research paper on gonorrhea

• Open access
• Published: 11 November 2021

Gonorrhoea: a systematic review of prevalence reporting globally

• Jane Whelan   ORCID: orcid.org/0000-0003-3784-2749 1 ,
• Victoria Abbing-Karahagopian   ORCID: orcid.org/0000-0003-1987-363X 1 ,
• Laura Serino   ORCID: orcid.org/0000-0002-8618-9726 2 &
• Magnus Unemo   ORCID: orcid.org/0000-0003-1710-2081 3  

BMC Infectious Diseases volume  21 , Article number:  1152 ( 2021 ) Cite this article

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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.

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.

Peer Review reports

Gonorrhoea is a sexually transmitted infection (STI) caused by Neisseria gonorrhoeae (the gonococcus). In 2016, an estimated 87 million incident cases occurred among persons aged 15–49 years worldwide with an incidence rate of 20 cases/1000 women and 26/1000 men [ 1 ].

Gonorrhoea affects the urogenital tract, oropharynx, rectum, or conjunctiva, and repeat infections are common. Urogenital infections are often asymptomatic, particularly in women, but irrespective of symptoms, gonorrhoea is associated with substantial morbidity. Serious complications and sequelae include pelvic inflammatory disease, chronic pelvic pain, ectopic pregnancy, and infertility in women [ 2 ]. Infection during pregnancy is also associated with low birth weight and neonatal conjunctivitis, which can progress to blindness [ 2 , 3 ]. In men, gonorrhoea can cause epididymitis [ 2 ]. Rectal and pharyngeal gonorrhoea cases, mostly asymptomatic, are prevalent in men-who-have-sex-with-men (MSM), but can be common also in women and, particularly pharyngeal infection, in men who have sex only with women [ 4 ]. The presence of gonorrhoea is also a co-factor in human immunodeficiency virus (HIV) transmission [ 5 ].

Gonorrhoea is substantially underdiagnosed and underreported worldwide [ 3 ]. Even in high-income economies with well-established STI surveillance systems, it is estimated that more than half of infections are unidentified or unreported [ 6 , 7 ]. This underdiagnosis/underreporting is higher in less-resourced settings and settings using syndromic management with limited access to state-of-the-art diagnostics such as nucleic acid amplification tests (NAATs). Though partially explained by the asymptomatic nature of the infection, underreporting is also due to delays in seeking healthcare and inaccessible or inadequate STI testing/treatment in underserved populations or those particularly vulnerable to infection: adolescents and young people, some ethnic and racial groups, communities of lower socioeconomic status, MSM, sex workers, and others [ 8 ].

The World Health Organization (WHO)’s global target is a 90% reduction in gonorrhoea cases by 2030 [ 9 ]. To monitor progress towards this goal, STI trend monitoring at the national level is recommended. This should include routine prevalence assessments (every two to three years) of bacterial STIs among general populations of men and women (e.g. including pregnant women, women attending family planning clinics, military recruits and men undergoing employment physicals) [ 3 ]. Monitoring in high-risk priority populations including MSM and sex workers is also recommended [ 3 , 9 ].

The WHO reports prevalence estimates of curable non-viral STIs at a global and regional level using epidemic models, while recognizing the small number of prevalence data points that are available to generate reliable estimate [ 1 , 3 ]. Notably, for key population groups such as MSM and sex workers, who likely contribute substantially to the worldwide infection burden, gonorrhoea prevalence in global estimates is indirectly accounted for [ 1 ] and estimates do not reflect rectal and pharyngeal infection.

N. gonorrhoeae is progressively developing antimicrobial resistance (AMR) to all therapeutic antibiotics, and the WHO has issued warnings that untreatable gonorrhoea may be on the horizon [ 10 ]. National prevalence estimates are an essential indicator of the state of gonorrhoea and STI control at state level and globally [ 3 ]. In this review, we aimed to evaluate global prevalence reporting in the general population, and proxies thereof, on a country-by-country basis, extending previous reviews to report on key population groups of MSM and female and male sex workers (FSW and MSW), including extragenital as well as urogenital infection.

Search strategy and selection criteria

We conducted a systematic search of PubMed following PRISMA guidelines (Additional file 1 ) for papers published from 1 January 2010 to 11 April 2019. We derived a sensitive search strategy requiring at least one medical subject headings (MeSH) term related to a sexually transmitted disease (STD) or gonorrhoea and at least one reference to the keyword ‘gonorrhoea’ in the title or abstract. We did not specify the population (e.g. MSM, FSW or MSW), as we noted substantial overlap in reporting of risk groups and inclusion of terms such as ‘prevalence’, ‘epidemiology’ or ‘rate’ rendered the search too specific, omitting relevant papers (Additional file 2 ). Two authors (JW and VAK) independently screened all titles and abstracts against pre-specified inclusion and exclusion criteria (Additional file 3 ) and agreed on the selection of articles to be obtained as full text. English-language abstracts were reviewed but the full text was translated as necessary, from Portuguese, Spanish, and Chinese, where relevant. The systematic search was supplemented with an online English-language country-by-country search of websites, data repositories and surveillance reports of public health and/or governmental agencies using the country name, and ‘gonorr*’ or ‘sexually transmitted’ and ‘disease’ or ‘infection’ to identify data sources and provide context to prevalence estimates. We reviewed regional and international health agency data (WHO, European Centre for Disease Prevention and Control [ECDC]) and contacted relevant experts in the field. AMR monitoring, an essential component of gonorrhoea surveillance [ 10 ] and worthy of a separate review, was beyond the scope of this search.

