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In 2016, the United Nations (UN) World Health Assembly endorsed the WHO global health sector strategy on sexually transmitted infections 2016–2021. One of the major targets is a 90% reduction in the incidence of gonorrhea globally [ 14 ]; to achieve this goal, gonococcal AMR needs to be addressed. In 2012, WHO launched a global action plan to control the spread and impact of gonococcal AMR [ 5 , 15 ]; key priorities are summarized in Box 1 . This plan is linked to the WHO global action plan on AMR, adopted by the World Health Assembly in 2015 [ 16 ], which was reaffirmed during the UN General Assembly High-level Meeting on AMR in September 2016.

Widespread antimicrobial resistance (AMR) in highly variable strains of N. gonorrhoeae has continuously compromised the management and control of gonorrhea. Because of widespread AMR, the persistence of AMR determinants in gonococci, and the unavailability of diagnostic tests that provide AMR results at the time of treatment, clinicians resort to empiric treatment for gonorrhea. Since the introduction of antimicrobial treatment, resistance has rapidly emerged to sulphonamides, penicillins, tetracyclines, macrolides, fluoroquinolones, and early-generation cephalosporins. Currently, in most countries, the injectable extended-spectrum cephalosporin (ESC) ceftriaxone is the only remaining empiric monotherapy for gonorrhea. However, gonococcal in vitro resistance and/or treatment failures to the last-line oral ESC cefixime—and, more rarely, to ceftriaxone—have been verified in many countries [ 5 – 8 ]. Consequently, dual antimicrobial therapy, mainly ceftriaxone plus azithromycin, is recommended [ 9 – 13 ].

Gonorrhea is a sexually transmitted infection (STI) caused by Neisseria gonorrhoeae (gonococcus), and it is a major public health priority globally. In 2012, the World Health Organization (WHO) estimated that there were 78 million cases among adults worldwide, including 35.2 million in the WHO Western Pacific Region, 11.4 million in the Southeast Asian Region, 11.4 million in the African Region, 11 million in the Region of the Americas, 4.7 million in the European Region, and 4.5 million in the Eastern Mediterranean Region [ 1 ]. According to the 2013 Global Burden of Disease Study, gonorrhea is responsible for 225,400 years lived with disability (YLD) per year and 313,900 disability-adjusted life years (DALYs) [ 2 , 3 ]. The complications of gonorrhea disproportionally affect women and include pelvic inflammatory disease, ectopic pregnancy, and infertility, as well as increased transmission and acquisition of HIV [ 4 – 6 ].

The vast majority of verified treatment failures are from well-resourced countries. Accordingly, these reports do not reflect the true global public health burden of ESC treatment failures, since surveillance data from resource-constrained settings are scarce. As emphasized by WHO [ 5 , 33 , 54 ], it is essential to strengthen the surveillance—including verification and follow-up—of treatment failures.

Treatment failures with cefixime have been identified in Japan since the early 2000s [ 36 , 37 ], followed by verified treatment failures in Austria, Canada, France, Norway, South Africa, and the UK [ 38 – 44 ]. Rare treatment failures with ceftriaxone (250–1,000 mg single dose) administered for pharyngeal gonorrhea have been verified in Australia, Japan, Slovenia, and Sweden [ 45 – 51 ]. The first verified treatment failure with the UK-recommended dual therapy (ceftriaxone 500 mg plus azithromycin 1 g) was recently identified [ 52 ]. To date, 3 extensively drug-resistant gonococcal strains with high-level resistance to ceftriaxone (“superbugs”) have also been reported—in France, Japan, and Spain [ 41 , 45 , 53 ].

High levels of ciprofloxacin resistance have been reported in a majority of countries globally, especially in the WHO Southeast Asia Region and the Western Pacific Region. In these WHO regions, nearly all countries have reported high rates of resistance, including 9 countries reporting >90% resistance. Notably, a few WHO Western Pacific Region countries (Fiji and New Caledonia) have reported less than 2% resistance to ciprofloxacin. The majority of countries in the WHO European Region, the Region of the Americas, and the African Region have reported high resistance rates, which are still significantly lower than those in Asia ( Fig 3 ).

In the WHO African Region, in 2014, only 3 out of 47 countries (6%; Côte d’Ivoire, Kenya, and Uganda) reported on azithromycin susceptibility, and all three had ≥5% resistance. Furthermore, South Africa reported ≥5% resistance in 2013. In the WHO Eastern Mediterranean Region, only Pakistan reported data regarding azithromycin susceptibility in 2014 (0% resistance).

