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Increasing antibacterial resistance in Neisseria gonorrhoeae is threatening the success of routine treatment. This letter describes the clinical failure of ceftriaxone and azithromycin in a patient with gonorrhea. To the Editor: Resistance to all antimicrobial agents has developed in some Neisseria gonorrhoeae strains. Dual antimicrobial therapy (ceftriaxone plus azithromycin) is a recommended first-line empirical treatment in many countries. 1 – 3 We describe treatment failure with dual therapy in a patient with gonorrhea. In December 2014, a heterosexual man presented to a sexual health clinic in the United Kingdom with a 2-week history of urogenital symptoms (Table 1). Ten days previously, he had returned from Japan, where his Japanese female partner had been treated for gonorrhea. He reported having no other recent sexual partners. N. gonorrhoeae was detected in a . . .

Antimicrobial resistance in Neisseria gonorrhoeae compromises gonorrhoea treatment worldwide. Novel and optimized treatments and/or treatment strategies that effectively eradicate the infection with low selection of resistance are imperative. A new prospective clinical study provides further evidence that resistance-guided treatment of gonorrhoea with single-dose oral ciprofloxacin is efficacious in relevant settings and can reduce the selection pressure for resistance.

The new superbug has retained resistance to antimicrobials previously recommended for first-line treatment and has now demonstrated its capacity to develop resistance to the extended-spectrum cephalosporin, ceftriaxone, the last remaining option for first-line empiric treatment of gonorrhea. An era of untreatable gonorrhea may be approaching, which represents an exceedingly serious public health problem. Herein, we review the evolution, origin and spread of antimicrobial resistance and resistance determinants (with a focus on extended-spectrum cephalosporins) in , detail the current situation regarding verified treatment failures with extended-spectrum cephalosporins and future treatment options, and highlight essential actions to meet the large public health challenge that arises with the possible emergence of untreatable gonorrhea. Essential actions include: implementing action/response plans globally and nationally; enhancing surveillance of gonococcal antimicrobial resistance, treatment failures and antimicrobial use/misuse; and improving prevention, early diagnosis and treatment of gonorrhea. Novel treatment strategies, antimicrobials (or other compounds) and, ideally, a vaccine must be developed.

Quantifying sexually transmitted infection (STI) prevalence and incidence is important for planning interventions and advocating for resources. The World Health Organization (WHO) periodically estimates global and regional prevalence and incidence of four curable STIs: chlamydia, gonorrhoea, trichomoniasis and syphilis. WHO's 2012 estimates were based upon literature reviews of prevalence data from 2005 through 2012 among general populations for genitourinary infection with chlamydia, gonorrhoea, and trichomoniasis, and nationally reported data on syphilis seroprevalence among antenatal care attendees. Data were standardized for laboratory test type, geography, age, and high risk subpopulations, and combined using a Bayesian meta-analytic approach. Regional incidence estimates were generated from prevalence estimates by adjusting for average duration of infection. In 2012, among women aged 15-49 years, the estimated global prevalence of chlamydia was 4.2% (95% uncertainty interval (UI): 3.7-4.7%), gonorrhoea 0.8% (0.6-1.0%), trichomoniasis 5.0% (4.0-6.4%), and syphilis 0.5% (0.4-0.6%); among men, estimated chlamydia prevalence was 2.7% (2.0-3.6%), gonorrhoea 0.6% (0.4-0.9%), trichomoniasis 0.6% (0.4-0.8%), and syphilis 0.48% (0.3-0.7%). These figures correspond to an estimated 131 million new cases of chlamydia (100-166 million), 78 million of gonorrhoea (53-110 million), 143 million of trichomoniasis (98-202 million), and 6 million of syphilis (4-8 million). Prevalence and incidence estimates varied by region and sex. Estimates of the global prevalence and incidence of chlamydia, gonorrhoea, trichomoniasis, and syphilis in adult women and men remain high, with nearly one million new infections with curable STI each day. The estimates highlight the urgent need for the public health community to ensure that well-recognized effective interventions for STI prevention, screening, diagnosis, and treatment are made more widely available. Improved estimation methods are needed to allow use of more varied data and generation of estimates at the national level.