Data analysis

The primary outcome (prevalence of gonorrhoea) was defined as the proportion of persons with laboratory-confirmed (culture and/or NAAT positive) gonorrhoea in the population within a specified time. It became apparent early in the literature search that population-based prevalence estimates were very limited and so to address the WHO recommendation to derive estimates from studies which are not necessarily population-based but nevertheless relevant, we defined a post-hoc secondary objective to report test positivity, categorizing these as proxy general population samples. Data were tabulated by population group (classified as ‘general population’, MSM and sex workers) and summarized per WHO region and country. ‘General population’ samples were identified according to WHO recommendations, to include studies conducted ‘among pregnant women, women attending family planning clinics, male military recruits and men undergoing employment physicals’ [ 3 ]. These samples served as proxies for the general population where population-based sampling was not, or could not, be conducted. The point estimates reported were adjusted for diagnostic test performance by applying a standardization factor for urogenital infection as utilized by WHO (Additional file 4 ) [ 3 , 11 ]. For rectal and pharyngeal infections, a separate literature review was undertaken to derive sensitivity and specificity values (for culture and/or NAAT) and adjustments were applied in the same manner as for the urogenital samples (Additional file 4 ). Due to obvious heterogeneity in study populations and study designs, widespread inclusion of non-representative samples and frequent lack of reporting of key parameters to judge the study quality, a quality score was not assigned. Similarly, a meta-analysis could not be conducted as we were limited in our ability to appropriately compare studies directly. We did not calculate a median summary estimate per country because only a small number of countries had three or more available estimates. Instead, guided by the principles of Campbell et al [ 12 ], we conducted a narrative synthesis, presenting the prevalence and test positivity estimates reported in the context of the source population and the type of sampling conducted, rather than directly comparing estimates. General population estimates were considered ‘population-based’ and representative if participants were sampled from a general population sampling frame and some form of random selection was performed. Studies employing other forms of sampling from proxy general population samples are labelled as such. As MSM and sex workers are defined in terms of their sexual behaviour, population-based denominator samples are generally not available. For these groups, screening and/or enhanced testing is frequently recommended irrespective of symptom status (and thus may be more reflective of prevalence). Therefore, studies conducted at STI clinics and at other venues frequented by MSM and sex workers were eligible for inclusion, excepting studies including persons presenting with symptoms, which were excluded to minimize bias. The median sample size and interquartile range were estimated using Excel’s ‘quartile.exc’ function.

Prevalence reporting in the general population

We identified 2015 citations relating to gonorrhoea ‘prevalence’ (Fig. 1 ), subsequently categorized into (a) the general population or proxy general population groups (men, women, and pregnant women separately), (b) MSM, and (c) FSW and MSW. Following title and abstract screening, we reviewed 424 full-text publications, of which 174 addressed the primary or secondary objective and were eligible for inclusion, reporting data from the following WHO regions: Africa (n=41), the Western Pacific (n=41), high-income North America that is part of the Region of the Americas (n=25), the Americas excluding high-income North America (n=25), Europe (n=19), South-East Asia (n=18), and the Eastern Mediterranean (n=5). The number of countries where prevalence and/or test positivity estimates were identified from the general population was limited, with data points identified from only 18.0% of countries worldwide (35/194) for women and 9.8% (19/194) for men (Fig. 2 ). Prevalence of gonorrhoea in the general population by WHO region and country is summarized in Table 1 and test positivity estimates from proxy general population samples in Table 2 .

PRISMA diagram describing selection of citations reporting gonorrhoea prevalence. Note: Some articles reported outcomes on several of the populations of interest or provided data for >1 country and therefore the total number of included data points does not amount to 174. n=number of articles

Availability of gonorrhoea prevalence reporting globally. Maps represent the availability of prevalence data in general population samples worldwide, including pregnant women, women attending family planning clinics, male military recruits, and work-based health screening programmes and other similar groups. General population estimates were considered ‘national population-based’ or ‘local population-based’ if participants were sampled from a general population sampling frame and some form of random selection was performed. Studies where probability sampling was not conducted, and which may not be generalizable beyond the study, are labelled as ‘non-population based’

For several countries, we did not identify prevalence or test positivity data. The grey literature search led to one additional estimate [ 63 ], but also allowed us to set the prevalence estimates identified in the context of the extent of surveillance otherwise ongoing in the country. To this end, expert consultation led to identification of surveillance data from three international reporting networks (WHO Global, WHO European Regional Office, and ECDC), and national surveillance data or reports from an additional seven countries, the United States of America (USA), Canada, Australia, Singapore, New Zealand, Japan, and the Republic of Korea.

Prevalence data and/or test positivity in general population samples were identified in 13.2% (seven out of 53) of countries in the WHO European region (nine estimates in women, including pregnant women [ 18 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 ], and five in men [ 18 , 56 , 57 , 58 , 59 ]) (Tables 1 and 2 ). We identified only one representative, population-based prevalence study in the United Kingdom (UK) that was of national scope [ 18 ]. These data were derived from the National Survey of Sexual Attitudes and Lifestyles (NATSAL) in 2010–2012. A probability sample of 15 162 men and women aged 16–74 years was drawn from the general population. Gonorrhoea testing was conducted for 2665 women and 1885 men and an overall prevalence of <0.1% was recorded (Table 1 ), higher in women and men aged 20–24 (0.2% and 0.1%, respectively). Data from all other countries represented test positivity data that were drawn from proxy groups of the general population, mainly non-probability samples, drawn from antenatal/obstetric clinics, primary care, community/youth clinics, with one study in a high school setting [ 56 ]. The median study sample size was 1004 in all women (interquartile range [IQR]: 220–5337) and 1236 in men (IQR: 802–6620). In all general population studies, NAAT testing conducted on urine (men, women) or genital fluid (women) was most common; confirmation by both NAAT and culture was used in pregnant women in France and Portugal [ 61 , 62 ]. Data on both sexes were available in only five studies [ 18 , 56 , 57 , 58 , 59 ]. One study reported samples from the urogenital and rectal site in aggregate [ 57 ]. All other studies included urogenital infection only.

