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BackgroundThe emergence and spread of multidrug resistance to antibiotics used to treat gonorrhoea has resulted in a dramatic loss of effective regimens for the condition. Currently, the extended spectrum cephalosporin, ceftriaxone, is the only viable monotherapy option available, however, resistance to this last line treatment is now emerging globally. Herein, we assessed the in vitro activity of a novel small molecule antimicrobial with a new mechanism of action, SMT-571, against a large collection of N. gonorrhoeae clinical isolates and reference strains including numerous MDR and XDR gonococcal isolates.MethodsMICs (mg/L) of SMT-571 were determined by agar dilution according to current CLSI guidelines. The MICs of ceftriaxone, cefixime, azithromycin, ciprofloxacin, spectinomycin, tetracycline, and ampicillin were determined using the Etest method (AB bioMérieux, Marcy l’Etoile, France).ResultsSMT-571 showed potent in vitro activity against all the tested N. gonorrhoeae isolates (n=262) with MICs ranging from 0.064 to 0.125 mg/L, and the MIC50, MIC90 and modal MIC were all 0.125 mg/L. The compound was not influenced by pre-existing resistance mechanisms with no cross-resistance or correlation between the MICs of SMT-571 and comparator agents being observed.ConclusionThis study is the first broad evaluation of the in vitro activities of a new mechanism, novel small molecule antimicrobial for the treatment of gonorrhoea. SMT-571 demonstrated high in vitro activity against a large geographically, temporally and genetically diverse collection of clinical N. gonorrhoeae isolates and international reference strains, including various types of high-level resistant, MDR and XDR gonococcal isolates.DisclosureNo significant relationships.

BackgroundIn Toronto, gonorrhea is the second most commonly reported sexually transmitted infection, after chlamydia. From 2000 to 2012, rates of gonorrhea in Toronto were stable, ranging from 56/100,000 to 72/100,000. However, rates started to rise in 2013. In 2018, rates increased by 37% from 2017, the largest observed annual increase since 2000, reaching a high of 158/100,000. This study aimed to describe gonorrhea trends in Toronto between 2012 and 2018.MethodsData for gonorrhea cases reported between 2012 and 2018 were extracted from the integrated Public Health Information System on January 29 2019. Analyses were conducted in SAS 9.4.ResultsIn 2018, 4,549 gonorrhea cases were reported in Toronto, 135% higher than 1,939 cases (71/100,000) reported in 2012. The increase was driven by a rise in reports among males, increasing by 192% while females increased by 24%; males comprised 81% of cases in 2018. Males most commonly reported engaging in sex with men (MSM), and the proportion with this risk factor increased from 55% in 2012 to 69% in 2018. Conversely, the proportion of males reporting sex with women declined from 25% in 2012 to 17% in 2018. Females in 2018 most commonly reported not using a condom (77%) in the last sexual encounter, slightly higher than 2012 (71%). In 2018, 38% of cases (44% of males, 9% of females) had rectum and/or pharyngeal gonorrhea, higher than 20% of cases in 2017.ConclusionThe rising rates in gonorrhea, particularly among MSM, may be due to changes in screening guidelines in 2013 that included extragenital screening of gonorrhea. In April 2018, both rectal and pharyngeal specimens were approved for Nucleic Acid Amplification Testing in Ontario, potentially playing a role in the additional increase in 2018. This study demonstrates that it is important that physicians continue to screen for extragenital gonorrhea among MSM.DisclosureNo significant relationships.

IntroductionGentamicin is effective against N. gonorrhoeae in vitro and systematic reviews have reported cure rates of 62%–98% but the quality of studies was low and there are few data on pharyngeal or rectal infections. A recent large non comparative trial reported a cure rate of 100% when gentamicin was combined with 2g oral azithromycin, but a high incidence of gastrointestinal adverse effects limited tolerability and few extra-genital infections were included. The aim of this study was to evaluate the efficacy and safety of gentamicin versus ceftriaxone, each combined with 1g of azithromycin, for the treatment of gonorrhoea.MethodsA multi-centre, blinded, randomised controlled trial in participants with genital, pharyngeal or rectal gonorrhoea who received either gentamicin 240 mg or ceftriaxone 500 mg (each as a single intramuscular injection). The diagnosis of gonorrhoea was based on a positive nucleic acid amplification test (NAAT) or gram stained smear on microscopy. The primary endpoint was microbiological cure based on NAAT two weeks after treatment. The trial had 90% power to detect non-inferiority with a lower CI for an absolute risk difference of 5%. Data collection was completed in March 2017.Results720 patients from 14 sexual health clinics in England were randomised to receive ceftriaxone (n=362) or gentamicin (n=358). Baseline characteristics of the two groups were well balanced. 306 participants randomised to ceftriaxone (85%) and 292 randomised to gentamicin (82%) had primary outcome data available. 98% (299/306) and 91% (267/292) of participants randomised respectively had clearance of gonorrhoea at 2 weeks – adjusted risk difference −6.4% (95% CI −10.4%, −2.4%). Pre-specified sensitivity analyses supported this result. Clearance at the genital site was 98% and 94%, at pharynx 96% and 80% and at rectum 98% and 90%. The frequency of side effects was similar between treatment groups.ConclusionGentamicin is not non-inferior to ceftriaxone for the treatment of gonorrhoea.

