern in today’s world. In 2012, the World Health Organization (WHO) published a Global Action Plan to control the spread and impact of antimicrobial resistance in Neisseria gonorrhoeae.1 A year later, the United States' Centers for Disease Control and Prevention (CDC) listed drug-resistant N. gonorrhoeae as one of three urgent antimicrobial resistance threats, along with Clostridium difficile and carbapenem-resistant Enterobacteriaceae.2 As a recommended response, both the WHO and the CDC have emphasized the need for urgent public health attention to identify gonococcal infections and reduce transmission.
Ironically, we are arguably less able to identify and control the spread of antimicrobial-resistant gonorrhoea in 2017 than we were two decades ago. This is due to 2 major changes in the way sexually transmitted infections (STI) are now diagnosed and treated, namely, the introduction of syndromic management in many countries and a switch from culture-based to molecular-based diagnostic testing for N. gonorrhoeae in others.
The introduction of the syndromic management approach as a tool to improve the diagnosis and treatment of symptomatic STIs in many low- and middle-income countries in the late 1990s has undoubtedly made significant gains with predominantly symptomatic diseases, such as chancroid which has virtually disappeared as a cause of genital ulceration. However, it has failed to control those STIs which are frequently asymptomatic in nature and for which laboratory diagnostic testing is essential for case identification. This is particularly true for gonorrhoea. For example, in the case of women, only about half of gonococcal infections produce genital symptoms, whereas among men who have sex with men (MSM), up to 90% of oropharyngeal and anorectal infections are asymptomatic. The syndromic approach to STI control has focused on a “see-and-treat” approach using syndrome-based flowcharts and standardized antimicrobial therapy, in the absence of laboratory testing, to guide patient management.
For higher income countries, the past 10 to 15 years has seen a significant trend toward molecular testing for gonorrhoea, often in combination with testing for Chlamydia trachomatis on dual platforms. The use of more sensitive molecular tests has increased our ability to diagnose gonorrhoea in higher risk patients, such as MSM and sex workers, particularly at the oropharyngeal and anorectal sites. However, there has been a simultaneous and dramatic decline in the number of N. gonorrhoeae culture-based antimicrobial susceptibility testing requests received by laboratories. Currently, we lack commercial molecular N. gonorrhoeae assays that can both detect and predict antimicrobial susceptibility. Although development of such assays would be relatively straight forward for the detection of the various plasmids responsible for high-level penicillin and tetracycline resistance as well as for detection of the very limited and well characterized point mutations for fluoroquinolone and high-level macrolide resistance, it is technically much more challenging to develop assays for detection of resistance to those antibiotics where multiple mutations affecting several genes are involved, for example, the detection of cephalosporin resistance or low level chromosomal resistance to penicillin, tetracycline, and macrolides.
Given the global decrease in N. gonorrhoeae antimicrobial susceptibility testing data derived from routine culture-based testing of patient samples, attention must now focus on strengthening existing, or establishing new, antimicrobial surveillance programs to generate the strategic information required to inform treatment algorithms. The best examples of long-standing surveillance programs include the Gonococcal Resistance to Antimicrobials Surveillance Programme in England and Wales, the Gonorrhea Isolate Surveillance Project run by the US CDC, and the Australian Gonococcal Surveillance Programme.3–5 The WHO's Gonococcal Antimicrobial Surveillance Programme, which provides a global rather than a national picture, has highlighted important gaps in global surveillance, particularly in low and middle income countries.6 This is a concern, given that gonococcal antimicrobial resistance has traditionally emerged from the Western Pacific, Southeast Asian, and African regions.7
Setting up effective surveillance programs is not an easy task. They rely on several key components, specifically (i) a willingness to participate on the part of patients, clinicians, and laboratory staff; (ii) appropriate human resources with the required skills to successfully collect the required specimens, record data and culture N. gonorrhoeae; (iii) a robust quality control system and access to relevant N. gonorrhoeae control strains; (iv) a co-ordinating institution with staff able to analyze data and publish regular and timely reports; (v) adequate and sustainable funding to support surveillance activities; and (vi) engaged policy makers willing to act on surveillance findings in a timely manner.