For countries where no prevalence or test positivity estimate from the general population was identified, some degree of surveillance data was discoverable through the grey literature search. Most European Union (EU)/European Economic Area (EEA) Member States have comprehensive surveillance systems and report a national notification rate annually, except for Germany, Liechtenstein, Austria (not since 2014), and Greece (not since 2017) [ 85 , 86 ]. Belgium, France, and the Netherlands have sentinel surveillance systems. In countries outside the EU/EAA region (mostly the eastern European region), data were less discoverable. In 2017, countries including Armenia, Azerbaijan, Belarus, Georgia, Kazakhstan, Kyrgyzstan, Russian Federation, Turkmenistan, and Uzbekistan reported gonorrhoea cases to the WHO European Regional Office (M. Dara and G. Kuchukhidze, personal communication, 24 February 2019). Indicators included the absolute number of cases identified, the male to female ratio, and only for Armenia, the proportion of reported MSM among the cases. Prevalence data or comprehensive syndromic and aetiologic case reporting were not otherwise identified in the wider European region.

High-income North America

In the USA, laboratory-confirmed gonorrhoea is mandatorily notifiable and data collection is comprehensive, from diverse clinical settings including STD clinics, laboratories, family planning and school-based clinics, hospitals, emergency rooms, drug treatment centres, correctional facilities, and the military [ 87 ]. The most recent estimate of nationwide population prevalence identified was from the National Health and Nutrition Examination Survey (NHANES), a series of cross-sectional, bi-annual household surveys representative in terms of sex, age and race/ethnicity of the USA civilian, non-institutionalized population [ 19 ]. Between 1999 and 2008, screening for cervical or urethral gonorrhoea was a study component, and 15 885 persons, aged 14–39 years participated. An extrapolated national prevalence of 0.3% (95% confidence interval [CI]: 0.1%–0.5%) among 14–39-year-olds was estimated, higher in women than in men (Table 1 ). N. gonorrhoeae testing within NHANES stopped at the end of 2008 and, in 2009, gonorrhoea prevalence and notification rates were at an all-time low in the USA [ 19 ].

In terms of non-probability samples, an estimate of prevalence from a sentinel surveillance population of young people at elevated risk for gonorrhoea is provided annually by the Centers for Disease Control and Prevention (CDC), using data from the ‘National Job Training Program’ (NJTP), a nationwide vocational programme for socioeconomically disadvantaged youth aged 16 to 24 years who are considered at risk of STIs [ 63 ]. Participants are offered gonorrhoea and chlamydia screening at programme entry. In 2018, the median state-specific estimated gonorrhoea prevalence for programme entrants aged 16–24 years was 2.2% in women (range 0.4% to 7.6%), and 0.7% in men (range 0.0% to 4.8%) (Table 2 ) [ 63 ].

In the USA, we identified a further seven test positivity estimates from proxy general population samples in women (including one from a chart review of women screened [ 64 ], two studies in high schools [ 65 , 66 ], and four in pregnant women who are routinely tested [ 67 , 68 , 69 , 70 ]) and three data points in men (the same two studies in high schools [ 65 , 66 ] and one study in college students [ 81 ]) that met the inclusion criteria for the secondary objective (Table 2 ). There was a wide range in study sample size and in estimates reported, reflecting diversity in study participants and settings, and study population characteristics. Test positivity estimates from non-probability samples from the two studies in high schools were identified: one reported the proportion positive over almost 8 years (9.0% [3270/36 263] in girls and 4.1% [1588/39 010] in boys) and another yielded a combined estimate of 2.4% in girls and boys (Table 2 ) [ 65 , 66 ]. No comparison could be made across studies. Where reported, studies used NAAT testing.

In Canada, no prevalence study or proxy general population study was identified. Gonorrhoea is mandatorily notifiable, and laboratory-confirmed cases are reported to the Public Health Agency of Canada through the Canadian Notifiable Disease Surveillance System. Summary data are published annually by age and sex, and are available online [ 88 ], and a detailed surveillance report is produced every five years.

Americas (excluding high-income North America)

Prevalence and/or test positivity estimates from the general population were identified in 18.2% (six out of 33) of countries in this WHO region excluding the USA and Canada (12 estimates in women, including pregnant women [ 16 , 17 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 ], and four in men [ 17 , 48 , 49 , 80 ]) (Tables 1 and 2 ). One study in Peru could be considered population-based and of national scope. In this study, the substantial sample included 13 925 randomly selected 18–29-year-old men and women who were resident in 24 cities with populations >50 000 people [ 17 ]. Additionally, a local population-based study in Brazil, also urban, was conducted using two-stage sampling of households and young women in middle size cities in Central Brazil [ 16 ]. The remaining studies were non-probability samples, mainly from community settings including educational facilities, primary healthcare, adolescent health clinics and ANCs. The median study sample size was 399 in women (IQR: 309-1719) and 371 in men (IQR: 180-5749). All studies involved NAAT screening of urine (n=4) [ 16 , 44 , 45 , 49 ] and urogenital swab samples (n=7) [ 17 , 46 , 47 , 48 , 50 , 51 , 53 ] for women (clinical specimen not specified, n=1 [ 52 ]), and urine (n=3) [ 17 , 48 , 49 ] for men (clinical specimen not specified, n=1 [ 80 ]).

