The sexually transmitted infection (STI) gonorrhea is a very old malady that can be traced to ancient Chinese, Egyptian, Roman, and Greek literature as well as in the Old Testament of the Bible (Leviticus 15:1–3). Neisseria gonorrhoeae (gonococcus), the obligate human pathogen and etiological agent of gonorrhea, is primarily transmitted from an infected individual by direct human-to-human contact between the mucosal membranes of the urogenital tract, anal canal, or the oropharynx, usually during sexual activities. Neonates can be infected during passage through the birth canal if the mother has urogenital gonorrhea. After transmission, N. gonorrhoeae causes urethritis in males and cervicitis in females. Relatively few males (≤10%) but a large proportion of females (≥50%) can have an asymptomatic urogenital infection. Rectal and pharyngeal gonorrhea is commonly asymptomatic in both genders. These infections are most frequently identified in men who have sex with men (MSM), but dependent on sexual practice they can be encountered in both genders in many settings. The urogenital infections, if untreated, might ascend to the upper genital tract and result in severe reproductive complications (mostly, but not only, in females), such as pelvic inflammatory disease and epididymitis (rare) that can result in infertility or even loss of life through ectopic pregnancy. Gonococcal infections also facilitate the transmission and acquisition of HIV (1–4). N. gonorrhoeae may also cause conjunctivitis, mostly in neonates (ophthalmia neonatorum) infected from their mother during delivery, but also in adults. Conjunctivitis may, if untreated, result in blindness. Disseminated gonococcal infection is an uncommon complication of gonococcal infection and, although rare, this can lead to, for example, arthritis, meningitis and endocarditis (1, 2, 5, 6).

Gonorrhea has remained a major global public health concern and in 2012 the World Health Organization (WHO) estimated 78.3 million cases among adults (15–49 years of age) worldwide. The largest burden was in the WHO Western Pacific Region (35.2 million cases), WHO South-East Asia Region (11.4 million cases) and WHO Africa Region (11.4 million cases) (7). Nevertheless, the number of reported cases is much lower, particularly from resource-poor settings, than the true number of cases due to poor diagnostics, lack of laboratory testing, and incomplete case reporting. In the United States of America (USA) gonorrhea is the second most commonly reported notifiable disease. In 2013, a total of 333,004 cases of gonorrhea were reported, and the national gonorrhea rate was 106.1 cases per 100,000 population (http://www.cdc.gov/std/stats13/gonorrhea.htm). As in previous years, the South had the highest rate of reported gonorrhea cases (128.6 cases per 100,000 population) followed by the Midwest (108.6 cases per 100,000 population), Northeast (85.5 cases per 100,000 population), and West (83.5 cases per 100,000 population).

In the absence of a gonococcal vaccine, the mainstay in the public health control of gonorrhea relies entirely on appropriate generalized and targeted prevention efforts, sexual contact notification, epidemiological surveillance, diagnosis and particularly the availability of effective antimicrobial treatment. N. gonorrhoeae was initially highly susceptible to many antimicrobials. However, since the introduction of sulphonamides for treatment of gonorrhea in the 1930s N. gonorrhoeae has repeatedly shown an extraordinary capacity to develop resistance to all antimicrobials introduced for treatment during the past 70–80 years. Currently, the prevalence of gonococcal strains with resistance to most antimicrobials previously recommended for treatment (e.g., sulphonamides, penicillins, early-generation cephalosporins, tetracyclines, macrolides and fluoroquinolones) is high in many settings. The recent emergence of resistance to the third generation extended-spectrum cephalosporins (ESCs) cefixime and ceftriaxone, and emergence of N. gonorrhoeae strains exhibiting high-level clinical resistance to all ESCs (8–13), combined with resistance to nearly all other available gonorrhea antimicrobials (including azithromycin, which is now recommended with ceftriaxone in dual therapy of gonorrhea), is of grave concern (1, 11, 14–21). The ESCs are at the front line of antimicrobial therapy and treatment failures particularly with cefixime, but also sporadically with ceftriaxone (mainly pharyngeal gonorrhea), have been verified in Japan, Australia, several European countries, Canada, and South Africa (5, 12, 13, 22). This developing situation requires immediate international attention and resources internationally. The emergence of resistance to ESCs is a public health concern also in the USA and in 2013 the US Centers for Disease Control and Prevention (CDC) included N. gonorrhoeae on the list of organisms where drug resistance is an urgent public health threat (http://www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf). N. gonorrhoeae has additionally been classified by the CDC as a “Superbug” and the prospect of untreatable gonorrhea was voiced in 2012 by both the CDC (19) and WHO (1). Clearly, we are now facing a threatening major public health crisis that would result in significant reproductive morbidity (including infertility) and socioeconomic cost worldwide.