In this issue, Yu et al8 report an evaluation of antimicrobial susceptibility among 244 N. gonorrhoeae isolates collected from patients attending STI clinics in three distantly located cities in China, namely Guangzhou, Nanjing and Tianjin. Most isolates tested (225, 92.2%) were derived from male urethral samples and the few remaining isolates were cultured from endocervical samples of women. The authors reported a higher prevalence of gonococci with ceftriaxone minimum inhibitory concentrations (MICs) of 0.125 mg/L or greater in Guangzhou (28.6%) compared with Nanjing (15.5%) and Tianjin (2.8%). However, only 2 ceftriaxone-resistant isolates (MIC ≥ 0.25 mg/l) were reported overall and both were from Guangzhou. Based on their antimicrobial susceptibility data, the authors concluded that only ceftriaxone and spectinomycin can be used with confidence to treat gonorrhoea in China.
To further understand the dynamics of gonococcal transmission within the three cities studied, Yu et al8 successfully used multiple-locus variable number repeat analysis to discriminate between the various N. gonorrhoeae strains tested in their study. Five key clusters were identified which yielded a few interesting epidemiological associations. For example, the authors reported that cluster II contained male-derived isolates only. Cluster II isolates were also associated with a higher proportion of ceftriaxone MIC values greater or equal to 0.125 mg/L, a non-PPNG phenotype and a patient history of recent antibiotic use. In contrast, cluster III was associated with PPNG.
The study reported by Yu et al. provides us with a valuable but rather limited insight into the epidemiology of antimicrobial-resistant gonorrhoea in China. Indeed, the study methodology and findings actually raise far more questions than they answer. As the authors remind us in their introductory paragraph, China has more than 90,000 new gonococcal infections per year, and gonorrhoea is the second most prevalent STI in the country. A study testing less than 250 isolates from 3 cities, which represents less than 0.3% of the national N. gonorrhoeae burden, cannot be deemed representative enough to recommend treatment guidelines for the whole country, and more extensive surveillance is required. In addition, it is not clear as to whether the participants were recruited consecutively or randomly. Yu et al. also make the point that sampling patients from STI clinic settings alone may have biased their results in terms of detecting a higher prevalence of antimicrobial resistance than might be observed in other settings. Surveillance studies should also report on the number of patients with the disease under surveillance that are either tested or not tested in order for the representativeness of the sample to be accurately assessed.
The observation that multiple-locus variable number repeat analysis cluster II included only isolates derived from men raises the question as to whether this is a MSM-associated cluster. However, the study of Yu et al., as well as many existing STI surveillance programs, is handicapped by the lack of data collected on patients’ sexual orientation and behavior. For many countries, there remains an unacceptably high level of stigma which makes collection of these critical data extremely difficult, if not impossible. Stigma and legal discrimination against certain populations, including MSM and sex workers, remain key barriers for effective STI control worldwide; such human rights concerns remain poorly addressed in global health policies related to sexual and reproductive health.
Men who have sex with men, as well as sex workers and their clients, are important populations to include in gonococcal antimicrobial surveillance programs. These populations frequently provide the required early warning signals to institute public health STI control measures with respect to emerging N. gonorrhoeae antimicrobial resistance.7 It is no coincidence that the first case of ceftriaxone resistance gonorrhoea emerged in a female sex worker with oropharyngeal gonorrhoea and that subsequent cases were identified in MSM.7,9,10 There is growing acceptance of the importance of oropharyngeal gonorrhoea as a driver of both the emergence of cephalosporin resistance and the high rate of gonococcal transmission among MSM. N. gonorrhoeae oropharyngeal isolates should therefore be prioritized for testing wherever possible in gonococcal antimicrobial resistance surveillance programs.
Public health interventions can only be put in place when antimicrobial resistance surveillance is robust enough to clearly define the population(s) at risk and the geographical locations where interventions need to take place, particularly in a large country, such as China. Even though a relatively small number of isolates were tested, Yu et al. were able to provide MIC data that suggest that cephalosporin resistance may be more likely to emerge in Guangzhou compared with Tianjin.8 However, it is far from clear as to which population(s) within Guangzhou should be targeted with health promotion messages and condom promotion initiatives.