From the grey literature search, we identified only aetiological or syndromic case reporting in adult men through WHO Global AIDS Monitoring (GAM; known as Global AIDS Response Progress Reporting prior to 2015) for other countries in the region [ 3 ]. No further prevalence or test positivity data were identified in the region.

In the WHO African region, prevalence data and/or test positivity estimates from the general population were identified in 25.5% (12 out of 47) of countries (25 estimates in women, including pregnant women [ 13 , 14 , 15 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 ], and six in men [ 13 , 14 , 15 , 29 , 31 , 34 ]) (Tables 1 and 2 ). Three of the studies were local population-based, derived from household samples, and none were of national scope. The first was from the urban centre of Cotonou in Benin, where 2507 subjects aged 15–49 years, from 1070 households sampled from 38 census areas, participated [ 13 ]. In Malawi, another estimate was derived from a largely rural population from the eastern lakeside regions of the Mangochi district [ 14 ]. Most recently, 1342 young people aged 15–24 years were selected from a ‘health and demographic surveillance site’ sampling frame in rural South Africa [ 15 ]. The remaining studies (Table 2 ) were derived from non-probability samples with diverse recruitment sites, including antenatal clinic (ANC) settings, schools and universities, primary healthcare sites, and community-based recruitment. The median study sample size was 322 in women (IQR: 200–553) and 422 in men (IQR: 351–755). Laboratory confirmation was mainly by NAAT on urogenital swab samples and, to a lesser extent, on urine for women; in four studies [ 23 , 24 , 30 , 40 ], Gram stain and/or culture only were used. For men, urine samples were tested by NAAT in all cases where reported.

In the African region, 43% of countries reported to WHO in 2013 having STI surveillance systems in place and 40% had national strategies or plans for preventing and controlling STIs [ 89 ], but beyond limited reporting of aetiological surveillance among men and syndromic surveillance in men and women, we did not identify any further prevalence reporting in the region.

Western Pacific

Prevalence data and/or test positivity data from the general population were identified in 22.2% (six out of 27) of countries and territories in the WHO Western Pacific region (11 estimates in women, including pregnant women [ 20 , 21 , 22 , 73 , 74 , 75 , 76 , 77 , 78 , 79 ], and four in men [ 20 , 22 , 73 , 84 ]) (Tables 1 and 2 ). There were three population-based studies. One was of national scope in New Caledonia [ 22 ]. It included men and women selected during a national three-stage random sampling of general practice surgeries and public dispensaries, and the sample was then weighted to reflect the general population aged 18–49 years. The other two population-based studies were local in scope and were both in China. In one study from the Shandong province [ 20 ], men and women were sampled in a complex multi-stage sampling process based on urban and rural communities within geographic regions. The second study, from Shenzhen City [ 21 ], included women only and was designed to be representative of the entire population in the Nanshan District of the city. Beyond these prevalence data, for both men and women, test positivity estimates from non-probability, proxy general population samples were derived from a range of study settings including community settings, primary care, and hospital-based maternity clinics/ANCs. One study was in an occupational group (miners) in men in China [ 84 ]. The median study sample size in the region was 765 in women (IQR: 362–3581) and 1290 in men (IQR: 376–4490). In some countries in the region where no data were identified, gonorrhoea is a notifiable infection; routine national surveillance is conducted and opportunistic/risk-based screening and/or testing is recommended for some population groups (Australia, New Zealand, and Singapore) [ 90 , 91 , 92 ]. Sentinel surveillance is conducted in the Republic of Korea and in Japan, mostly in urology departments. In both countries, reported cases per sentinel are low and have decreased in recent years [ 93 , 94 ]. GAM data for men are also notified to WHO from many countries [ 3 ], but no further prevalence data were identified in the region.

South-East Asia

Among 11 countries in the WHO South-East Asian region, we did not identify any population-based prevalence estimates. Test positivity data in general population samples were identified from 18.2% (two out of eleven) of countries (two estimates in women, including pregnant women [ 71 , 72 ], and two in men [ 82 , 83 ]) (Table 2 ). Non-probability samples from the general population were community-based in women in India, hospital-based in young pregnant women aged <18 years in Thailand, and in occupational groups in men (migrant workers in India and military conscripts in Thailand). The median study sample size was 466 in women (range: 121–811) and 1482 in men (range: 840–2123).

We did not identify further information on gonorrhoea surveillance in the region, with the exception of GAM data from some countries [ 3 ].

Eastern Mediterranean

We identified non-probability samples in 4.8% (one out of 21) of countries in the WHO Eastern Mediterranean region: a single study in a hospital involving pregnant women [ 54 ] (Iran, n=239; standardized prevalence: 0.5%) (Table 2 ). According to the WHO, ten countries surveyed in 2013 reported having an STI surveillance system, four reported conducting aetiological studies, 11 had updated national STI guidelines or recommendations in place and nine had a national strategy or action plan for STI prevention and control [ 89 ], but no further estimates were identified in the region.