The evolution of AMR, particular the emergence of ceftriaxone resistance in gonococci, with retained resistance to all previously used therapeutic antimicrobials, and fear of exceedingly-difficult-to-treat and even untreatable gonorrhea, has resulted in great concern and attention internationally, that is, in lay media, public health community and scientific societies (12). Consequently, dual antimicrobial treatment regimens were introduced as first-line treatment for uncomplicated anogenital and pharyngeal gonorrhea in USA (94), Canada (114), Australia (115) and Europe (2). These treatment regimens are summarized in Table 2 and mainly recommend intramuscular ceftriaxone (250 mg (94) or 500 mg (2, 95, 114, 115), single dose) together with an oral single dose of azithromycin (1 g (95, 114, 115) or 2 g (2)). Furthermore, in 2012 to control and decrease the spread of multidrug resistant gonococcal strains the WHO, CDC and European Centre for Disease Prevention and Control (ECDC) published a global action plan and regional response plans, respectively (1, 19–21).

The AMR gonococcal strains do not recognize any borders and, accordingly, international actions, collaborations, and political will, advocacy, research, and funding are essential. Some key components of the WHO global action plan are summarized in Table 3. Briefly, these plans emphasize the need for a substantially increased awareness among clinical microbiologists, scientists, epidemiologists, clinicians and on political levels, as well as more holistic actions. For example, these plans call for significant improvements in the prevention, diagnosis, contact tracing, treatment and surveillance of gonorrhea, in order to reduce the global burden of infection, as essential to control the AMR emergence and spread internationally. Linked to this, it is essential to establish and/or strengthen existing strategies for general antimicrobial control (updated and implemented guidelines for appropriate use, selection, supplies, quality, etc.). There is also an urgent need for an enhanced focus on reducing the incidence of gonorrhea in high-risk frequently transmitting populations (such as commercial sex workers and particularly MSM) and effective prevention (e.g. condom use when practicing oral sex), diagnosis and treatment of pharyngeal gonorrhea, which is significantly more difficult to eradicate and represents an asymptomatic reservoir for gonorrhea and emergence of antimicrobial resistance. Implementation of test-of-cure is also crucial, particularly for pharyngeal gonorrhea, to identify treatment failures as well as reinfections. It is also evident that the global burden of gonococcal AMR is largely unknown and, accordingly, it is imperative to significantly enhance the quality-assured surveillance of N. gonorrhoeae AMR and verified gonorrhea treatment failures (using recommended treatment) locally, nationally and internationally.