Surveillance for susceptibility to ceftriaxone, as well as other antimicrobials, is very limited in the WHO African Region and the WHO Eastern Mediterranean Region. In 2014, only 9% (4/47) of countries in the WHO African Region and only Pakistan in the Eastern Mediterranean Region reported on ceftriaxone susceptibility (4.9% decreased susceptibility or resistance). Of note, only 15% (7/47) of WHO African Region countries and 14% (3/22) of WHO Eastern Mediterranean Region countries have reported on ceftriaxone susceptibility for at least 1 year from 2009–2014. Only 2 of these countries (South Africa and Uganda) have reported any decreased susceptibility or resistance to ceftriaxone.

In the WHO Region of the Americas, decreased susceptibility or resistance to ceftriaxone was described in 40% of 10 reporting countries in 2014 (Argentina, Bolivia [disc diffusion results not verified by MIC determination], Canada, and the US [ 24 ]). The levels of decreased susceptibility or resistance to ceftriaxone in Canada and the US [ 24 ] were 1.1% and 0.4%, respectively. Decreased susceptibility or resistance to cefixime was noted in Argentina, Chile, and Uruguay in 2013–2014.

In the WHO Southeast Asian Region, decreased susceptibility or resistance to ceftriaxone was noted by 50% (3/6) of the countries (Bhutan, India, and Indonesia) reporting ceftriaxone susceptibility data in 2014; 33% (2/6; India and Indonesia) reported ≥5% decreased susceptibility or resistance. From 2009 to 2014, 83% (5/6) of countries reported isolates with decreased susceptibility or resistance to ceftriaxone, and 50% (3/6) reported ≥5% decreased susceptibility or resistance.

In the WHO Western Pacific Region, decreased susceptibility or resistance to ceftriaxone was reported by 71% (5/7) of settings reporting ceftriaxone susceptibility data in 2014, 3 of which (Hong Kong, Japan, and Korea) reported decreased susceptibility or resistance in ≥5% of isolates. Prior to this, China, Mongolia, and Tonga have reported ≥5% of isolates with decreased susceptibility or resistance to ceftriaxone (in Tonga, 1 of only 4 tested isolates showed decreased susceptibility with the disc diffusion method and was not, as recommended ( S1 Text ), verified by minimum inhibitory concentration [MIC] determination). Only 2 countries (New Caledonia and the Philippines) reported that all isolates were susceptible to ceftriaxone from 2009 to 2014.

Twenty-three countries in the WHO European Region reported on gonococcal AMR. In the Euro-GASP [ 21 , 22 ], cefixime is tested and accounted for nearly all the ESC resistance in the WHO European Region in 2014 ( Fig 1 ). Two percent of isolates in the Euro-GASP, detected in 43% (10/23) of the reporting countries, showed resistance to cefixime in 2014. Seventeen percent of countries (4 countries: Belgium, Denmark, Greece, and Norway) reported ≥5% resistance, and 26% of countries (6/23) reported <5% cefixime resistance. No resistance to cefixime was reported in 57% (13/23) of countries; however, 10 of these have reported cefixime resistance in previous years. Resistance to ceftriaxone was only identified in 0.2% (5/2,151) of isolates (from Germany, Greece, and Norway) [ 35 ].

Fig 3. The percentage (%) of isolates with resistance to ciprofloxacin according to the most recent World Health Organization (WHO) Gonococcal Antimicrobial Surveillance Programme (GASP) data (2014 for most countries, but for a few countries, only 2011–2013 data were available).

Fig 2. The percentage (%) of isolates with resistance to azithromycin according to the most recent World Health Organization (WHO) Gonococcal Antimicrobial Surveillance Programme (GASP) data (2014 for most countries, but for a few countries, only 2011–2013 data were available).

Fig 1. The percentage (%) of isolates with decreased susceptibility or resistance to extended-spectrum cephalosporin (ESC) (cefixime and/or ceftriaxone) according to the most recent World Health Organization (WHO) Gonococcal Antimicrobial Surveillance Programme (GASP) data (2014 for most countries, but for a few countries, only 2011–2013 data were available).

WHO GASP data from 2009–2014 showed continued widespread resistance to penicillin, tetracycline, and ciprofloxacin; increasing resistance to azithromycin; and emergence of decreased susceptibility and resistance to ESCs. Of countries monitoring susceptibility to ciprofloxacin (n = 72), azithromycin (n = 58), and ESCs (n = 77), 97%, 81%, and 66% of countries, respectively, described resistant isolates (decreased susceptibility and resistance to ESCs were combined due to the different breakpoints used) for at least 1 year from 2009–2014 ( Table 1 ).