IntroductionGonorrhoea notifications are rapidly rising in men who have sex with men (MSM). We developed a model to assess mouthwash as a novel intervention for gonorrhoea control. MethodsWe developed a model of Neisseria gonorrhoeae (NG) transmission to explain anatomic site-specific prevalence of gonorrhoea among MSM. The model was calibrated to available epidemiological and behavioural data. We estimated the contribution of various sexual acts to gonorrhoea incidence and evaluate the potential impacts of screening scale-up and utilisation of mouthwash on the gonorrhoea epidemic. ResultsWe calibrated the model to prevalence of oropharyngeal, anal and urethral gonorrhoea of 8.6% (7.7%–9.5%), 8.3% (7.4%–10.4%) and 0.20% (0.04%–0.35%), respectively, among MSM. Oropharynx to oropharynx transmission through kissing is estimated to account for nearly three quarters of all incident cases (71.6% [64.4–80.5%]%]) of gonorrhoea in MSM. Substantially increasing annual oropharynx screening for gonorrhoea from the current 40% to 100% may only halve the prevalence of gonorrhoea in MSM. In contrast, the use of mouthwash with moderate efficacy (additional 1% clearance per daily use) would further reduce the corresponding prevalence rates to 3.1% (2.2%–4.4%), 3.8% (2.3%–4.9%) and 0.10% (0.06%–0.11%), and a high efficacy mouthwash (additional 1.5% clearance per daily use) may further halve the gonorrhoea prevalence. Without oropharynx to oropharynx transmission, we could not replicate current prevalence data. ConclusionOur model suggests that kissing may play a key role in NG transmission among MSM. Focusing on STI screening alone is not sufficient to control the rising epidemic. Promotion of regular mouthwash may achieve near elimination of gonorrhoea in MSM.

Expedited partner therapy (EPT), the practice of treating the sex partners of persons with sexually transmitted infections without their medical evaluation, increases partner treatment and decreases gonorrhea and chlamydia reinfection rates. We conducted a stepped-wedge, community-level randomized trial to determine whether a public health intervention promoting EPT could increase its use and decrease chlamydia test positivity and gonorrhea incidence in women. The trial randomly assigned local health jurisdictions (LHJs) in Washington State, US, into four study waves. Waves instituted the intervention in randomly assigned order at intervals of 6-8 mo. Of the state's 25 LHJs, 24 were eligible and 23 participated. Heterosexual individuals with gonorrhea or chlamydial infection were eligible for the intervention. The study made free patient-delivered partner therapy (PDPT) available to clinicians, and provided public health partner services based on clinician referral. The main study outcomes were chlamydia test positivity among women ages 14-25 y in 219 sentinel clinics, and incidence of reported gonorrhea in women, both measured at the community level. Receipt of PDPT from clinicians was evaluated among randomly selected patients. 23 and 22 LHJs provided data on gonorrhea and chlamydia outcomes, respectively. The intervention increased the percentage of persons receiving PDPT from clinicians (from 18% to 34%, p < 0.001) and the percentage receiving partner services (from 25% to 45%, p < 0.001). Chlamydia test positivity and gonorrhea incidence in women decreased over the study period, from 8.2% to 6.5% and from 59.6 to 26.4 per 100,000, respectively. After adjusting for temporal trends, the intervention was associated with an approximately 10% reduction in both chlamydia positivity and gonorrhea incidence, though the confidence bounds on these outcomes both crossed one (chlamydia positivity prevalence ratio = 0.89, 95% CI 0.77-1.04, p = 0.15; gonorrhea incidence rate ratio = 0.91, 95% CI .71-1.16, p = 0.45). Study findings were potentially limited by inadequate statistical power, by the institution of some aspects of the study intervention outside of the research randomization sequence, and by the fact that LHJs did not constitute truly isolated sexual networks. A public health intervention promoting the use of free PDPT substantially increased its use and may have resulted in decreased chlamydial and gonococcal infections at the population level. ClinicalTrials.gov NCT01665690.