Prevalence and test positivity reporting in vulnerable population groups

Men-who-have-sex-with-men

Prevalence and/or non-probability test positivity data on gonorrhoea in the MSM population were identified in 64 studies from 25 countries (seven countries in Africa, five in Europe, two in North America, four in the Americas [excluding high-income North America], four in the Western Pacific, and three in South-East Asia) (Fig. 3 ; Additional file 5 ) [ 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 ]. For 56.0% (14 out of 25) of countries, data originated from a single study in an urban setting. In five studies, men testing HIV-positive were excluded at the outset [ 96 , 119 , 124 , 148 , 149 ]. HIV status was reported in five studies with variable HIV-positivity [ 98 , 100 , 103 , 115 , 127 ]. Three studies included asymptomatic cases only [ 120 , 131 , 150 ]. Urogenital screening and/or opportunistic testing (predominantly on urine samples) was most often performed. An equal proportion of studies involved recruitment from community settings or STI clinics, but there was diversity in terms of the populations included, including HIV status, which was often not reported. Both rectal and urogenital sampling were reported in 26 studies; rates of rectal infection were higher than urogenital rates in 69.2% (n=18) of these studies (Fig. 3 ). NAAT testing was reported in 22 of these studies, culture-only testing in two, and culture or NAAT testing in two. Reported rates of pharyngeal testing from 27 studies were mostly (51.9%) between 5.0% and 10.0%, 22.2% were between 1.0% and 5.0%, and 14.8% were >10.0%. Though variable, on average, the standardized estimate of pharyngeal infection was similar to urogenital positivity where reported in the same study.

Reported prevalence and/or test positivity of urethral (a) and/or rectal (b) gonorrhoea-positive cases in men-who-have-sex-with-men. 1 Prevalence rates for urethral gonorrhoea could not be standardized. 2 Prevalence rates for rectal gonorrhoea could not be standardized

Sex workers

Data on gonorrhoea prevalence and/or test positivity in MSW, FSW or both were available from 23 countries (Table 3 ), with 38 studies reporting on FSW and six on MSW. Of 41 unique studies, 14 were conducted in a clinic setting (including STI clinics, genito-urinary clinics and outreach clinics) and 13 at commercial sites (including hotels, brothels, street and residence). The remainder (n=14) were described as community-based or conducted at other mixed locations. Only urogenital testing was performed except for one study in China that also performed pharyngeal testing [ 184 ]. Overall, the median study sample size was 655 in women (IQR: 323–2165) and 240 in men (IQR: 113–584). The positivity estimates ranged from 0.0% (MSW in the Republic of Korea) to 29.2% (FSW in Indonesia).

Gonorrhoea prevalence monitoring is one of four key components of national STI surveillance programmes that is recommended by WHO to reduce the burden of gonorrhoea infections by 90% between 2018 and 2030 (in addition to case reporting, assessment of the aetiology of STI syndromes, and monitoring of antimicrobial resistance) [ 9 ]. WHO recommends prevalence assessments in the general population every two to three years, and in key populations such as MSM and sex workers [ 3 , 9 ]. From our review, it is clear that substantive prevalence data among representative samples of the general population were seriously lacking on a worldwide basis. We identified national population-based data from only four countries (USA [ 19 ], UK [ 18 ], Peru [ 17 ], and New Caledonia [ 22 ]), all pre-dating 2013. Recent local population-based data were identified from China [ 20 , 21 ] (2016 and 2017) and South Africa [ 15 ] (2018), but otherwise samples used for local population-based estimates were collected more than 10 years ago (Brazil, Benin, and Malawi [ 13 , 14 , 16 ]). The majority of the remaining test positivity estimates were derived from non-probability samples from groups that might be considered proxies of the general population, as proposed by WHO [ 3 ].

Based on our findings, most studies were conducted in single centres or discrete geographic regions or populations. We excluded STI clinic settings to avoid overestimating the prevalence in general population samples. As estimates (mainly from proxy general population groups) tended to be high, albeit with wide variation in the magnitude and precision of the estimate, it is highly likely that the risk profile of proxy populations was also higher than that of the general population. Even within groups, representativeness may not always have been similar (e.g. military conscripts residing in barracks versus those living at home). The median study sample size in the Americas (excluding high-income North America), Africa and the Eastern Mediterranean was <500 in both men and women, which further limits generalizability beyond the study population in question. Where national data were available to comment (e.g. USA), estimates from non-probability samples in defined younger populations [ 63 , 65 , 66 ] were higher than nationwide population-based estimates [ 19 ] or estimates from older populations [ 64 ], further highlighting the need for continued nationally representative population sampling. Diagnostic testing used varied widely and the sensitivity and specificity of these are an essential factor, contributing to differences in reported estimates. We standardized estimates for differences in laboratory methods (NAAT versus culture) and clinical specimens (urine or urogenital samples) where reported [ 3 , 11 ]. For consistency, we also adjusted for NAAT versus culture on rectal and pharyngeal samples, based on reported sensitivities and specificities in the literature and using a similar standardization procedure, to allow for within-study comparison. The specimen and test were not always reported, but NAAT-based testing was most common.

For most countries, no prevalence estimate or test positivity estimate from general population groups was identified. It was clear from our online (English) grey literature search, that surveillance is ongoing more widely, as we retrieved surveillance reports from online national and international data repositories, syndromic surveillance reports in some countries, and intermittent summaries of laboratory surveillance in others. Generally, the quality and quantity of data identified were highly variable and often neither timely nor contemporaneous. In the absence of prevalence data, low case rates reported in some settings likely reflect limited testing and restricted availability of appropriate laboratory diagnostics rather than actual infection rates. In many African countries, for example, prevalence reports (where available) and syndromic surveillance suggest that the very limited aetiological reporting substantially underestimates the true infection burden.