In the age of easy and rapid travelling, a global approach is certainly demanded. Accordingly, the WHO Global Gonococcal Antimicrobial Surveillance Programme (WHO Global GASP) was initiated in early 1990s, but revisited and relaunched in 2009 (13). The WHO Global GASP network aims to recruit laboratories worldwide to: monitor gonococcal AMR data using quality-assured methods (with main focus on ESCs); provide support to establish gonococcal culture and AMR testing; inform public health authorities and revisions of treatment guidelines on trends in gonococcal AMR; optimize early detection of emerging resistance; and identify and confirm treatment failures with ESCs (1, 21). In this work, the WHO Global GASP works collaboratively with other GASPs. For example, in the European Union/European Economic Area (EU/EEA) the ECDC is funding the regional Euro-GASP (54, 55, 80, 116–118) and national GASPs are running since several years in the UK (49, 119; http://www.hpa.org.uk/Publications/InfectiousDiseases/HIVAndSTIs/GRASPReports/), USA (75, 121, 122; http://www.cdc.gov/std/gisp), and several additional countries. The objectives with these GASPs are to timely monitor trends in resistance (including regional differences), provide high-quality susceptibility data that inform timely revisions of evidence-based empiric management guidelines, and ideally to identify newly emerging AMR. Disquietingly, longitudinal quality-assured GASPs have been insufficient in some geographic regions (e.g. Latin America and the Caribbean (48, 79)) or have been sporadic or entirely lacking in large geographic regions such as WHO Eastern Mediterranean Region, Eastern Europe, Central Asia, and Africa (53, 55, 123). It is essential to establish and maintain N. gonorrhoeae culture and AMR surveillance in these geographic regions and additional regions globally. This surveillance should ideally be integrated in the diagnostics and/or surveillance of sexually transmitted infections. Furthermore, for international comparison of quality-assured AMR data ideally MIC-based and, whenever feasible, standardized methods, resistance breakpoints and internal and external quality assurance should be used. It is also crucial that rapid and effective mechanisms exist to use the valid AMR data to update and implement the empirical management guidelines. Finally, significantly intensified research efforts to develop rapid molecular methods for AMR testing, novel therapeutic strategies and especially compounds for treatment of gonorrhea need to be a very high priority (1, 12, 124).

In the USA, the antimicrobial susceptibility patterns of N. gonorrhoeae has been monitored since 1986 through the Gonococcal Isolate Surveillance Project (GISP), a national sentinel surveillance program and the oldest continuously running antimicrobial susceptibility surveillance program in the world (120). Since its inception GISP has provided valuable information that has been used to update the CDC’s Sexually Transmitted Diseases (STD) Treatment Guidelines as well as provided data used by CDC to modify the treatment recommendations for gonorrhea in real time. For example, data from GISP was pivotal in alerting public health officials about the increasing prevalence of gonorrhea among MSM in the late 1990’s (125), the recommendation to avoid the use of fluoroquinolones among MSM with gonorrhea in 2004 (75) and, in 2007, the recommendation that fluoroquinolones should not be used for any patient that presents with gonorrhea, leaving ESCs as the only remaining class of antimicrobials recommended for treatment of gonorrhea (126). Furthermore, in 2010, due to concerns regarding emergence of ESC resistance CDC introduced recommendations for dual antimicrobial therapy. These CDC 2010 STD treatment guidelines recommended an ESC (ceftriaxone 250 mg intramuscularly or cefixime 400 mg orally) plus azithromycin 1 g orally or doxycycline 100 mg orally twice daily for 7 days (127). More recently, in 2012, data from GISP led the CDC to no longer recommend oral cephalosporin for the treatment of gonorrhea. Accordingly, cefixime was excluded from the recommended regimens in the CDC STD treatment guidelines and cefixime was only an alternative regimen (together with azithromycin 1 g orally) when ceftriaxone was not available (128). In 2015, due to the high prevalence of tetracycline resistance among GISP isolates, particularly those with elevated cefixime MICs, doxycycline was excluded from the recommended regimen. Consequently, currently the CDC 2015 STD Treatment Guidelines recommend for the treatment of uncomplicated urogenital, anogenital and pharyngeal gonorrhea, only dual therapy with a single intramuscular injection of ceftriaxone (250 mg) plus azithromycin 1 g orally (94). Clearly the emergence and spread of ESC-resistant N. gonorrhoeae would severely limit the treatment options for gonorrhea in the USA and globally. As mentioned above, in response to the threat of ESC-resistant N. gonorrhoeae, the Division of STD Prevention at CDC has developed a response plan (19) that includes GISP as a critical component of the surveillance for ESC-resistant N. gonorrhoeae.

