ABSTRACT
Neisseria gonorrhoeae is the predominant cause of male urethral discharge in South Africa, and escalating prevalence of gonococcal antimicrobial resistance (AMR) is a major health concern both in-country and globally. We analyzed the demographic, behavioral, and clinical characteristics of 685 men presenting with gonococcal urethral discharge to sentinel surveillance clinics over a 3-year period (2017 to 2019) to determine the burden of factors that are known to be associated with N. gonorrhoeae AMR to first-line therapy (defined as group 1 isolates exhibiting resistance or reduced susceptibility to extended-spectrum cephalosporins or azithromycin). Among 685 men with gonococcal urethral discharge, median age was 28 years (interquartile range [IQR], 24 to 32). Only two men (2/632; 0.3%) self-identified as homosexual; however, on further enquiry, another 16 (2%) confirmed that they had sex with men only. Almost 30% practiced oral sex and were at risk for pharyngeal gonococcal infection. In univariate analysis, male circumcision (odds ratio [OR], 0.69; 95% confidence interval [CI], 0.49 to 0.99) and recent sex outside the country (OR, 1.83; 95% CI, 1.21 to 2.76) were significantly associated with having a category 1 N. gonorrhoeae isolate. In a multivariable model, only sex outside South Africa increased the odds of being infected with a decreased susceptible/resistant N. gonorrhoeae isolate (adjusted odds ratio [aOR], 1.64; 95% CI, 1.05 to 2.55). These findings warrant the intensification of N. gonorrhoeae AMR surveillance among recently arrived migrant and overseas traveler populations, as well as the inclusion of extragenital specimens for N. gonorrhoeae AMR surveillance purposes.
KEYWORDS: Neisseria gonorrhoeae, South Africa, antimicrobial resistance, gonococcal urethritis, male urethritis, risk factors
INTRODUCTION
Neisseria gonorrhoeae, the causative agent of the sexually transmitted infection (STI) gonorrhea is a rapidly evolving organism. In 2017, it was categorized as a high-priority human pathogen by the World Health Organization (WHO), owing to its propensity to develop antimicrobial resistance (AMR) to all first-line therapeutic agents and thus potentially become untreatable (1). The Centre for HIV and STIs at the National Institute for Communicable Diseases (NICD) in Johannesburg, South Africa, has been conducting etiological surveillance of STI syndromes since 2008. N. gonorrhoeae is the predominant cause of male urethritis syndrome (MUS) in South Africa and is implicated in about 70 to 85% of cases (2, 3). N. gonorrhoeae AMR testing is an important component of this surveillance and involves the collection of limited data and a urethral swab specimen from symptomatic men presenting with MUS to sentinel primary health care facilities. No extragenital specimens are collected for routine surveillance.
NICD’s surveillance of N. gonorrhoeae AMR profiles over a 10-year period (2008 to 2017) at a sentinel site in Johannesburg, Gauteng Province, revealed a high prevalence of resistance to penicillin, tetracycline, and ciprofloxacin (4). However, resistance to extended-spectrum cephalosporins (cefixime and ceftriaxone) and azithromycin has not been detected in recent years. N. gonorrhoeae AMR data are used to periodically update and revise the national STI syndromic management guidelines and are submitted annually to the WHO Global Antimicrobial Resistance and Use Surveillance System (GLASS) database (5). South Africa routinely employs STI syndromic management for the treatment of symptomatic patients as a pragmatic strategy to offer same-day, affordable, and effective therapy in an environment where diagnostic testing for STI pathogens is not undertaken or easily accessible at the primary health care level. The current national treatment algorithm for MUS includes combination therapy with single-dose intramuscular ceftriaxone (250 mg) and oral azithromycin (1 g) in accordance with WHO guidelines (6). Screening for asymptomatic STI is not offered at public health care facilities. Instead, etiological and AMR testing are reserved for STI syndromes and symptoms that persist following first-line treatment. Ceftriaxone-resistant gonorrhea is a notifiable medical condition in South Africa (7).
