Ceftriaxone-resistant Neisseria gonorrhoeae in Singapore: Eight years of sentinel surveillance

Introduction

Gonorrhoea remains a major global public health challenge, with an estimated 82 million new infections annually, disproportionately affecting young adults and vulnerable populations. ¹ The burden of disease is further compounded by the pathogen’s capacity for rapid acquisition of antimicrobial resistance (AMR), undermining standard treatment approaches. ² Effective antimicrobial therapy is crucial not only for individual clinical outcomes but also for breaking transmission chains, reducing sequelae such as pelvic inflammatory disease and infertility, and preventing co-infections, particularly with HIV.

Over the past decade, ceftriaxone, a third-generation cephalosporin, has emerged as the cornerstone of empirical therapy for uncomplicated gonorrhoea, following widespread resistance to previously used agents including penicillin, tetracyclines, and fluoroquinolones. ² Dual therapy with azithromycin was initially adopted to delay resistance emergence, although this strategy has been recently reconsidered due to rising azithromycin resistance and insufficient additive benefit.

The emergence of ceftriaxone-resistant Neisseria gonorrhoeae now represents a critical and escalating threat to global STI control efforts. Although such strains remain rare in many regions, they have been documented in East Asia, Europe, North America, and Oceania, including several high-profile treatment failures. Importantly, resistance is no longer limited to key populations, including men who have sex with men (MSM) but has increasingly been reported within heterosexual networks.^3,4 This diffusion across sexual networks increases the potential for silent community spread and raises concern for untreatable gonorrhoea becoming a realistic scenario.

Pharyngeal gonorrhoea has emerged as a specific concern in the context of ceftriaxone resistance. Pharyngeal infections are frequently asymptomatic, underdiagnosed, and more difficult to eradicate due to reduced drug penetration and local microbiota that may facilitate genetic exchange. ² These factors create a permissive environment for persistence and resistance selection. The oropharynx acts as a biological “incubator” where the unique microenvironment facilitates horizontal gene transfer between Neisseria gonorrhoeae and commensal Neisseria species. Notably, treatment failure at pharyngeal sites has occurred even when minimum inhibitory concentrations (MICs) remain within nominal susceptibility ranges, underscoring the limitations of relying solely on MIC-based interpretations. ⁴

Interpretation of ceftriaxone susceptibility remains challenging because resistance definitions have evolved over time and are not uniformly applied across guideline bodies. Differences between interpretive criteria used by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and the Clinical and Laboratory Standards Institute (CLSI), as well as surveillance frameworks such as the Australian Gonococcal Surveillance Programme (AGSP), complicate direct comparison of resistance trends across studies and regions. In this context, sustained culture-based surveillance is essential for monitoring minimum inhibitory concentration distributions, detecting emerging resistance signals, and informing evidence-based updates to treatment guidelines.

Singapore is a regional travel and commercial hub with a dense urban population and high volume of international arrivals. Its diverse sexual networks and interconnectedness increase vulnerability to AMR importation and spread. Since 2014, the Department of STI Control (DSC) at the National Skin Centre has conducted sentinel culture-based surveillance for gonococcal antimicrobial resistance, with isolates referred to the Department of Microbiology at Singapore General Hospital for antimicrobial susceptibility testing. Although the first ceftriaxone-resistant isolate was identified in 2018, ⁵ longitudinal analyses integrating microbiological findings with behavioural and clinical outcome data from this surveillance stream have not been well documented. Given that DSC reports the majority of the notifiable STI cases, including gonorrhoea nationally, ⁶ findings from this sentinel surveillance provide important insight into emerging resistance patterns.

This study reports findings from culture-based sentinel surveillance of ceftriaxone-resistant Neisseria gonorrhoeae detected between January 2018 and October 2025. We examine detection patterns, antimicrobial susceptibility characteristics, associated behavioural risk factors, and clinical outcomes.

