To Örebro University

BACKGROUND: Chancroid, a sexually transmitted infection (STI) caused by Haemophilus ducreyi resulting in genital ulcer disease (GUD), is now considered rare in many parts of the world. However, chancroid has remained highly prevalent in Malawi since the 1990s.

METHODS: We combined data from two recent studies conducted in Malawi (2019-2022, 2021) that screened and enrolled patients ≥ 18 years of age presenting to a STI clinic with GUD. Polymerase chain reaction (PCR) was conducted for H. ducreyi and other STIs from ulcer swabs. We evaluated demographic, sexual and clinical characteristics of participants with positive H. ducreyi PCRs to describe the epidemiology of chancroid using descriptive statistics.

RESULTS: Among 618 participants with GUD, 137 (22%) tested positive for H. ducreyi by PCR. Of these, most were male 85 (63%), the median age was 27 years (interquartile range [IQR]: 23, 33) and 19 (17%) had HIV co-infection. About a third (n=42, 31%) were co-infected with other STIs. Among 15 (11%) enrolled participants with additional clinical data, most reported one sexual partner in the past month (median = 1 [IQR: 1, 1). However, a history of prior transactional sex was reported by 5/15 (33%). The clinical presentation of the ulcers varied and over half presented with multiple ulcers (53%). Most ulcers (89%) were associated with pain, but few (20%) had associated inguinal lymphadenopathy.

CONCLUSIONS: This review confirmed the high prevalence and persistence of chancroid in Malawi. However, additional investigations are needed to further characterize the epidemiology of chancroid and determine the reasons for its persistence in Malawi.

OBJECTIVES: The spread of ceftriaxone-resistant Neisseria gonorrhoeae is threatening the last option for gonorrhoea treatment, ceftriaxone. Gepotidacin, the first-in-class triazaacenaphthylene bacterial topoisomerase type IIA inhibitor, recently showed non-inferiority compared to ceftriaxone-azithromycin for treatment of uncomplicated urogenital gonorrhoea in a Phase 3 randomized controlled trial. We evaluated the in vitro susceptibility to gepotidacin in clinical gonococcal isolates (n = 2912), including 125 (4.3%) ceftriaxone-resistant isolates, collected 2021-24 in eight WHO Enhanced Gonococcal Antimicrobial Surveillance Programme (EGASP) countries in three WHO regions.

METHODS: Isolates from Cambodia (n = 474), Indonesia (n = 107), Malawi (n = 111), the Philippines (n = 817), South Africa (n = 578), Thailand (n = 249), Uganda (n = 342) and Vietnam (n = 234) were examined. MICs of gepotidacin were determined using agar dilution. Gepotidacin target genes (gyrA and parC) were examined with Illumina sequencing.

RESULTS: Gepotidacin showed high in vitro activity, with MICs ranging from <0.016 to 4 mg/L. The modal MIC was 0.5 mg/L, MIC₅₀ 0.5 mg/L and MIC₉₀ 1 mg/L. Minor variations in the MIC distributions across countries were observed. ParC D86N, which in suboptimal gepotidacin concentrations predisposes for resistance development, was found in 35.5% of isolates.

CONCLUSIONS: We show that the in vitro susceptibility to gepotidacin in N. gonorrhoeae isolates, including 4.3% ceftriaxone-resistant isolates, collected 2021-24 in eight WHO EGASP countries, including five Asian countries, is high. Our findings support gepotidacin's continued clinical development, registration and introduction as a novel oral treatment for gonorrhoea. However, as with all new novel antimicrobials, cautious and optimal introduction, and surveillance of phenotypic and genomic susceptibility to gepotidacin internationally, pre- and post-licencing, should accompany any clinical implementation.

In 2024, based on the European Committee on Antimicrobial Susceptibility Testing breakpoint, we observed a tetracycline resistance prevalence of 62.3% (2,231/3,579) in Neisseria gonorrhoeae isolates from 22 European countries (range: 16.5-100%). Multivariable analysis of correlations between resistance and patients' epidemiological characteristics found tetracycline resistance associated with men who have sex with men (aOR: 1.38; 95% CI: 1.06-1.79). Our results are important when considering measures against transmission of sexually transmitted bacterial infections in Europe, such as in the context of doxycycline post-exposure prophylaxis (doxy-PEP).