Risk factors associated with AMR in N. gonorrhoeae have been studied in Europe and Australia and have included age, country of birth, sexual orientation, sexual behavior, anatomical site of infection, coinfection with other STIs, and history of prior treatment for gonorrhea (8, 9). Such studies are important, as they identify and better define high-risk groups for N. gonorrhoeae AMR, which may require additional targeted interventions, such as close follow-up for symptom resolution and test-of-cure. There is a dearth of information from Africa on demographic, epidemiological, and behavioral characteristics associated with antimicrobial-resistant gonorrhea.
We aimed to determine the burden of known antimicrobial resistance-associated risk factors among symptomatic men with culture-positive gonococcal urethral discharge in South Africa between 2017 and 2019. We also sought to ascertain whether there was an association between these risk factors and the identification of gonococci that exhibited resistance or reduced susceptibility to first-line therapeutic agents.
RESULTS
Demographic characteristics and risk behaviors.
Overall, 1,000 men with clinically evident urethral discharge provided written consent to participate, completed the survey, and had urethral specimens collected for laboratory testing. Most men (860/1,000, 86%) had PCR-confirmed urogenital gonorrhea; nearly 80% of these men (685/860) were also culture positive for N. gonorrhoeae. Clinical data from men with culture-confirmed gonorrhea were analyzed in conjunction with laboratory results. Demographic, behavioral, and epidemiological characteristics of these men are presented in Table 1. The majority (99.4%) of these male participants were black African. The median age of participants was 28 years (interquartile range [IQR], 24 to 32 years), and the median age of sexual debut was 17 years (IQR, 15 to 18 years). Most men had sex with women; reported sex between men was rare (Table 1). A few men (16, 2.3%) provided inconsistent responses when they reported sex with only men in the past 1 year but then reported vaginal sex in the past 3 months. In the 3 months prior to presentation, over 25% of men reported having sex with a partner living in another province and nearly 20% with someone residing in another country (Table 1). Among the latter group, the majority of partners (83/127; 65.4%) were residents of neighboring Zimbabwe.
TABLE 1.
Prevalence of demographic, behavioral, and clinical risk factors for antimicrobial resistance in 685 men with culture-confirmed gonococcal urethral discharge, South Africa, 2017 to 2019
| Risk factor category | Patient characteristic | n/total n (%) |
|---|---|---|
| Demographic and behavioral | Age 25 yrs and above | 513/685 (74.9) |
| Sex with women (past 1 yr) | 669/685 (97.7) | |
| Sex with men (past 1 yr) | 18/685 (2.6) | |
| Sex with both men and women (past 1 yr) | 0/685 (0.0) | |
| Vaginal sex (past 3 mo) | 678/685 (99.0) | |
| Receptive anal sex (past 3 mo) | 0/685 (0.0) | |
| Oral sex (past 3 mo)a | 204/685 (29.8) | |
| 2 or more sexual partners (past 3 mo) | 36/228b (15.8) | |
| At least one casual sexual partner (past 3 mo) | 381/685 (55.6) | |
| Clinical/epidemiological | Unsuccessful treatment for male urethritis syndrome (past 3 mo)c | 37/685 (5.4) |
| History of previous STI (past 12 mo) | 123/685 (18.0) | |
| Sex outside province of testing (past 3 mo) | 193/685 (28.2) | |
| Sex outside South Africa (past 3 mo) | 127/685 (18.5) | |
| Circumcised | 447/685 (65.3) | |
| C. trachomatis coinfection | 111/685 (16.2) | |
| HIV coinfectiond | 125/682 (18.3) |
Includes fellatio, cunnilingus, and anilingus.
Data available only for 2019.
Eighteen of these 37 men (48.6%) received only tablets for treatment and not the recommended intramuscular ceftriaxone injection.
Serum specimens of 3 participants were hemolyzed and not tested.
Neisseria gonorrhoeae antimicrobial resistance profiles.
Overall, Neisseria gonorrhoeae isolates from 685 men presenting to publicly funded clinics with urethral discharge were tested in 2017 to 2019. N. gonorrhoeae resistance to extended-spectrum cephalosporins (ESCs) was rarely observed among surveillance isolates. All isolates were susceptible to ceftriaxone (Table 2). There was only one cefixime-resistant isolate (MIC = 0.25 μg/ml) from the Western Cape. This isolate also exhibited relatively high MICs for ceftriaxone (0.06 μg/ml) and azithromycin (0.25 μg/ml). When group 1 agents were categorized separately, only 0.1% (1/685) and 0.6% (4/685) of isolates had MICs ≥ 0.06 μg/ml for ceftriaxone and cefixime, respectively.