WHO recommends that men who have sex with men (MSM) receive gonorrhoea and chlamydia testing, but many evidence-based preventive services are unaffordable. The pay-it-forward strategy offers an individual a gift (eg, a test for sexually transmitted diseases) and then asks whether they would like to give a gift (eg, a future test) to another person. This study examined the effectiveness of a pay-it-forward programme to increase gonorrhoea and chlamydia testing among MSM in China. We did a randomised controlled superiority trial at three HIV testing sites run by MSM community-based organisations in Guangzhou and Beijing, China. We included MSM aged 16 years or older who were seeking HIV testing and met indications for gonorrhoea and chlamydia testing. Restricted randomisation was done using computer-generated permuted blocks. 30 groups were randomised into three arms (1:1:1): a pay-it-forward arm in which men were offered free gonorrhoea and chlamydia testing and then asked whether they would like to donate for testing of prospective participants, a pay-what-you-want arm in which men were offered free testing and given the option to pay any desired amount for the test, and a standard-of-care arm in which testing was offered at ¥150 (US$22). There was no masking to arm assignment. The primary outcome was gonorrhoea and chlamydia test uptake ascertained by administrative records. We used generalised estimating equations to estimate intervention effects with one-sided 95% CIs and a prespecified superiority margin of 20%. The trial is registered with ClinicalTrials.gov, NCT03741725. Between Dec 8, 2018, and Jan 19, 2019, 301 men were recruited and included in the analysis. 101 were randomly assigned to the pay-it-forward group, 100 to the pay-what-you-want group, and 100 to the standard-of-care group. Test uptake for gonorrhoea and chlamydia was 56% (57 of 101 participants) in the pay-it-forward arm, 46% (46 of 100 participants) in the pay-what-you-want arm, and 18% (18 of 100 participants) in the standard-of-care arm. The estimated difference in test uptake between the pay-it-forward and standard-of-care group was 38·4% (95% CI lower bound 28·4%). Among men in the pay-it-forward arm, 54 of 57 (95%) chose to donate to support testing for others. The pay-it-forward strategy can increase gonorrhoea and chlamydia testing uptake among Chinese MSM and could be a useful tool for scaling up preventive services that carry a mandatory fee. US National Institute of Health; Special Programme for Research and Training in Tropical Diseases, sponsored by UNICEF, UNDP, World Bank, and WHO; the National Key Research and Development Program of China; Doris Duke Charitable Foundation; and Social Entrepreneurship to Spur Health.

Increased rates of sexually transmitted infections (STIs) are reported among men who have sex with men (MSM) and new interventions are needed. We aimed to assess whether post-exposure prophylaxis (PEP) with doxycycline could reduce the incidence of chlamydia or syphilis (or both) and whether the meningococcal group B vaccine (4CMenB) could reduce the incidence of gonorrhoea in this population. ANRS 174 DOXYVAC is a multicentre, open-label, randomised trial with a 2 × 2 factorial design conducted at ten hospital sites in Paris, France. Eligible participants were MSM aged 18 years or older, HIV negative, had a history of bacterial STIs within the 12 months before enrolment, and who were already included in the ANRS PREVENIR study (a cohort of MSM using pre-exposure prophylaxis with tenofovir and emtricitabine for HIV prevention). Participants were randomly assigned (2:1) to doxycycline PEP (two pills of 100 mg each orally within 72 h after condomless sex, with no more than three doses of 200 mg per week) or no PEP groups and were also randomly assigned (1:1) to the 4CMenB vaccine (GlaxoSmithKline, Paris, France; two intramuscular injections at enrolment and at 2 months) or no vaccine groups, using a computer-generated randomisation list with a permuted fixed block size of four. Follow-up occurred for at least 12 months (with visits every 3 months) up to 24 months. The coprimary outcomes were the risk of a first episode of chlamydia or syphilis (or both) after the enrolment visit at baseline for the doxycycline intervention and the risk of a first episode of gonorrhoea starting at month 3 (ie, 1 month after the second vaccine dose) for the vaccine intervention, analysed in the modified intention-to-treat population (defined as all randomly assigned participants who had at least one follow-up visit). This trial is registered with ClinicalTrials.gov, NCT04597424 (ongoing). Between Jan 19, 2021, and Sept 19, 2022, 556 participants were randomly assigned. 545 (98%) participants were included in the modified intention-to-treat analysis for the doxycycline PEP and no PEP groups and 544 (98%) were included for the 4CMenB vaccine and no vaccine groups. The median follow-up was 14 months (IQR 9–18). The median age was 40 years (34–48) and all 545 participants were male. There was no interaction between the two interventions (p≥0·1) for the primary outcome. The incidence of a first episode of chlamydia or syphilis (or both) was 8·8 per 100 person-years (35 events in 362 participants) in the doxycycline PEP group and 53·2 per 100 person-years (80 events in 183 participants) in the no PEP group (adjusted hazard ratio [aHR] 0·17 [95% CI 0·12–0·26]; p<0·0001). The incidence of a first episode of gonorrhoea, starting from month 3 was 58·3 per 100 person-years (103 events in 274 participants) in the 4CmenB vaccine group and 77·1 per 100 person-years (122 events in 270 participants) in the no vaccine group (aHR 0·78 [95% CI 0·60–1·01]; p=0·061). There were no deaths during the study. One drug-related serious adverse event (fixed-drug eruption) occurred in the doxycycline PEP group. Six (2%) participants in the doxycycline group discontinued doxycycline PEP because of gastrointestinal adverse events. Doxycycline PEP strongly reduced the incidence of chlamydia and syphilis in MSM, but we did not show efficacy of the 4CmenB vaccine for gonorrhoea. Doxycycline PEP should be assessed in other populations, such as heterosexual men and women, and its effect on antimicrobial resistance carefully monitored. ANRS Maladies Infectieuses Emergentes. For the French translation of the abstract see Supplementary Materials section.