The cumulative number of countries reporting gonococcal AMR data for any antimicrobial increased from 56 in 2009 to 77 in 2014. However, the number of countries reporting gonococcal AMR data for at least 1 antimicrobial each year declined, from 56 countries in 2009 to 52 countries in 2014. The WHO European Region [ 28 ] and Western Pacific Region GASPs [ 29 ] include many countries that consistently report on AMR, and many Latin American countries (LACs) also have a long tradition of consistently reporting gonococcal AMR [ 30 , 31 ]. Countries in the WHO African Region [ 32 ] and Eastern Mediterranean Region are the least represented in terms of gonococcal AMR reporting. The number of countries reporting data on N. gonorrhoeae antimicrobial susceptibility to ESCs, azithromycin, and ciprofloxacin in 2009–2014 are detailed in S2 Table .

There are significant variations between WHO regions with regard to the proportion of countries participating in the WHO GASP, which antimicrobials are monitored, the AMR testing methods used, and the level of quality assurance (QA). The methodologies used, including QA methods, are described in S1 Text [ 19 – 34 ].

The WHO Global Gonococcal Antimicrobial Surveillance Programme (WHO GASP), a collaborative global network of regional and subregional reference laboratories, was initiated in 1990 to monitor gonococcal AMR worldwide [ 17 ]. WHO GASP data have since then informed revisions of global, regional, and national gonorrhea treatment guidelines, as well as public health strategies and policies developed by WHO and other organizations. WHO recommends that treatment guidelines are refined based on data from recent and quality-assured gonococcal AMR surveillance and that the use of an antimicrobial in empiric treatment is discontinued when the rates of therapeutic failures and/or AMR reach a level of 5% [ 5 , 18 ]. Since 2009, WHO has substantially strengthened the WHO GASP, which is coordinated by regional coordinating centers (“focal points”) (see S1 Table ). To ensure quality-assured, valid, and comparable data among countries, regional focal points provide technical support and training in countries to strengthen laboratory capacities (e.g., for sample collection and transport, gonococcal culturing, preservations of strains, AMR testing), to conduct a GASP external quality assurance (EQA) program, and to curate, update, and distribute the WHO gonococcal reference strains for EQA and internal quality control (QC) [ 19 , 20 ]. The 2016 WHO reference strains can also be used for QC in phenotypic and molecular diagnostics, molecular AMR prediction, molecular epidemiology, and as fully characterized reference genomes in whole-genome sequencing analysis [ 20 ]. The WHO GASP works in close collaboration with other international and national quality-assured GASPs, including Euro-GASP [ 21 , 22 ], United States Gonococcal Isolate Surveillance Project (GISP; https://www.cdc.gov/std/gisp/ ) [ 23 , 24 ], Canadian GASP [ 25 ], Australian Gonococcal Surveillance Programme (AGSP) [ 26 ], and United Kingdom Gonococcal Resistance to Antimicrobials Surveillance Programme (UK GRASP) [ 27 ].