TABLE 2.
Antimicrobial MIC data for N. gonorrhoeae isolates cultured from men presenting with urethral discharge, South Africa, 2017 to 2019
| Antimicrobial (total no.) | MIC distribution (μg/ml) |
|||
|---|---|---|---|---|
| Range | MIC50 | MIC90 | Modal MIC | |
| Ceftriaxone (n = 685) | 0.002–0.064 | 0.004 | 0.008 | 0.002 |
| Cefixime (n = 685) | 0.016–0.25 | 0.016 | 0.016 | 0.016 |
| Azithromycin (n = 667)a | 0.032–0.5 | 0.128 | 0.25 | 0.128 |
Eighteen isolates were nonviable on subculture for azithromycin agar dilution MIC testing.
Resistance to azithromycin (MIC > 1 μg/ml) was not seen among the isolates tested: only 2% (13/667) displayed an MIC of 0.5 μg/ml, and in total, less than 25% (159/667) were categorized as group 1 with MIC values ≥ 0.25 μg/ml.
Association between participant risk factors and N. gonorrhoeae MIC category.
In univariate analysis, male circumcision and recent sex with a partner from another country were the only two risk factors significantly associated with having a group 1 N. gonorrhoeae isolate (Table 3). Circumcised males were 30% less likely to be infected with isolates having relatively high MICs (odds ratio [OR], 0.69; 95% confidence interval [CI], 0.49 to 0.99), and recent sex outside the country increased the likelihood by 80% (OR, 1.83; 95% CI, 1.21 to 2.76). In the multivariable model, after adjustment for age, site of enrollment, circumcision status, receiving tablets only for an MUS episode in the preceding 3-month period, and a recent history of sex outside the country, only sex outside South Africa increased the odds of being infected with a decreased susceptible N. gonorrhoeae isolate (adjusted odds ratio [aOR], 1.64; 95% CI, 1.05 to 2.55). Recent failed treatment for MUS, with assumed inappropriate therapy (tablets only), was associated with a nonsignificant but 2-fold higher likelihood of being infected with an N. gonorrhoeae isolate exhibiting decreased susceptibility to first-line antimicrobial agents (aOR, 2.01; 95% CI, 0.76 to 5.34).
TABLE 3.
Association between N. gonorrhoeae MIC-based group and participants’ demographic, behavioral, and clinical characteristics (univariate and multivariable analyses)
| Risk factor | Group 1a (total n = 178) (no. [%]) | Group 2b (total n = 507) (no. [%]) | Crude OR (95% CI) | P value | Adjusted OR (95% CI) | P value |
|---|---|---|---|---|---|---|
| Age > 25 yrs | 135 (75.8) | 378 (74.6) | 1.07 (0.72–1.59) | 0.73 | 0.98 (0.65–1.47) | 0.93 |
| Sex with men | 3 (1.7) | 15 (3.0) | 0.56 (0.16–1.97) | 0.37 | ||
| Oral sex (past 3 mo) | 54 (30.3) | 150 (29.6) | 1.04 (0.71–1.50) | 0.85 | ||
| ≥2 sexual partners (past 3 mo)c | 8 (13.8) | 28 (16.5) | 0.81 (0.35–1.90) | 0.63 | ||
| At least one casual sexual partner (past 3 mo) | 93 (52.3) | 288 (56.8) | 0.83 (0.59–1.17) | 0.29 | ||
| MUS treated without success (past 3 mo) | 10 (5.6) | 27 (5.3) | 1.06 (0.50–2.23) | 0.88 | ||
| Received tablets only, if treated without success | 7 (3.9) | 11 (2.2) | 1.85 (0.70–4.84) | 0.21 | 2.01 (0.76–5.34) | 0.16 |
| Circumcised | 105 (59.0) | 342 (67.5) | 0.69 (0.49–0.99) | 0.042 | 0.79 (0.54–1.15) | 0.22 |
| Previous STI (past 12 mo) | 33 (18.5) | 90 (17.6) | 1.05 (0.68–1.64) | 0.81 | ||
| Site (Gauteng Province) | 122 (68.5) | 315 (62.1) | 1.33 (0.92–1.91) | 0.13 | 1.13 (0.76–1.68) | 0.56 |
| Sex outside province (past 3 mo) | 49 (27.5) | 144 (28.4) | 0.96 (0.65–1.40) | 0.82 | ||
| Sex outside country (past 3 mo) | 46 (25.8) | 81 (16.0) | 1.83 (1.21–2.76) | 0.004 | 1.64 (1.05–2.55) | 0.03 |
| C. trachomatis coinfection | 31 (17.4) | 80 (15.8) | 1.13 (0.71–1.77) | 0.61 | ||
| HIV coinfection | 29 (16.4) | 96 (19.0) | 0.83 (0.53–1.32) | 0.44 |
Participants with N. gonorrhoeae isolates having ceftriaxone MICs of ≥0.06, cefixime MICs of ≥0.06, or azithromycin MICs of ≥0.25. All MICs in μg/ml.