BACKGROUND: Zoliflodacin, a first-in-class oral bacterial, DNA gyrase (GyrB) inhibitor, showed non-inferiority to ceftriaxone combined with azithromycin in a recent large international, phase 3, randomised controlled trial for treatment of uncomplicated urogenital gonorrhoea. The aim of this study was to describe the microbiological and whole-genome sequencing (WGS) analyses of paired baseline (pre-treatment) and test-of-cure (TOC) gonococcal isolates from the zoliflodacin phase 3, randomised controlled trial to further characterise and evaluate the protocol-specified microbiological failures with zoliflodacin (n=22) or ceftriaxone and azithromycin (n=1).

METHODS: In this retrospective, genomic, observational study, results from antimicrobial susceptibility testing (agar dilution method) of isolates (n=960; 936 baseline isolates from 763 participants and 24 TOC isolates [23 with a paired baseline isolate in the same anatomical site] from 20 participants) collected during the zoliflodacin phase 3, randomised controlled trial done in 16 outpatient clinics in Belgium, the Netherlands, South Africa, Thailand, and the USA (Nov 6, 2019-March 16, 2023) are described. WGS analysis was performed on paired baseline and TOC isolates from participants with microbiological failures (zoliflodacin 44 isolates [19 participants]; ceftriaxone and azithromycin two isolates [one participant]), and the three baseline isolates with highest zoliflodacin minimum inhibitory concentration (MIC 0·5 mg/L).

FINDINGS: All isolates were inhibited by the same zoliflodacin concentrations (MICs ≤0·008 to 0·5 mg/L) as wild-type strains cultured internationally in 2013-23. In participants with a microbiological failure after zoliflodacin treatment (n=22, 19 participants), zoliflodacin MIC values for baseline and TOC isolates were similar, and resistance selection was lacking. WGS showed that five (23%) of 22 infections (95% CI 10-43 [in four participants]) of zoliflodacin microbiological failures had different strains at TOC versus baseline. In 17 zoliflodacin microbiological failures (15 participants), isolates at baseline and TOC were indistinguishable. 13 of these 17 microbiological failures, corresponding to 59% (95% CI 39-77; 13 of 22) of all zoliflodacin microbiological failures, were in urogenital or rectal sites in 11 participants and the isolates had zoliflodacin MICs less than or equal to 0·008 to 0·25 mg/L. The single microbiological failure after ceftriaxone and azithromycin treatment had different strains at TOC versus at baseline. No sequenced isolates had mutations associated with elevated zoliflodacin MICs.

INTERPRETATION: In the zoliflodacin phase 3, randomised controlled trial, 23% of the zoliflodacin microbiological failures and the single ceftriaxone and azithromycin microbiological failure had different gonococcal strains at TOC versus baseline, which suggests reinfections and not treatment failures. In addition, 59% of the zoliflodacin microbiological failures, all in anogenital sites, had no obvious microbiological explanation based on the low zoliflodacin MICs, previous pharmacodynamic studies, and no evidence of resistance selection after zoliflodacin therapy. A reinfection as the cause for these microbiological failures could not be excluded. We recommend that WGS is implemented in future randomised controlled trials for gonorrhoea treatment to further evaluate possible microbiological failures, exclude reinfections (to avoid underestimating the cure rates), and characterise antimicrobial resistance determinants. 

BACKGROUND: Development of new treatments for gonorrhoea is a global public health priority. We aimed to evaluate the efficacy and safety of zoliflodacin versus ceftriaxone plus azithromycin in patients with uncomplicated urogenital gonorrhoea.

METHODS: In this phase 3, multinational, randomised, controlled, open-label, non-inferiority clinical trial, participants aged 12 years and older with clinical suspicion of uncomplicated urogenital gonorrhoea were eligible for inclusion. The trial was done in 17 outpatient clinics in Belgium, the Netherlands, South Africa, Thailand, and the USA. Participating countries with high disease prevalence were identified for participation in the study. Sites selected for participation were led by principal investigators with research experience, who were knowledgeable in HIV or sexually transmitted infections and treatment. Feasibility questionnaires and prestudy visits assessed sexually transmitted infection case management guidelines, clinical services, and resources (ie, facility, staff, proposed composition of the study team, standard sexually transmitted infection services offered at the site, assessment of laboratory capacity, research experience and ethical review of clinical trials). Eligible participants were randomly assigned (2:1) to receive a single dose of zoliflodacin 3 g (oral) or ceftriaxone 500 mg (intramuscular) plus azithromycin 1 g (oral). Treatment assignment was known to the participants and their treating clinicians; however, microbiology laboratory staff were masked and the sponsor's central study team were masked until after database lock. The primary endpoint was the proportion of patients with microbiological cure (eradication of Neisseria gonorrhoeae, determined by urethral or endocervical culture) at test of cure (TOC; day 6 ± 2) in the microbiological intention-to-treat population. The primary efficacy analysis declared non-inferiority if the upper bound of the two-sided 95% CI for the treatment difference (comparator minus zoliflodacin) fell below the 12% non-inferiority margin. The trial is registered with ClinicalTrials.gov, NCT03959527, and EudraCT, 2019-000990-22.