GISP is a collaborative project among selected STD clinics, five regional laboratories, and CDC (see Figure 1). In GISP, N. gonorrhoeae specimens and demographic and clinical data of corresponding patients are collected each month from the first 25 men who attend the involved STD clinics in 26 selected US cities and who have also been diagnosed with urethral gonorrhea (presumptive or confirmed diagnosis). These isolates are then shipped to one of five regional laboratories (Atlanta, Baltimore, Birmingham, Seattle, and Austin) where they are confirmed as N. gonorrhoeae, tested for β-lactamase production using nitrocefin test and analyzed for antimicrobial susceptibility by agar dilution. The antimicrobials tested are ceftriaxone, cefixime, azithromycin, ciprofloxacin, gentamicin, penicillin G, and tetracycline. More information can be found in the GISP Protocol available at: http://www.cdc.gov/std/gisp/gisp-protocol-feb-2015_v3.pdf. Results are interpreted according to criteria recommended by the Clinical and Laboratory Standards Institute (CLSI) or, when CLSI criteria do not exist, according to expert opinion of what constitutes decreased susceptibility or resistance. The results of these tests are then transmitted to CDC where they are collated and analyzed together with the demographic and clinical data (see below). If isolates meet the predefined “Alert Value” MIC, the isolates are retested to confirm the result and CDC and the sentinel site are notified. The demographic and clinical data submitted for each GISP patient include date and place of specimen collection, age, age and sex of sex partner, ethnicity, race (census categories), presence of symptoms, treatment for gonorrhea, HIV status, and history of previous gonorrhea, travel outside the USA during the previous 60 days, giving or receiving drugs/money for sex in the previous 12 months, antibiotic use during the previous 60 days, and drug use in the previous 12 months.

In total, GISP collects between 5000–6000 isolates per year and, although all speciments come from men, the proportion of these men who report being MSM has steadily increased and is now over 30% of GISP participants. The breakpoint MIC’s for intermediate (decreased) susceptibility and resistance of different antimicrobials are shown in Figure 2. While GISP monitors resistance to multiple antimicrobials the major concen now is the development of resistance to ESCs (cefixime and ceftriaxone) and to azithromycin. Susceptibility testing for cefixime began in 1992, was discontinued in GISP in 2007, and was restarted again in 2009. Since 2009 over 90% of isolates have exhibited cefixime MICs ≤0.03 μg/ml. The percentage of isolates with elevated cefixime MICs (≥0.25 μg/ml) increased from 0.1% in 2006 to 1.4% in 2010 and 2011, and declined to 0.4% in 2013. In 2014, 0.8% of isolates in GISP had reduced susceptibility to cefixime. This percentage was higher in isolates from MSM with 1.3% that had decreased cefixime susceptibility (121). Susceptibility testing for ceftriaxone began in 1987. Between 2009 and 2013, each year, approximately 90% of isolates exhibited ceftriaxone MICs ≤0.015 μg/ml. The percentage of GISP isolates that exhibited elevated ceftriaxone MICs, defined as ≥0.125 μg/ml, increased from 0.1% in 2008 to 0.4% in 2011, and decreased to <0.1% in 2013 (www.cdc.gov/std/gisp2013/gisp-2013-text-figures-tables.pdf). Susceptibility testing for azithromycin began in 1992. From 2009 to 2013 most isolates had azithromycin MICs of 0.125–0.25 μg/ml. The proportion of GISP isolates with azithromycin MICs of ≥ 2.0 μg/ml varied by year between 0.2% and 0.6% (122). Preliminary data for 2014 suggests that 2.5% of isolates have an MIC >2 μg/ml to azithromycin which is clearly cause for concern (unpublished data). The prevalence (%) of resistance to penicillin G, tetracycline and fluoroquinolones as well as reduced susceptibility to cefixime and azithromycin in N. gonorrhoeae in the GISP from 2000 to 2014 has been summarized in Figure 3.