Participants with N. gonorrhoeae isolates having lower MICs for these three antimicrobials.
Data available for only 228 participants (2019).
DISCUSSION
We analyzed the association between two defined N. gonorrhoeae MIC groupings with known resistance-associated risk factors reported by 685 men with culture-proven gonococcal urethral discharge. After adjusting for other variables, only recent sex with partner(s) living outside South Africa remained significantly associated with the isolation of gonococci exhibiting reduced susceptibility to extended spectrum cephalosporins or azithromycin.
Risk factors for N. gonorrhoeae AMR have been widely investigated in other parts of the world. In a study of predominantly MSM at a tertiary hospital in Spain, ESC resistance was associated with older age, previous gonorrhea episode(s) in the past 12 months, and risky sexual behavior, which included recent sex in a foreign country (10). Similarly, data from the European Gonococcal Antimicrobial Surveillance Program (Euro-GASP, 2009 to 2011) and the Gonococcal Resistance to Antimicrobial Surveillance Program in England and Wales (2007 to 2013) revealed an association between N. gonorrhoeae cefixime resistance or ceftriaxone MICs of ≥0.015 μg/ml and older age (≥25 years), as well as a negative association with Chlamydia trachomatis coinfection among heterosexuals (8, 11). In the Netherlands, only male-to-male sexual activity remained significantly associated with cefotaxime resistance after adjusting for other variables (12).
Our risk stratification by sexual orientation was hampered by the relatively small number of MSM in our study population. However, it is noteworthy that the first and only published case reports of cefixime treatment failure and cefixime resistance in South Africa were described in two MSM in 2012; these men had possible links to sexual networks in Europe and North America (13). Although South Africa has the highest global burden of HIV infection (14) and the HIV prevalence is higher among those presenting with STIs than in the general population (2, 3), we were unable to establish an association with HIV owing to a relatively low prevalence of decreased susceptibility to first-line antimicrobials among gonococcal isolates. However, a significant association between ciprofloxacin resistance and HIV seropositivity was previously reported in South Africa among men with urethral discharge during a period of rapidly escalating N. gonorrhoeae resistance to this oral fluoroquinolone (15).
Our study found that the risk factor most strongly associated with reduced susceptibility to first-line anti-gonorrhea agents is a history of recent sex outside South Africa. South Africa has a large population of economic migrants and workers from neighboring countries, and frequent cross-border travel occurs. Surveillance data from England and Wales showed that sex abroad in the preceding 3-month period had 2-fold higher odds of infection with N. gonorrhoeae having relatively high ceftriaxone MICs (≥0.015 μg/ml) (11). Importation of resistant isolates has been described in Australia, where immigrants from Northeast Asia (encompassing China, Japan, Mongolia, South and North Korea) were independently associated with multidrug resistant (MDR) N. gonorrhoeae infection (9). In recent years, there have been several case reports of extensively drug-resistant (XDR) N. gonorrhoeae exhibiting dual antimicrobial resistance to current first-line agents, i.e., ceftriaxone and azithromycin (16, 17). Cases of the XDR FC428 strain have been described in Europe (18–20), North America (21), Australia (22, 23), and China (24). Case reports of ceftriaxone-resistant N. gonorrhoeae have been linked to Southeast Asia and Europe and highlight the importance of international sexual networks in disseminating resistant clones (16–18, 20–22, 25).