FINDINGS: Between Nov 6, 2019, and March 16, 2023, 1011 patients were screened. 81 patients did not meet screening criteria and 930 participants were randomly assigned to zoliflodacin (n=621) or comparator (n=309). The mean participant age was 29·7 years (SD 9·4). 815 (88%) of 930 participants were assigned male at birth and 115 (12%) participants were assigned female at birth. 514 (55%) of 930 participants were Black or African American, 285 (31%) were Asian, and 113 (12%) were White. Microbiological cure rates at TOC in the microbiological intention-to-treat (urogenital) population (primary efficacy endpoint) were 460 (90·9%, 95% CI 88·1-93·3) of 506 participants for zoliflodacin and 229 (96·2%, 92·9-98·3) of 238 participants for comparator. The estimated difference between groups was 5·3% (95% CI 1·4-8·6) and the upper confidence interval limit was within the prespecified non-inferiority margin of less than 12%. Zoliflodacin was generally well tolerated and adverse events were similar between treatment groups. The most frequently reported treatment-emergent adverse events included headache (61 [10%] of 619 patients), neutropenia (42 [7%]), and leukopenia (24 [4%]) in the zoliflodacin group and injection site pain (38 [12%] of 308 patients), neutropenia (24 [8%]), and diarrhoea (22 [7%]) in the comparator group. The majority of adverse events were mild or moderate in severity. No serious adverse events were reported.

INTERPRETATION: Zoliflodacin was non-inferior to ceftriaxone plus azithromycin for the treatment of uncomplicated urogenital gonorrhoea and had a similar safety profile. These data suggest a potential role for zoliflodacin as an effective oral treatment option for uncomplicated urogenital gonorrhoea. 

Sexually transmitted Chlamydia trachomatis infections remain common globally and most frequently are asymptomatic. The 2025 European C. trachomatis guideline provides up-to-date guidance regarding indications for testing and treatment of C. trachomatis infections. It includes advice on urogenital and extragenital C. trachomatis testing including the use of self-collected specimens; recommendation to use only validated NAATs for diagnosis; and recommendation to treat all C. trachomatis infections with doxycycline as first line in preference to single-dose azithromycin regimens. The absence of evidence and limited value of broad screening in asymptomatic populations for C. trachomatis infections is also discussed.

Background: Since 2009, the European Centre for Disease Prevention and Control (ECDC) has coordinated the European Gonococcal Antimicrobial Surveillance Programme (Euro-GASP) to monitor antimicrobial resistance (AMR) in Neisseria gonorrhoeae across the European Union and European Economic Area (EU/EEA). The aims of this study were to report Euro-GASP 2022 data and to compare with the most recently published Euro-GASP data (from 2016 to 2019), to identify changes in AMR and in risk groups for AMR.

Methods: In this observational study, 23 EU/EEA countries submitted AMR data for gonococcal isolates from 2022, linked to patient epidemiological data, to The European Surveillance System (TESSy). Statistical analyses (Z-test) were used to determine the significance of the differences between the epidemiological data and proportion of AMR isolates in 2022 versus 2019 and 2016. The risk factors associated with AMR isolates were assessed using univariate and multivariable logistic regression analyses of odds ratios.

Findings: Ceftriaxone resistance in 2022 (0.03%, 1/3008) remained low (0.06% (2/3239) in 2019), and cefixime resistance (0.3%, 10/3008) had decreased (0.8% (26/3239) in 2019). Azithromycin resistance (24.9%, 749/3008) and ciprofloxacin resistance (65.8%, 1980/3008) had increased (9.0% (284/3159) and 57.4% (1665/2884), respectively, in 2019). A marked increase in the number (575; 502 in 2019) and proportion (19.2%; 15.8% in 2019) of female gonorrhoea cases was also identified in 2022. In the univariate analysis, azithromycin resistance was associated with oropharyngeal (OR 1.67, CI 1.28-2.18; p < 0.0001) and anorectal infections (OR 1.38, CI 1.08-1.76; p = 0.0094), men-who-have-sex-with-men (MSM) (OR 3.88, CI 2.80-5.37; p < 0.0001), and females (1.71, CI 1.21-2.41; p = 0.0022). In the multivariable logistic regression model, only azithromycin resistance and MSM remained associated (OR 2.85, CI 1.33-4.73; p = 0.0040).