In clinical practice, antimicrobial treatment of gonorrhea is mostly given empirically, at the first clinical visit, using the recommended antimicrobials in accordance with evidence-based management or treatment guidelines. Because gonorrhea is mostly diagnosed based on microscopy of Gram- or methylene blue-stained smears or molecular testing, antimicrobial susceptibility is rarely performed and thus not available to the clinician. Furthermore, even if culture and AMR testing is performed these results are not available at the first clinic visit when treatment is given. As mentioned above, these guidelines are essential to maintain updated recommendations based on quality-assured AMR surveillance data. Traditionally, the first-line antimicrobial therapy should be highly effective, widely available and affordable, lack toxicity, single dose, and (rapidly) cure at least >95% of infected patients (1, 129). However, the evidence base for this >95% cut-off level that was initially stated by the WHO is limited. Levels of >1% and >3% AMR in high-risk patient groups have also been proposed as cut-offs for changing empiric first-line antimicrobial therapy (129, 130). Ideally, additional criteria such as gonorrhea prevalence, local epidemiology, diagnostics used, transmission frequency, sexual contact tracing strategies, treatment strategies and cost should additionally be taken into account in the decision to change the recommended first-line antimicrobial therapy. Furthermore, an identical cut-off level and recommended treatment regimen(s) will not be the most cost-effective solution in all geographic regions and populations (12, 22, 131).

In the USA, the antimicrobials used for the treatment of gonorrhea since the late-1980s can be seen in Figure 4; note that azithromycin would be included in the “other” category shown in this figure. During the last decade, in many geographic regions worldwide cefixime 400 mg×1 orally or ceftriaxone 125–1000 mg×1 intramuscularly (IM) or intravenously (IV) has been the recommended first-line for empiric antimicrobial monotherapy of gonorrhea (11, 12, 22, 106). However, due to the emergence of in vitro resistance, including high-level, to all ESCs as well as clinical treatment failures using the most potent ESCs cefixime and ceftriaxone dual antimicrobial therapy (mainly ceftriaxone 250–500 mg×1 and azithromycin 1–2 g×1, which additionally eradicates concomitant Chlamydia trachomatis infections) has been introduced as first-line empirical therapy for uncomplicated anogenital and pharyngeal gonorrhea treatment in the USA (94), Canada (114), Australia (115) and Europe (2) (Table 2). Adequate clinical data to support the different ceftriaxone and azithromycin doses recommended for the currently circulating gonococcal strains are mainly lacking. The dual antimicrobial treatment regimens have instead been based on early clinical trials, pharmacokinetic/pharmacodynamic simulations (101), in vitro AMR surveillance data, predicted trends in AMR emergence, case reports of treatment failures, and expert consultations. In general, these dual antimicrobial treatment regimens are currently highly effective and recommended to be used in all geographic regions where comprehensive, high-quality local AMR surveillance data are lacking or not evidently supporting some other treatment regimen(s).

However, the decreased susceptibility or resistance to ceftriaxone in N. gonorrhoeae has been increasing worldwide, and azithromycin resistance is easily selected and already prevalent in many geographic regions. Furthermore, N. gonorrhoeae strains with high-level azithromycin resistance (MIC≥256 μg/ml) have been reported from an increasing number of countries, including Scotland (82), UK (37), Ireland (84), Italy (85), Sweden (86), China (88), Australia (87), Argentina (38), Canada (91), and the USA (39). It is also of grave concern that the first global gonorrhea treatment failure using dual antimicrobial therapy (ceftriaxone 500 mg×1 and azithromycin 1 g×1) was recently verified. This was a case of pharyngeal gonorrhea in a heterosexual male in UK who was infected by his female partner in Japan (13). Consequently, the recently introduced dual antimicrobial regimens might not be effective long-term solutions and, most important, are not affordable in many less-resourced settings, many of which have the highest burden of gonorrhea. This will significantly limit the mitigation of emergence and spread of gonococcal AMR globally (4, 11, 12, 16, 22).