Almost one-third of men surveyed stated that they practiced oro-genital sex and, if sexual practices involved exposure of men’s oropharynx to ano-genital secretions, they would be at risk for oropharyngeal gonorrhea. Higher mean ceftriaxone MIC values and ceftriaxone treatment failure has been linked to oropharyngeal infection (8, 16, 26). Infection in the oropharynx is more difficult to eradicate owing to the evolution of N. gonorrhoeae resistance by horizontal gene transfer from commensal Neisseria species in the oropharynx and also subtherapeutic antimicrobial levels at that anatomical site (27, 28). Importantly, oropharyngeal gonococcal infections may also significantly contribute to bridging transmission of resistant N. gonorrhoeae from MSM to heterosexual networks and vice versa.
Our results suggest that the establishment of sentinel sites and intensified surveillance in areas with a high migrant population may be a useful strategy to detect the emergence of XDR N. gonorrhoeae. This will enable the implementation of targeted public health action, such as tailored antimicrobial treatment and enhanced partner testing and treatment protocols. Future surveillance strategies should also consider incorporating pharyngeal sampling for N. gonorrhoeae AMR, including test-of-cure in those with oropharyngeal gonorrhea.
The strengths of our study include the large number of isolates from men for whom matching demographic, clinical, and laboratory data were available. The main limitation of our study was the small number of isolates with reduced susceptibility and the presence of only one ESC-resistant gonococcal isolate in the collection; this may have limited the statistical power to discern significant differences by risk stratification for antimicrobial resistance. Furthermore, two-thirds of the isolates (437, 63.8%) were from a single site based in Gauteng, South Africa’s most populated province, which limits generalizability and representativeness of our findings. Social desirability and recall bias may also have influenced the responses of some participants during the administration of the questionnaire. This may explain the inconsistency in responses from some participants regarding their sexual history, with respect to gender of sex partner and type of sex act.
In conclusion, in our population of men presenting with gonococcal urethral discharge to sentinel surveillance clinics in South Africa, a history of recent sex outside South Africa was independently associated with relatively high MICs to first-line antimicrobials used in gonorrhea treatment. We identified a high burden of risk factors associated with the evolution of antimicrobial resistance that warrants the establishment of additional surveillance sites among specific population groups and the collection of extragenital specimens for N. gonorrhoeae culture and antimicrobial susceptibility testing as part of routine surveillance.
MATERIALS AND METHODS
Participant recruitment.
Consecutive consenting adult men 18 years or older presenting to sentinel primary health care clinics with a new episode of visible urethral discharge were systematically enrolled. Surveillance was conducted at one sentinel site per province annually in Gauteng and periodically in the Western Cape, Free State, Eastern Cape, Northern Cape, and Limpopo provinces between 2017 and 2019. Written informed consent was followed by a short deidentified nurse-administered questionnaire, which captured demographic, behavioral, and clinical information of participants. Each participant was allocated a unique survey number, which was delinked from personal identifiers. Ethical approval for the study was granted by the Human Research Ethics Committee (Medical) of the University of the Witwatersrand, Johannesburg, South Africa (certificate number M131129).
Specimen collection.
Urethral discharge specimens were collected by the surveillance nurse from consenting males using the ESwab collection system (Copan Italia SpA, Brescia, Italy). For gonococcal culture, swab specimens from Gauteng province were inoculated directly on New York City (NYC) agar (Diagnostic Media Products, National Health Laboratory Service). The agar plate was then placed in a holding candle jar prior to same-day transfer, together with the ESwab specimen, to the STI reference laboratory at the Centre for HIV and STIs, NICD, in Johannesburg. ESwab specimens from all other provinces were transported on ice to the STI reference laboratory. Additionally, a 10-ml venous blood specimen was collected from each participant for HIV serological testing.
Laboratory testing.