Doxycycline postexposure prophylaxis has been shown to prevent STIs in cisgender men and transgender women. In this trial involving cisgender women in Kenya, STI incidence was not lower with doxycycline than with standard care.

Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) are the most common bacterial causes of sexually transmitted infection (STI) in the United States (US). The purpose of this study was to determine the frequency of reinfection during a six-month study period and to evaluate the retesting interval for those infected with CT or NG. We conducted a prospective, six-month follow-up study among US military personnel with new onset, laboratory-confirmed CT or NG, recruited from an STI clinic at a large military base from January 2018 to January 2020. Each participant was randomly assigned to one of four groups, which differed only by the timing of the first study-associated follow-up visit after CT or NG diagnosis. Of the 347 initially recruited into the study, 267 participants completed a follow-up visit prior to their scheduled, final visit 6 months after initial infection. The median age at enrollment was 22 years and 41.0% were female. There were 32 (12.0%) reinfections (30 CT and 2 NG) after treatment of an index diagnosis of CT or NG within the six-month study period. Six of the CT reinfections were only detected at the final visit. A review of medical records revealed additional CT and NG reinfections. The probability of detecting a reinfection did not vary significantly by timing of follow-up. The likelihood of detecting CT or NG reinfection did not differ according to time of follow up visit among study participants, thus supporting CDC guidance to retest three months post treatment. Efforts should continue to focus on STI prevention and risk reduction.

New approaches are urgently required to address increasing rates of gonorrhoea and the emergence and global spread of antibiotic-resistant Neisseria gonorrhoeae. We used whole-genome sequencing to study transmission and track resistance in N gonorrhoeae isolates. We did whole-genome sequencing of isolates obtained from samples collected from patients attending sexual health services in Brighton, UK, between Jan 1, 2011, and March 9, 2015. We also included isolates from other UK locations, historical isolates from Brighton, and previous data from a US study. Samples from symptomatic patients and asymptomatic sexual health screening underwent nucleic acid amplification testing; positive samples and all samples from symptomatic patients were cultured for N gonorrhoeae, and resulting isolates were whole-genome sequenced. Cefixime susceptibility testing was done in selected isolates by agar incorporation, and we used sequence data to determine multi-antigen sequence types and penA genotypes. We derived a transmission nomogram to determine the plausibility of direct or indirect transmission between any two cases depending on the time between samples: estimated mutation rates, plus diversity noted within patients across anatomical sites and probable transmission pairs, were used to fit a coalescent model to determine the number of single nucleotide polymorphisms expected. 1407 (98%) of 1437 Brighton isolates between Jan 1, 2011, and March 9, 2015 were successfully sequenced. We identified 1061 infections from 907 patients. 281 (26%) of these infections were indistinguishable (ie, differed by zero single nucleotide polymorphisms) from one or more previous cases, and 786 (74%) had evidence of a sampled direct or indirect Brighton source. We observed multiple related samples across geographical locations. Of 1273 infections in Brighton (including historical data), 225 (18%) were linked to another case elsewhere in the UK, and 115 (9%) to a case in the USA. Four lineages initially identified in Brighton could be linked to 70 USA sequences, including 61 from a lineage carrying the mosaic penA XXXIV allele, which is associated with reduced cefixime susceptibility. We present a whole-genome-sequencing-based tool for genomic contact tracing of N gonorrhoeae and demonstrate local, national, and international transmission. Whole-genome sequencing can be applied across geographical boundaries to investigate gonorrhoea transmission and to track antimicrobial resistance. Oxford National Institute for Health Research Health Protection Research Unit and Biomedical Research Centre.