Ultimately, novel and cost-effective antimicrobials for empiric antimicrobial monotherapy or for inclusion in new dual antimicrobial therapy regimens are essential.

Strict adherence to evidence-based treatment guidelines should be the mainstay in the future treatment of gonorrhea. These treatment or management guidelines should be continuously updated using data from quality assured surveillance of AMR, such as the GISP described above, and ideally also treatment failures. The currently recommended dual antimicrobial therapy (ceftriaxone plus azithromycin (2, 94, 114, 115)) is recommended to be used in all countries where appropriate and comprehensive AMR data do not clearly support other recommended treatment regimens. These dual treatment regimens additionally treat concomitant Chlamydia trachomatis infections and many Mycoplasma genitalium infections.

However, as mentioned above, the currently recommended dual antimicrobial treatment regimens (ceftriaxone plus azithromycin) might not be a long term solution. Two new dual antimicrobial regimens were recently evaluated for treatment of gonorrhea, that is, gentamicin (240 mg×1 intramuscularly) plus azithromycin (2 g×1 orally), and gemifloxacin (320 mg×1 orally) plus azithromycin (2 g×1 orally) (132). The cure rate was 100% and 99.5%, respectively. However, gastrointestinal side effects were common, e.g. 3.3% and 7.7% of patients, respectively, vomited within one hour and, accordingly, lost a substantial amount of the given antimicrobial(s) (132). Either of these two regimens might be considered as alternative treatment options in the presence of ceftriaxone resistance, treatment failure with recommended regimen, or ESC allergy (94).

Clearly, new, cost-effective and widely accessible antimicrobials for antimicrobial monotherapy or for inclusion in new dual antimicrobial treatment regimens are essential. Spectinomycin is effective for treatment of anogenital gonorrhoea and the spectinomycin susceptibility is very high globally, including in South Korea where it has remained commonly used for treatment (12, 22, 38, 47–49, 51–55, 61, 80, 118, 133, 134,). Nevertheless, spectinomycin is not effective against pharyngeal gonorrhe; for example, 52% eradication rate has been reported (63), and spectinomycin is not available in many geographic settings (2, 12, 94). Additional previously developed antimicrobials suggested for future treatment of gonorrhoea include ertapenem (135, 136), fosfomycin (137), and gentamicin. In fact, since 1993 gentamicin has been recommended first-line treatment (together with doxycycline) in syndromic management in Malawi (11, 12, 16, 38, 132, 117, 138–141). However, all these antimicrobials have shortcomings in their use as first-line therapy of gonorrhea, which have been detailed elsewhere (11, 12, 22, 136, 137, 140, 141). Accordingly, most likely they are primarily options for ESC-resistant gonorrhea, ESC allergy and in new dual antimicrobial therapies. A multi-centre (n=8), non-inferiority, randomized, controlled Phase 3 clinical gentamicin trial is also currently running. In this trial, treatment with gentamicin 240 mg×1 IM plus azithromycin 1 g×1 orally is compared to ceftriaxone 500 mg×1 IM plus azithromycin 1 g×1 orally (www.research.uhb.nhs.uk/gtog).