At the STI reference laboratory, the ESwabs were vortexed and a 100-μl volume of liquid Amies medium from each plastic tube was transferred onto NYC agar using a sterile pipette. The inoculated agar plates were incubated at 35 to 37°C in 5 to 10% CO2 and examined daily for growth up to a total of 72 h. Suspected N. gonorrhoeae colonies were definitively identified using a biochemical test (oxidase) as well as a specific slide coagglutination immunological assay, the Phadebact monoclonal GC test (MKL Diagnostics AB, Kung Hans Vag, Sollentuna, Sweden). The isolates were subsequently subcultured onto antibiotic-free NYC plates for purity and additional testing. Antimicrobial susceptibility testing (AST) for cefixime and ceftriaxone was performed using Etest (bioMérieux, Marcy l’Etoile, France), while agar dilution batch testing was done for azithromycin MIC determination according to established standard operating protocols based on CLSI methodology. Isolates for batch testing were stored at −70°C using the Microbank system (Pro Lab Diagnostics Inc.); these were subcultured on antimicrobial-free NYC agar for purity prior to testing. Antimicrobial MICs were interpreted according to criteria recommended by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) (29). A panel of WHO reference strains of N. gonorrhoeae, with known MICs for each antimicrobial, was included in every batch of clinical isolates tested for the purpose of quality control (30). DNA, extracted from swab specimens using two automated DNA extractors (X-tractor Gene and QIAxtractor platforms, Qiagen, Hilden, Germany) was tested by a validated in-house real-time multiplex PCR assay for discharge-causing STI pathogens, including N. gonorrhoeae and Chlamydia trachomatis. Serum specimens were screened for HIV using two rapid immunochromatographic assays (Unigold Trinity Biotech; Trinity Biotech PLC, Wicklow, Ireland; Alere Determine; Alere Medical Co. Ltd, Chiba, Japan).
Data analysis.
Only data from participants with culture-confirmed urogenital gonorrhea were included in the analysis for this study. Data from clinical questionnaires and results of gonococcal antimicrobial susceptibility testing were exported into Stata 16 (StataCorp, College Station, TX, USA) for analysis. Risk factor analysis for enrolled participants was undertaken using frequencies and proportions for categorical data and medians and interquartile ranges for continuous variables. Analysis of antimicrobial susceptibility trends in N. gonorrhoeae involved determination of MIC range, modal MIC, MIC50, and MIC90. To investigate the association of known N. gonorrhoeae resistance-associated risk factors with antimicrobial resistance, the outcome of interest was infection with an N. gonorrhoeae isolate exhibiting reduced susceptibility (i.e., a high MIC within the susceptible range) or resistance to any of the first-line antimicrobials tested (ceftriaxone MIC of ≥0.06, cefixime MIC of ≥0.06, or azithromycin MIC of ≥0.25), denoted “group 1.” Participants infected with N. gonorrhoeae isolates having lower MICs for all three of these antimicrobials were used as the reference group for comparison (group 2). These MIC cutoffs were chosen, as they were just two dilutions below the resistance breakpoint for each antimicrobial and gave us a sufficient sample size for statistical analysis. Univariate and multivariable logistic regressions were used to identify significant association between the independent variables (risk factors) and outcome of interest (reduced antimicrobial susceptibility/resistance, i.e., group 1). The odds ratio (OR) and 95% confidence intervals (CI) were calculated for the univariate analysis, and a Pearson chi-square test was used to test the likelihood of chance occurrence. Any associations in the univariate model with a P of <0.2 were included in the multivariable analysis to model the odds of relative resistance controlling for other variables, with an age of ≥25 years and receiving prior inadequate treatment for urethritis being included a priori. In the multivariable model, significance was set at a P value of ≤0.05.
ACKNOWLEDGMENTS
We acknowledge Valencia Kekana, Alex Vezi, and staff of NICD GERMS-SA for patient enrollment and specimen collection for the surveillance study. Our thanks go to the national and provincial departments of health as well as clinic staff for the use of clinic facilities.
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conceptualization, Ranmini S. Kularatne; data curation, Tendesayi Kufa; formal analysis, Ranmini S. Kularatne, Tendesayi Kufa; methodology, Lindy Gumede, Dumisile V. Maseko; writing—original draft, Ranmini S. Kularatne; writing—review and editing, Ranmini S. Kularatne, David A. Lewis, Tendesayi Kufa, Lindy Gumede, Dumisile V. Maseko.
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