[...]these reports do not reflect the true global public health burden of ESC treatment failures, since surveillance data from resource-constrained settings are scarce. [...]AMR surveillance is not simply a research project. [...]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. [...]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. [...]high-throughput genomics is revolutionizing our understanding of AMR and the spread of AMR gonococcal strains, as well as research aimed at improving diagnostics, AMR prediction, and vaccine development [20,63-71].

Background The World Health Organization (WHO) recommends periodic gonorrhoea prevalence assessments in the general population or proxies thereof (including pregnant women, women attending family planning clinics, military recruits, and men undergoing employment physicals for example) and in population groups at increased risk, including men-who-have-sex-with-men (MSM) and sex workers. Method We evaluated reported prevalence data, including estimates from proxy general population samples to reflect the WHO recommendations. We describe the outcomes from the general population country-by-country and extend previous reviews to include MSM, sex workers, and extragenital infections. Result and conclusion In our systematic search, 2015 titles were reviewed (January 2010–April 2019) and 174 full-text publications were included. National, population-based prevalence data were identified in only four countries (the United States of America, the United Kingdom, Peru, New Caledonia) and local population-based estimates were reported in areas within five countries (China, South Africa, Brazil, Benin, and Malawi). The remaining studies identified only reported test positivity from non-probability, proxy general population samples. Due to the diversity of the reviewed studies, detailed comparison across studies was not possible. In MSM, data were identified from 64 studies in 25 countries. Rectal infection rates were generally higher than urogenital or pharyngeal infection rates, where extragenital testing was conducted. Data on sex workers were identified from 41 studies in 23 countries; rates in female sex workers were high. Current prevalence monitoring was shown to be highly suboptimal worldwide. Serial prevalence monitoring of critical epidemiological variables, and guidelines to optimize prevalence study conduct and reporting beyond antenatal settings are recommended.

Neisseria gonorrhoeae has developed antimicrobial resistance (AMR) to all drugs previously and currently recommended for empirical monotherapy of gonorrhoea. In vitro resistance, including high-level, to the last option ceftriaxone and sporadic failures to treat pharyngeal gonorrhoea with ceftriaxone have emerged. In response, empirical dual antimicrobial therapy (ceftriaxone 250–1000 mg plus azithromycin 1–2 g) has been introduced in several particularly high-income regions or countries. These treatment regimens appear currently effective and should be considered in all settings where local quality assured AMR data do not support other therapeutic options. However, the dual antimicrobial regimens, implemented in limited geographic regions, will not entirely prevent resistance emergence and, unfortunately, most likely it is only a matter of when, and not if, treatment failures with also these dual antimicrobial regimens will emerge. Accordingly, novel affordable antimicrobials for monotherapy or at least inclusion in new dual treatment regimens, which might need to be considered for all newly developed antimicrobials, are essential. Several of the recently developed antimicrobials deserve increased attention for potential future treatment of gonorrhoea. In vitro activity studies examining collections of geographically, temporally and genetically diverse gonococcal isolates, including multidrug-resistant strains particularly with resistance to ceftriaxone and azithromycin, are important. Furthermore, understanding of effects and biological fitness of current and emerging ( in vitro induced/selected and in vivo emerged) genetic resistance mechanisms for these antimicrobials, prediction of resistance emergence, time-kill curve analysis to evaluate antibacterial activity, appropriate mice experiments, and correlates between genetic and phenotypic laboratory parameters, and clinical treatment outcomes, would also be valuable. Subsequently, appropriately designed, randomized controlled clinical trials evaluating efficacy, ideal dose, toxicity, adverse effects, cost, and pharmacokinetic/pharmacodynamics data for anogenital and, importantly, also pharyngeal gonorrhoea, i.e. because treatment failures initially emerge at this anatomical site. Finally, in the future treatment at first health care visit will ideally be individually-tailored, i.e. by novel rapid phenotypic AMR tests and/or genetic point of care AMR tests, including detection of gonococci, which will improve the management and public health control of gonorrhoea and AMR. Nevertheless, now is certainly the right time to readdress the challenges of developing a gonococcal vaccine.