Discussion

Challenges and opportunities with GASPs Gonococcal AMR is a major problem globally, but the AMR situation varies in different parts of the world and changes over time. Sustained and quality-assured GASPs are essential but are very challenging to operate. Worryingly, gonococcal AMR surveillance remains lacking or exceedingly limited in many settings worldwide, e.g., Eastern Europe, Central Asia, parts of Latin America (including the Caribbean), the WHO Eastern Mediterranean Region, and the WHO African Region. Many of these settings also have high rates of gonorrhea, lack of (or suboptimal) diagnosis, over-the-counter access to antimicrobials without prescription, and limited access to optimal antimicrobial treatment, such as high-quality ceftriaxone or, ideally, dual therapy with ESC plus azithromycin. These factors create the perfect conditions for rapid emergence and spread of gonococcal AMR [5,6,28]. Accordingly, it is imperative to substantially strengthen and expand GASPs worldwide. There are many microbiological, epidemiologic, and programmatic difficulties to the achievement of high-quality, standardized, and comparable AMR data. Between different countries and WHO regions, the number of isolates examined varies significantly. Almost half of the WHO GASP countries do not have sufficient sample sizes (approximately 100 gonococcal isolates per year) to detect a 5% AMR level with high statistical confidence [5,18,33], nor have they collected samples from representative populations. This is a result of syndromic management of STIs used in resource-constrained settings and limited laboratory capacity and capability. Meanwhile, in well-resourced settings, nucleic acid amplification tests (NAATs) have replaced gonococcal culture for diagnosis. Both circumstances have resulted in limited specimen collection for culture and loss of capability to perform culture and AMR testing of gonococci. Situation analysis has revealed a lack of awareness of gonococcal AMR among policy-makers, clinicians, laboratory professionals, and patients in many settings [55]. Engagement of collaborators in sustainable GASPs is crucial. However, in addition to low awareness, other critical issues need to be addressed, such as data ownership, limited numbers of gonococcal-competent laboratories, clinical and laboratory training (in specimen collection, transport and preservation, and laboratory techniques such as culture and AMR testing), insufficient availability of appropriate laboratory tests and reagents (especially antimicrobials for testing), lack of or inadequate use of crucial QA components such as EQA and QC, loss of isolates during transport and storage (limited access to −70°C freezers, lyophilizators, lack of generators in case of power outages), and, most importantly, lack of sufficient funding. Additionally, it is important to further strengthen well-established GASPs [21–27] by consistently testing crucial antimicrobials (e.g., ceftriaxone and azithromycin), increasing the number of isolates tested, improving the representativeness of isolates (e.g., geographically diverse isolates from both sexes, all risk groups, and all anatomical sites), improving the completeness of reporting of epidemiological variables, collecting additional epidemiological data, and gathering information on treatment and treatment outcomes where possible. In some sentinel countries (e.g., the Philippines and Thailand), WHO has initiated an enhanced GASP (EGASP) aiming to collect standardized and quality-assured epidemiological and clinical information linked to microbiological and AMR data, similar to Euro-GASP and US GISP [21–24]. These data should be collected in a timely manner in order to provide an early detection and warning system for the emergence of AMR. Furthermore, in the WHO GASP, the use of MIC determination methods is being expanded and it is recommended that all instances of ESC resistance identified by the disc diffusion method be confirmed by MIC determination. In many settings, there is a lack of awareness among staff of national ministries of health and among healthcare professionals that continuous AMR surveillance and/or surveys should be the foundation of a national AMR action plan, should be part of routine diagnostics and/or surveillance, and should inform refinements of the recommended treatment algorithms. In settings in which clinical practices include syndromic management of STIs, this is especially important. Accordingly, AMR surveillance is not simply a research project. Thus, in most countries, it should not require approval from an ethical committee because the collection and antimicrobial-susceptibility testing of gonococcal isolates are part of standard care, and no patient identification information is made available in AMR surveillance. Finally, there are significant delays in the release of AMR data from the current GASPs, which limits their value as part of an early warning system for AMR emergence and limits their usefulness for informing prompt refinements of gonorrhea management guidelines and public health policy. Timely reporting by GASPs will require significant improvements in the procedures for release of country-specific AMR data (e.g., release directly to public health organizations before peer-review or through very timely peer-reviewed publications).

Prevention and control of gonorrhea Gonococcal AMR will only be effectively mitigated when the global gonorrhea burden is reduced. Improved prevention, management, and control of gonorrhea are imperative. Linking this to HIV and STI prevention in general will be essential, including education regarding symptomatic and asymptomatic STIs, promotion of safer sex behaviors including increased condom use, behavior change communication programs, enhanced partner notification and treatment, and expansion of targeted interventions for vulnerable populations (sex workers, men who have sex with men [MSM], adolescents, and STI patients and their sexual partners). In the absence of a gonococcal vaccine, optimal public health control of gonorrhea will continue to rely on effective, accessible, affordable, and timely antimicrobial treatment in combination with prevention strategies, diagnostics (index cases and traced sexual contacts), and surveillance. Appropriate gonorrhea case management is essential to reduce unnecessary or incorrect antimicrobial treatment and development of AMR. In 2016, WHO published new guidelines for the treatment of gonorrhea [9], based on consultative review of all evidence available from clinical efficacy trials, pharmacokinetic and pharmacodynamic simulations, and in vitro AMR surveillance. WHO recommends that national public health programs adapt their national gonorrhea management guidelines based on local AMR prevalence. Where recent, local, and quality-assured gonococcal AMR data are lacking, WHO recommends dual antimicrobial therapy over monotherapy for people with symptomatic and asymptomatic urogenital, anorectal, or oropharyngeal gonorrhea (e.g., ceftriaxone 250 mg plus azithromycin 1 g, or cefixime 400 mg plus azithromycin 1 g) [9]. Increased detection and effective treatment of asymptomatic gonorrhea in general and pharyngeal gonorrhea in particular are critical, because these infections are potential gonococcal reservoirs in which AMR (especially ESC AMR) can emerge [6,56]. Oropharyngeal infections are prevalent, mostly asymptomatic, and more difficult to treat; accordingly, screening and treatment in high-risk patients are important.