From a more international perspective, the advent of preexposure prophylaxis (PrEP) as a biomedical tool to reduce HIV transmission in high risk populations, such as MSM and sex workers, has been associated with a rising incidence of gonorrhoea, reflecting increases in the density of sexual networks and reduction in condom use with both regular and nonregular sexual partners. A recent meta-analysis reported that PrEP-using MSM were 25.3 times more likely to acquire gonorrhoea when compared with non-PrEP using MSM.11 It is therefore crucial for policy makers, clinicians and peer educators to promote multicomponent HIV prevention strategies that will also reduce bacterial STIs among high-risk populations. Given that PrEP use is likely to become a key driver of gonococcal transmission in the future, particularly among MSM, the use of biomedical HIV prevention tools, such as PrEP, should be recorded as part of routine data collection in N. gonorrhoeae antimicrobial resistance surveys.
We have limited time, resources and effective drugs to control the global burden of gonorrhoea before we enter a highly predictable era of nontreatable gonorrhoea. The most important strategies we can put in place today must focus on (i) addressing stigma and legal barriers to care, (ii) encouraging behavior change including ongoing condom promotion, (iii) ensuring appropriate therapy is always provided based on timely antimicrobial resistance surveillance data, (iv) designing novel molecular assays to determine susceptibility to antimicrobial agents, in particular cephalosporins, as part of integrated diagnostic algorithms, (v) developing and evaluating of new antimicrobial agents, and (vi) funding research aimed at developing an effective gonococcal vaccine.
High-quality strategic information is only achievable if gonococcal antimicrobial resistance surveillance programs are prioritized by clinicians, laboratory staff, governments, and donor agencies. The return on investment will remain poor unless there is linkage of laboratory-based antimicrobial susceptibility and molecular typing results to relevant patient-based epidemiological data. Regular collection of strategic information concerning N. gonorrhoeae antimicrobial resistance must remain a key pillar of gonorrhoea control programs.
1. World Health Organization. Global action plan to control the spread and impact of antimicrobial resistance in Neisseria gonorrhoeae
. Geneva, Switzerland: WHO Press; 2012.
2. Centers for Disease Control and Prevention. Antibiotic resistance threats in the United States, 2013. Atlanta: U.S. Department of Health and Human Services; 2013.
3. Public Health England. Surveillance of antimicrobial resistance in Neisseria gonorrhoeae
. London, UK: PHE Publications; 2016.
4. Centers for Disease Control and Prevention. Sexually Transmitted Disease Surveillance 2014: Gonococcal Isolate Surveillance Project (GISP) Supplement and Profiles. Atlanta: U.S. Department of Health and Human Services; 2016.
5. Lahra MM; Australian Gonococcal Surveillance Programme. Australian gonococcal surveillance programme annual report, 2014. Commun Dis Intell Q Rep 2015; 39:E347–E354.
6. World Health Organization. Baseline report on global sexually transmitted infection surveillance, 2012. Geneva, Switzerland: WHO Press; 2012.
7. Lewis DA. The role of core groups in the emergence and dissemination of antimicrobial-resistant N gonorrhoeae
. Sex Transm Infect 2013; 89(Suppl 4):iv47–iv51.
8. Yu R-X, Yin Y, Dai X-Q, et al. Antimicrobial susceptibility evaluation and multiple-locus number tandem repeat analysis of Neisseria gonorrhoeae
isolates in China, 2012. Sex Transm Dis 2017; 44(4):197–201.
9. Ohnishi M, Golparian D, Shimuta K, et al. Is Neisseria gonorrhoeae
initiating a future era of untreatable gonorrhea?: detailed characterization of the first strain with high-level resistance to ceftriaxone. Antimicrob Agents Chemother 2011; 55:3538–3545.
10. Unemo M, Golparian D, Nicholas R, et al. High-level cefixime- and ceftriaxone-resistant Neisseria gonorrhoeae
in France: novel penA mosaic allele in a successful international clone causes treatment failure. Antimicrob Agents Chemother 2012; 56:1273–1280.
11. Kojima N, Davey DJ, Klausner JD. Pre-exposure prophylaxis for HIV infection and new sexually transmitted infections among men who have sex with men. AIDS 2016; 30:2251–2252.