Heterogenous data in MSM were available for only 12.9% (25 out of 194) of countries, mainly single-centre studies in urban, community-based or STI clinic settings. Most studies performed testing at the urogenital site. Where both urogenital and extragenital testing were conducted, rates at rectal sites were typically higher. However, for modern NAATs no evidence-based consensus exists regarding sensitivity and specificity correction factors when using other diagnostic methods or different NAATs for urogenital and especially extragenital infections. International evidence-based consensus regarding these corrections is imperative to develop. Rates among FSW were often many multiples higher than general population estimates in women, in countries where data in both populations were available. Due to the dearth of data on sex workers in some regions, we erred on the side of inclusivity, including small studies of <100 from Iran for example, where no data were otherwise available.

Our review had limitations. There were undoubtedly data from studies not discoverable on PubMed. For example, a systematic review from China, which documented STI risk among MSM [ 189 ], included studies that we could not access through the library systems available to us. Systematic reviews on a regional basis with good local knowledge, including in setting and language, would be a valuable addition. For many countries, only one or two data points were identified. Limited data and marked heterogeneity between studies prohibited us from conducting a meta-analysis or reporting median estimates. Reporting of proportion testing positive was very diverse in terms of variables reported, degree of stratification by demographic and other factors (e.g. HIV status), details regarding diagnostic tests, and anatomic site, often with statistics omitted where data had clearly been collected. With improved reporting from diverse populations, novel methods for synthesizing diverse data may therefore be required.

Conclusions

Gonorrhoea prevalence is a core indicator to properly inform gonorrhoea management and control programmes, international and national guidelines, and policy documents. Gonorrhoea prevalence monitoring and reporting is suboptimal or absent in most countries. Many countries and regions have seen substantial increases in notification rates of gonorrhoea in recent years [ 63 , 85 ]. In the absence of serial prevalence data, however, it is difficult to disentangle how much of this reflects a true increase in the burden of gonorrhoea or some degree of improved awareness among groups at increased risk (in particular MSM), more consistent screening and/or testing, increased availability and use of NAATs, and improved (electronic) reporting. Irrespectively, among key populations such as MSM and sex workers, there is a substantial burden of infection where data are available. To inform STI control programmes at the national and regional level, and to inform innovative epidemiologic modelling initiatives such as SPECTRUM [ 11 ] and the Global Burden of Disease [ 190 ] that attempt to quantify and model the global burden, significantly more data of higher quality are required. There is an urgent need for more resources for researchers to design, conduct and report prevalence studies in a more consistent, standardized, and quality-assured way. Within countries, serial prevalence monitoring at intervals, including assessment and reporting of a minimum set of epidemiological variables, should be considered. Our review showed the need for more testing at extragenital sites, particularly, but not exclusively, among the MSM population. WHO currently provides guidance on the assessment of gonorrhoea and chlamydia prevalence among pregnant women at ANCs [ 191 ]. This guidance could be extended beyond the ANC setting. Consistent adherence to study reporting guidelines (e.g. adapted STROBE checklists [ 192 ] or equivalent), for all researchers is also advised.

Availability of data and materials

The dataset supporting the conclusions of this article is included within the article and its additional file (Additional file 6 ).

Abbreviations

Antimicrobial resistance

Antenatal clinic

Centers for Disease Control and Prevention

Confidence interval

European Centre for Disease Prevention and Control

European Economic Area

European Union

Female sex workers

Global AIDS Monitoring

Human immunodeficiency virus

Interquartile range

Medical subject headings

Male sex workers

Nucleic acid amplification tests

National Survey of Sexual Attitudes and Lifestyles

National Health and Nutrition Examination Survey

National Job Training Program

Sexually transmitted disease

Sexually transmitted infection

United Kingdom

United States of America

World Health Organization

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Acknowledgments

The authors thank the Modis platform for editorial assistance and manuscript coordination, on behalf of GSK. Kristel Vercauteren provided medical writing support and Maria Ana de la Grandière and Sara Blancquaert coordinated the manuscript development and provided editorial support. The authors also thank Masoud Dara and Giorgi Kuchukhidze (WHO European Regional Office, Copenhagen, Denmark); Jane Rowley (London, UK); and Nicholas J. Kassebaum (Institute for Health Metrics and Evaluation, IHME, Seattle, USA).

This work was funded by GlaxoSmithKline Biologicals SA. MU was not funded.

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JW supervised this work. JW, VAK, LS and MU contributed to the conceptualization, investigation, methodology, validation, and visualization of this work. JW, VAK, LS and MU participated in the development and the review of the manuscript and approved the final submitted version.

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Additional file 1..

PRISMA checklist.

Additional file 2.

Literature search strategy.

Additional file3.

Inclusion and exclusion criteria.

Additional file 4.

Standardizations adopted for urogenital, rectal and pharyngeal laboratory tests.

Additional file 5.

Reported gonorrhoea prevalence and/or test positivity in men-who-have-sex-with-men, by WHO region, country, and anatomic site.

Additional file 6.

Dataset supporting the output of the literature search.