Neisseria gonorrhoeae is an urgent public health threat due to rapidly increasing incidence and antibiotic resistance. In contrast with the trend of increasing resistance, clinical isolates that have reverted to susceptibility regularly appear, prompting questions about which pressures compete with antibiotics to shape gonococcal evolution. Here, we used genome-wide association to identify loss-of-function (LOF) mutations in the efflux pump mtrCDE operon as a mechanism of increased antibiotic susceptibility and demonstrate that these mutations are overrepresented in cervical relative to urethral isolates. This enrichment holds true for LOF mutations in another efflux pump, farAB , and in urogenitally-adapted versus typical N. meningitidis , providing evidence for a model in which expression of these pumps in the female urogenital tract incurs a fitness cost for pathogenic Neisseria . Overall, our findings highlight the impact of integrating microbial population genomics with host metadata and demonstrate how host environmental pressures can lead to increased antibiotic susceptibility. Antibiotic resistance in Neisseria gonorrhoeae is rising, yet sometimes strains emerge that have reverted to susceptibility. Here, the authors find that selective pressures from the host may influence susceptibility through loss-of-function mutations in genes that encode for efflux pumps.

WHO estimated that nearly 1 million people become infected every day with any of four curable sexually transmitted infections (STIs): chlamydia, gonorrhoea, syphilis, and trichomoniasis. Despite their high global incidence, STIs remain a neglected area of research. In this Commission, we have prioritised five areas that represent particular challenges in STI treatment and control. Chlamydia remains the most commonly diagnosed bacterial STI in high-income countries despite widespread testing recommendations, sensitive and specific non-invasive testing techniques, and cheap effective therapy. We discuss the challenges for chlamydia control and evidence to support a shift from the current focus on infection-based screening to improved management of diagnosed cases and of chlamydial morbidity, such as pelvic inflammatory disease. The emergence and spread of antimicrobial resistance in Neisseria gonorrhoeae is globally recognised. We review current and potential future control and treatment strategies, with a focus on novel antimicrobials. Bacterial vaginosis is the most common vaginal disorder in women, but current treatments are associated with frequent recurrence. Recurrence after treatment might relate to evidence that suggests sexual transmission is integral to the pathogenesis of bacterial vaginosis, which has substantial implications for the development of effective management approaches. STIs disproportionately affect low-income and middle-income countries. We review strategies for case management, focusing on point-of-care tests that hold considerable potential for improving STI control. Lastly, STIs in men who have sex with men have increased since the late 1990s. We discuss the contribution of new biomedical HIV prevention strategies and risk compensation. Overall, this Commission aims to enhance the understanding of some of the key challenges facing the field of STIs, and outlines new approaches to improve the clinical management of STIs and public health.

The large majority of studies investigating associations between bacterial vaginosis (BV) and sexually transmitted infections (STIs) have been conducted among predominantly young women with high risk for STIs. Since a risky sexual behavior is a significant risk factor for both STIs and BV, this creates a bias toward an increased association between BV and STIs. This study evaluated associations between BV-associated vaginal microbiota and STIs (Chlamydia trachomatis, Mycoplasma genitalium, Trichomonas vaginalis, and Neisseria gonorrhoeae) in a population of women with low risk for STIs and investigated STI outcomes depending on the dominating Lactobacillus species. Repository cervicovaginal samples collected from reproductive-age women from January 2014 to February 2019 were characterized for vaginal microbiota types and the STIs using multiplex real-time PCR assays. In total, 95 STI-positive and 91 STI-negative samples were included. A significant, age-independent association between BV-associated vaginal microbiota and the presence of C. trachomatis, M. genitalium, and T. vaginalis infections was identified (age-adjusted odds ratios 2.92 [95% confidence interval (CI) 1.24–7.03], 2.88 [95% CI 1.19–7.16], and 9.75 × 107 [95% CI 13.03-∞], respectively). Normal vaginal microbiota dominated by Lactobacillus crispatus, L. gasseri, or L. jensenii was a strong protective factor against C. trachomatis and/or M. genitalium infections, whereas L. iners-dominated microbiota was not significantly associated with C. trachomatis and/or M. genitalium positivity. The results of the present study confirm that STI prevention strategies should include interventions that also reduce the incidence of BV and promote a protective vaginal microbiota in both high- and low-risk women.