Methods

Results

Demographic and behavioural features

The median patient age was 35 years (IQR 24-48). All cases occurred in individuals reporting exclusively heterosexual contact; none of the male patients reported sex with men. Two cases were identified in women, both involving pharyngeal infection. One female patient reported transactional sex work, while the other reported a regular male partner. The remaining cases occurred in heterosexual men with urethral infection (Table 1).

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Table 1.

Demographic and behavioural characteristics of patients with ceftriaxone-resistant Neisseria gonorrhoeae in Singapore (n = 23), 2018–2025.

Variable	Category	Result
Median age	Years (IQR)	35 (24–48)
Gender	Male	21 (91%)
	Female	2 (9%)
Sexual orientation	Heterosexual	23 (100%)
	MSM	0 (0%)
Risk factors	Exposure to transactional sex	11 (48%)
	Unprotected oral sex	21/21 males (100%)
	Lifetime partners >10	8/21 males (38%)
Anatomical site	Urethral	21 (91%)
	Pharyngeal	2 (9%)

Among male patients, eight reported more than 10 lifetime sexual partners, and transactional sex exposure was documented in 11 of the 23 cases. Condom use during penetrative sex was inconsistent; only one man reported consistent condom use. All men reported never using condoms during oral sex. One male patient experienced a documented reinfection within 12 months. None of the patients had prior use of HIV pre-exposure or post-exposure prophylaxis.

HIV testing was offered routinely. Fourteen patients had documented negative HIV test results, while the remaining nine patients declined HIV testing.

Antimicrobial susceptibility profiles

Ceftriaxone MICs ranged from 0.25 to 1 mg/L. The highest MICs (1 mg/L) were observed in 2018–2019. Subsequent isolates fluctuated between 0.25 and 0.5 mg/L. All 2025 isolates had MICs of 0.5 mg/L, without upward drift (Table 2). Susceptibility profiles for other tested antimicrobials are summarised in Supplementary Table 1. Ciprofloxacin resistance was seen in all cases. Azithromycin resistance appeared in three cases (2 in 2020 and 1 in 2021) but all other isolates were susceptible. Spectinomycin susceptibility was retained in all tested cases. Gentamicin results were mixed (susceptible/intermediate) prior to discontinuation in 2025.

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Table 2.

Counts of ceftriaxone MICs over time, 2018–2025.

Counts of ceftriaxone MICs over time	2018	2019	2020	2021	2022	2023	2024	2025
0.25 mg/L	0	1	5	2	0	1	0	0
0.5 mg/L	0	1	0	0	0	2	0	8
1 mg/L	1	1	0	0	0	1	0	0
Total count	1	3	5	2	0	4	0	8

Discussion

This 8-year surveillance study documents the intermittent presence of ceftriaxone-resistant Neisseria gonorrhoeae in Singapore. Although the overall prevalence remains under 1%, the consistent reappearance of resistant isolates since 2018 suggests ongoing vulnerability to importation and spread. The data also underscore Singapore’s value as a sentinel site for regional AMR monitoring.

The behavioural profile observed, predominantly heterosexual men with inconsistent condom use and exposure to transactional sex, adds to growing evidence that ceftriaxone-resistant Neisseria gonorrhoeae is not confined to MSM populations and can arise in diverse sexual networks, as reported in multiple regions including East Asia and Europe.^7–9 None of the patients had prior use of HIV pre-exposure or post-exposure prophylaxis, suggesting that the observed resistance patterns were unlikely to be linked to biomedical HIV prevention settings, consistent with previous local data on bacterial STI incidence among PrEP users. ¹⁰ Importantly, oral sex was common and rarely protected, consistent with the hypothesis that the pharynx functions as both a reservoir and incubator of resistance. Both female cases involved pharyngeal infection, including one instance of treatment failure with ceftriaxone. The concentration of pharyngeal infection among women and its association with microbiological persistence following standard ceftriaxone therapy in this series suggest that the pharynx may not merely be a site of infection. This warrants further investigation into the role of the pharynx as an ecological niche where resistance may be selected, maintained, and transmitted onward to urogenital sites.