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Whelan, J., Abbing-Karahagopian, V., Serino, L. et al. Gonorrhoea: a systematic review of prevalence reporting globally. BMC Infect Dis 21 , 1152 (2021). https://doi.org/10.1186/s12879-021-06381-4

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• Antimicrobial resistance
• Bacterial infection
• Infectious-disease diagnostics
• Microbial genetics
• Urogenital diseases

The bacterium Neisseria gonorrhoeae causes the sexually transmitted infection (STI) gonorrhoea, which has an estimated global annual incidence of 86.9 million adults. Gonorrhoea can present as urethritis in men, cervicitis or urethritis in women, and in extragenital sites (pharynx, rectum, conjunctiva and, rarely, systemically) in both sexes. Confirmation of diagnosis requires microscopy of Gram-stained samples, bacterial culture or nucleic acid amplification tests. As no gonococcal vaccine is available, prevention relies on promoting safe sexual behaviours and reducing STI-associated stigma, which hinders timely diagnosis and treatment thereby increasing transmission. Single-dose systemic therapy (usually injectable ceftriaxone plus oral azithromycin) is the recommended first-line treatment. However, a major public health concern globally is that N. gonorrhoeae is evolving high levels of antimicrobial resistance (AMR), which threatens the effectiveness of the available gonorrhoea treatments. Improved global surveillance of the emergence, evolution, fitness, and geographical and temporal spread of AMR in N. gonorrhoeae , and improved understanding of the pharmacokinetics and pharmacodynamics for current and future antimicrobials in the treatment of urogenital and extragenital gonorrhoea, are essential to inform treatment guidelines. Key priorities for gonorrhoea control include strengthening prevention, early diagnosis, and treatment of patients and their partners; decreasing stigma; expanding surveillance of AMR and treatment failures; and promoting responsible antimicrobial use and stewardship. To achieve these goals, the development of rapid and affordable point-of-care diagnostic tests that can simultaneously detect AMR, novel therapeutic antimicrobials and gonococcal vaccine(s) in particular is crucial.

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Investigation of auranofin and gold-containing analogues antibacterial activity against multidrug-resistant Neisseria gonorrhoeae

Introduction.

The sexually transmitted infection (STI) gonorrhoea remains a major public health concern globally. The aetiological agent of gonorrhoea, the bacterium Neisseria gonorrhoeae (the gonococcus), generally causes mucosal infections of the urogenital tract, predominantly infecting columnar and transitional epithelia, although it can also attach to the stratified squamous epithelium of the ectocervix 1 , 2 . Such N. gonorrhoeae infections most frequently result in urethritis in men and cervicitis in women, but urethritis in women is also observed 3 , 4 . This obligate human host-adapted pathogen was described for the first time by Albert Neisser in Gram-stained microscopy of urethral discharge in 1879 (ref. 5 ). N. gonorrhoeae is a diplococcal (that is, it is typically composed of two joined cells with the adjacent sides flattened, resulting in a characteristic kidney or coffee bean appearance on microscopy), Gram-negative microorganism; it belongs to the bacterial class Betaproteobacteria and the family Neisseriaceae, and has been co-evolving with its human host for centuries. The family Neisseriaceae comprises the genus Neisseria and other genera such as Kingella and Eikenella 6 , 7 , 8 . The Neisseria genus currently consists of at least 23 species, of which about half are human-restricted species, some are animal-restricted and some can be isolated from mucosal surfaces in both humans and animals 8 . N. gonorrhoeae is genomically, morphologically and phenotypically closely related to the other pathogenic Neisseria species, Neisseria meningitidis , which is typically carried as a commensal in the (naso)pharynx of 10–15% of the general population but occasionally causes fatal septicaemia and/or meningitis 6 , 8 , 9 , 10 . N. gonorrhoeae is also related to several other commensal Neisseria species that reside particularly in the pharynx. Despite containing many of the pathogenicity and virulence factors of N. gonorrhoeae and N. meningitidis , the commensal Neisseria species, from which these two pathogenic Neisseria species have evolved, do not normally cause pathology 9 as they are unable to induce substantial polymorphonuclear leukocyte (PMNL)-based inflammation and lack several additional factors and mechanisms of interacting with host molecules, cells and tissues 11 . The pathogenesis and pathophysiology of N. gonorrhoeae have been studied for decades; however, detailed knowledge regarding many fundamental properties is lacking.

The majority of men with gonococcal urethritis are symptomatic, but substantially fewer women with urogenital gonorrhoea are symptomatic and, when present, symptoms are nonspecific. Nevertheless, signs of infection can be identified in most women with urogenital gonorrhoea. Rectal and pharyngeal gonorrhoea, which is mostly asymptomatic, are most frequently diagnosed in men who have sex with men (MSM), but are not rare in women either. Disseminated gonococcal infections (DGIs) are rare but can occur in both adults and neonates 6 , 12 , 13 . If infections are not detected and/or adequately treated, ascending infections, such as epididymitis and salpingitis, can result in a variety of serious complications and sequelae, particularly in women who bear the major burden of disease; these complications and sequelae include pelvic inflammatory disease (PID), chronic pelvic pain, ectopic pregnancy and infertility. Gonorrhoea also facilitates the transmission and acquisition of other STIs including HIV infection. Gonococcal infections can lead to complications during pregnancy, and infected women can also transmit infections to children during birth causing ophthalmia neonatorum, which was a leading cause of blindness in the pre-antimicrobial era. Conjunctivitis in adults is also observed sporadically. Thus, gonorrhoea causes substantial morbidity and socioeconomic consequences globally 12 , 14 , 15 .