Interpretation: While ceftriaxone resistance remains sporadically detected in Euro-GASP, the increase in reports of occasional ceftriaxone resistance in EU/EEA countries and substantial increase in azithromycin resistance underscore the urgent need for enhanced AMR surveillance. The Euro-GASP data is crucial for refining treatment guidelines and mitigating the spread of AMR gonococcal strains. Novel effective antimicrobials for gonorrhoea treatment remain imperative.

BACKGROUND: The global spread of antimicrobial resistance (AMR) in Neisseria gonorrhoeae threatens empiric single-dose gonorrhoea treatment. Enhanced global AMR surveillance is imperative. We report i) gonococcal antimicrobial susceptibility and resistance data from 2023 in the World Health Organization Enhanced Gonococcal Antimicrobial Surveillance Programme (WHO EGASP) in the WHO Western Pacific Region (Cambodia, the Philippines, Viet Nam), Southeast Asian Region (Indonesia, Thailand), and African Region (Malawi, South Africa, Uganda, Zimbabwe), and ii) metadata of the gonorrhoea patients.

METHODS: In 2023, WHO EGASP included men with urethral discharge (n = 3498) and gonococcal isolates (n = 2491). Minimum inhibitory concentrations (MICs, mg/L) values were determined for ceftriaxone, cefixime, azithromycin, gentamicin, and ciprofloxacin using Etest (bioMérieux). Breakpoints from the European Committee on Antimicrobial Susceptibility Testing (EUCAST) were applied. Clinical and epidemiological variables associated with AMR isolates were assessed using univariable and multivariable logistic regression analyses of odds ratios.

FINDINGS: Overall, 3.8% (95% confidence interval (95% CI) 3.1-4.6%; 95/2487), 8.9% (95% CI 7.9-10.1%; 222/2484), 3.6% (95% CI 2.9-4.4%; 89/2487), and 95.3% (95% CI 93.2-97.5%; 1801/1890) of isolates were resistant to ceftriaxone, cefixime, azithromycin, and ciprofloxacin, respectively. All the ceftriaxone-resistant isolates were from Cambodia (15.3% (95% CI 11.5-20.1%), 42/274) and Viet Nam (20.4% (95% CI 15.9-25.7%), 53/260). In univariable analysis, ceftriaxone resistance was associated with travelling within the country during previous 30 days (OR 4.66, 95% CI 3.06-7.16; p < 0.001), and this association remained in multivariable analysis (aOR 4.12, 95% CI 2.65-6.65; p < 0.001).

INTERPRETATION: Resistance to ceftriaxone, cefixime, and azithromycin is a major global concern, and expanded and improved resistance surveillance is essential. The WHO EGASP has been substantially expanded in the recent years. Additionally, resistance breakpoints have been harmonised and test-of-cure, whole-genome sequencing, and extragenital sampling implemented, where feasible. Novel antimicrobials for gonorrhoea treatment are critical; zoliflodacin and gepotidacin are promising.

With over 374 million new curable bacterial STI cases annually, we are far from meeting global health targets. Despite their serious consequences for sexual, reproductive, and mental health, control efforts often focus on individual-level interventions like condom promotion and behavior change, which are insufficient. A scientific framework for STI control emphasizes reducing infectiousness, decreasing the number of susceptible individuals, and lowering transmission probability. Effective strategies should focus on environmental modifications, including expanding access to quality sexual health care, rapid testing with same-visit treatment, and AI-enhanced diagnostics. Equally critical are protecting susceptible communities through vaccination and chemoprophylaxis (e.g., doxycycline post exposure prophylaxis). While individual behavioural interventions like condom promotion remain relevant, declining usage trends challenge their impact. Surveillance of STIs and antimicrobial resistance is essential, influ-encing all key drivers of transmission. To control STIs more effectively, we must shift from individual behaviour change to systems-level public health strategies. Prioritising accessible, stigma-free health services, leveraging technological advances, and investing in comprehensive public health policies will improve STI prevention and help meet global health goals.