The absence of a sustained upward drift in MICs over time may reflect repeated introductions of resistant strains rather than progressive local amplification; however, this remains speculative in the absence of genomic analysis of local isolates. Similar patterns of multiple independent origins have been demonstrated in genomic studies from other regions. The preservation of spectinomycin susceptibility offers some reassurance, although this agent is not widely used due to limited availability.

Despite universal ciprofloxacin resistance and some emergence of azithromycin resistance, ceftriaxone remains largely effective, though with a narrowing margin. The loss of treatment redundancy is concerning and underscores the importance of new therapeutic options. Zoliflodacin, now approved by the U.S. Food and Drug Administration for uncomplicated gonorrhoea, and gepotidacin, currently in phase III trials, represent promising alternatives for cases involving multidrug resistance. ¹¹

Although all cases in this series occurred among individuals reporting exclusively heterosexual contact, the emergence of ceftriaxone-resistant Neisseria gonorrhoeae within heterosexual networks raises broader public health concerns. Sexual networks are not static, and bridging between heterosexual and men-who-have-sex-with-men (MSM) communities has been well described, particularly through bisexual partnerships, individuals involved in transactional sex, and overlapping social venues.

In our Singapore context, our data suggest that sex work networks rather than MSM core groups are the primary drivers of ceftriaxone resistance. The intermittent detection pattern observed, characterised by years with no resistant isolates interspersed with sporadic clusters, supports the hypothesis of repeated introductions of resistant strains rather than sustained local transmission, consistent with Singapore’s role as a regional travel hub.^7,9 Importantly, the introduction of resistant strains into MSM networks could facilitate more rapid dissemination and increase opportunities for resistance amplification.

Together, these considerations underscore the importance of comprehensive surveillance across populations and reinforce the need for early detection and containment of resistant strains, regardless of the initial network in which they are identified.

This study has several limitations that warrant consideration. First, behavioural data were derived from retrospective chart review and may be subject to underreporting or misclassification of risk behaviours. Second, although the fluctuating pattern of detection suggests repeated introductions rather than sustained endemic transmission, molecular typing was not performed and phylogenetic relatedness between isolates could not be assessed. Nonetheless, phenotypic surveillance with quantitative MIC remains a cornerstone of gonococcal antimicrobial resistance monitoring and the primary evidence used to inform gonorrhoea treatment guidelines globally. Genomic sequencing of future surveillance can improve understanding of the evolution of resistant isolates and transmission. However, the absence of molecular data does not detract the current value of phenotypic surveillance in informing empirical therapy and public health preparedness. Third, test-of-cure was documented in only 52% of patients; however, most cases involved symptomatic urethral infection, and it is possible that patients with persistent symptoms would have re-presented for care, potentially mitigating under-ascertainment of treatment failure.

Nevertheless, this study provides valuable sentinel surveillance data linking ceftriaxone resistance phenotypes with epidemiological, behavioural and clinical characteristics over an extended period, and contributes important local evidence to the growing global literature on emerging gonococcal antimicrobial resistance.

Conclusion

Ceftriaxone-resistant Neisseria gonorrhoeae has been detected in Singapore through sentinel surveillance since 2018, occurring exclusively among individuals reporting heterosexual contact and associated with identifiable behavioural risk factors, including exposure to transactional sex and unprotected oral sex. While symptomatic urethral infections have generally responded to current therapy, pharyngeal infection remains a particular concern due to its potential for asymptomatic persistence and reduced microbiological clearance.

Ongoing surveillance should continue to prioritise extragenital sampling, particularly of the pharynx, alongside the collection of behavioural data. Test-of-cure strategies should focus on pharyngeal gonorrhoea to ensure treatment effectiveness. Given the capacity for resistant strains to spread across diverse sexual networks, sustained and comprehensive surveillance across populations is critical to facilitate early detection, prevent further transmission, and guide timely updates to treatment and prevention strategies.

Supplemental material