During recent years, many derivates/analogues of previously developed and used antimicrobials have also shown to have high in vitro activity against N. gonorrhoeae isolates. These include several new fluoroquinolones (142–145), tetracyclines (146, 147), carbapenems (148), macrolides (149, 150), and the lipoglycopeptide dalbavancin (151). These and some additional antimicrobials or therapeutic compounds have been recently reviewed elsewhere (11, 12, 22). The new oral fluoroketolide solithromycin (macrolide family) is most advanced in development. Solithromycin has been shown to have a high in vitro activity against N. gonorrhoeae, including azithromycin-resistant, ESC-resistant and multidrug-resistance gonococcal isolates (150). Nevertheless, N. gonorrhoeae strains with high-level resistance to azithromycin (MIC≥256 μg/ml) are likely resistant also to solithromycin (MIC=4–32 μg/ml) (150). A minor Phase 2 single-center, open-label study has also shown that solithromycin (in a single-dose of both 1.0 g and 1.2 g orally) is effective for treating uncomplicated gonorrhea (152). Currently, a multi-centre, open-label, randomized Phase 3 clinical solithromcyin trial is running. In this trial, participants with uncomplicated urogenital gonorrhea are treated with solithromycin 1 g×1 orally and the control group is treated with recommended first-line therapy, i.e. ceftriaxone 500 mg×1 IM plus azithromycin 1 g×1 orally (www.clinicaltrials.gov).

Ideally, novel antimicrobials, using new targets or mechanisms of action, should be developed to avoid cross-resistance with any of the previously used antimicrobials. Promisingly, during recent years several such antimicrobials have been developed and also proven to have a high in vitro efficacy against N. gonorrhoeae isolates. These include, for example, the new protein synthesis inhibitor pleuromutilin BC-3781 (153), the boron-containing inhibitor AN3365 (154), LpxC inhibitors (155), the species-specific FabI inhibitor MUT056399 (156), and novel bacterial topoisomerase inhibitors with different target(s) compared to previously used fluoroquinolones, that is, VXc-486 (VT12-008911; 157) and ETX0914 (AZD0914; 158–160). The oral spiropyrimidinetrione ETX0914, which also has a novel mode-of-action (161), is most advanced in development. Initially, a high in vitro susceptibility of ETX0914 was verified against a panel of 250 temporally, geographically and genetically diverse N. gonorrhoeae isolates, which included a high proportion of fluoroquinolone-, ESC- and multidrug-resistant isolates (158). It has now also been shown that the ETX0914 susceptibility among 873 contemporary clinical gonococcal isolates from 21 countries in the European Union/European Economic Area countries is exceedingly high and no ETX0914 resistance has yet been indentified (160). Currently, a multi-centre, open-label, randomized Phase 2 clinical ETX014 trial is running. In this trial, participants with uncomplicated urogenital gonorrhoea are treated ETX0914 (2 g orally), ETX0914 (3 g orally), or, for comparison, ceftriaxone (500 mg IM) (www.clinicaltrials.gov).

Gonorrhea continues to be a worldwide public health problem and is becoming even more so with the emergence of gonococcal strains resistant to most previously or currently used antibiotics. There is every reason to believe that the problem of antibiotic resistant strains will continue, challenging the effectiveness of clinical treatment regimens. In order to effectively meet this problem, efforts on many levels (Table 3), especially in the areas of new drug development, alternative treatment regimens and continued research on vaccines, genetic point of care diagnostics, and AMR testing are essential. In parallel to ongoing research on new antimicrobials to treat gonorrhea, it is important to note that after years of relative stagnation the quest for a gonococcal vaccine that would protect humans from infection or reduce the severity of disease has been rejuvenated and target antigens are now being pursued in pre-clinical vaccine studies (162). Additionally, high-throughput genomics, metabolomics, methylomics, transcriptomics, proteomics and other novel molecular technologies and approaches will revolutionize future research aimed at improving diagnostics, antimicrobial resistance detection and vaccine development (162–165). Given the remarkable history of the evolution of antibiotic resistance displayed by gonococci, how resistance has changed treatment regimens over the past 80 years, the relative dearth of new antimicrobials in the pharmaceutical pipeline that will soon be available in the clinic and the lack of a vaccine to prevent gonorrhea, there is every reason to be concerned that this STI will continue to be a major global public health problem in the 21^st century.