In the absence of a gonococcal vaccine, management and control rely on effective, affordable and accessible antimicrobial treatment, supported by adequate prevention, diagnostic testing or screening, notification and management of sex partners of infected individuals, and epidemiological surveillance. However, N. gonorrhoeae has developed or acquired antimicrobial resistance (AMR) to all antimicrobials recommended earlier as first-line or second-line empirical treatment of gonorrhoea (for example, sulfonamides, penicillins, tetracyclines, fluoroquinolones, early-generation macrolides, such as erythromycin, and cephalosporins, such as cefuroxime). This extensive resistance has been accomplished by an accumulation of AMR determinants, most of which do not seem to substantially reduce the biological fitness of the bacterium 16 , 17 , 18 , 19 , 20 , 21 (Fig.  1 ). This AMR is of serious public health concern as the pathogen has become highly resistant to all previously recommended antimicrobials, and resistance to the currently recommended extended-spectrum cephalosporin (ESC) ceftriaxone and macrolide azithromycin has also emerged. On the basis of the high global prevalence of gonorrhoea, the high level of antimicrobial use and/or misuse, suboptimal diagnosis, limited control and surveillance of AMR, suboptimal or slow update of management guidelines, and the extraordinary ability of N. gonorrhoeae to acquire or develop — and retain — AMR, it is likely that the global impact of gonorrhoea, including its severe complications and sequelae, will increase, and further N. gonorrhoeae AMR will evolve in the future. Consequently, improved global actions and research efforts to retain gonorrhoea as a readily treatable infection are essential.

Each bar represents a gonorrhoea therapy, and the length of the bar represents the time period from when the therapy started to be used until when clinical and/or in vitro resistance threatening the effectiveness of that specific antimicrobial therapy emerged. In vitro verified antimicrobial resistance (AMR) determinants are also shown 16 , 17 , 18 , 19 , 20 , 21 , 218 , 219 , 220 . PBP2 amino acid alterations that increase the minimum inhibitory concentration (MIC) of extended-spectrum cephalosporins (ESCs; verified, for example, by site-directed mutagenesis or transformation) in nonmosaic and mosaic (in which concomitant epistatic mosaic penA mutations are also needed) penA alleles are noted by an asterisk 218 , 219 , 220 . Additionally, PBP2 G542S, P551S, and P551L amino acid alterations in nonmosaic penA alleles have been statistically associated with gonococcal strains with decreased susceptibility to ESCs 221 , 222 , 223 . A grave concern is that during the past decade(s) resistance to azithromycin and decreased susceptibility to the ESC ceftriaxone, the last remaining option for empirical monotherapy, have been reported worldwide. The first Neisseria gonorrhoeae strain with high-level resistance to ceftriaxone was isolated in 2009 in Japan, which was followed by some isolates with high-level ceftriaxone resistance in 2011 in France and Spain. During subsequent years, ceftriaxone-resistant isolates have been characterized in many countries including Japan, China, Australia, Singapore, Canada, Argentina and several European countries. Furthermore, treatment failures with ceftriaxone were verified in Japan, Australia and in several European countries 15 , 16 , 153 , 224 , 225 , 226 , 227 , 228 , 229 , 230 , 231 , 232 , 233 , 234 , 235 , 236 , 237 , 238 , 239 , 240 . In 2014, the first failure of ceftriaxone–azithromycin dual therapy for gonorrhoea was verified in the UK 241 . Worryingly, since 2015, an international spread of one ceftriaxone-resistant gonococcal strain, initially described in Japan, has been confirmed 229 , 230 , 231 , 232 , 233 , 234 , 235 , 239 , 240 , 242 , 243 , and the first strain with resistance to ceftriaxone plus high-level azithromycin resistance was isolated in 2018 in the UK and Australia 236 , 237 , 238 . rRNA, ribosomal RNA; SNP, single-nucleotide polymorphism.

This Primer focuses on the epidemiology, aetiological agent, pathogenic mechanisms/pathophysiology, diagnosis, screening, prevention and management of gonorrhoea. We also discuss global actions and research efforts imperative for future management and control of gonorrhoea.

Epidemiology

In 2016, the WHO estimated that there were 86.9 (95% uncertainty interval 58.6–123.4) million incident global cases of gonorrhoea (global prevalence 0.9%) among adults 15–49 years of age 22 (Fig.  2 ). The epidemiological diversity of gonorrhoea manifests itself in the variability of the geographical distribution and the prevalence among certain populations; determinants of such variability include sexuality and sexual orientation, socioeconomics, demographics, geographical and cultural ramifications (including stigma and taboos), and access to and quality of sex education, prevention, testing and diagnostics, as well as political commitment in the provision of health services 23 , 24 , 25 .

Estimated numbers (in millions) of incident cases of gonorrhoea in adults (15–49 years of age) by WHO region 22 . These data correspond to 20 new gonococcal infections per 1,000 women and 26 per 1,000 men globally. The highest incidence was in the WHO African region, with 41 cases per 1,000 women and 50 per 1,000 men, followed by the WHO region of the Americas, with 23 cases per 1,000 women and 32 per 1,000 men; the lowest incidence was in the WHO European region, with 7 cases per 1,000 women and 11 per 1,000 men 22 . The World Bank Income Classification is also shown. Data from ref. 22 .

Epidemiological determinants

When individual countries, especially in industrialized settings, embarked on prevention and care of STIs on the basis of the established determinants of STIs, declines in rates of gonococcal infections were observed during the late 1980s. However, this decline was short-lived, as increases in gonococcal infections rates have been reported since the late 1990s. Observations have identified a number of factors, both established and new, as important to explain the high rates of STIs, including gonococcal infections; these factors include ethnic background, sexuality and sexual preferences, sexual mixing patterns, such as assortative mixing by race and/or ethnicity (that is, the tendency to connect with individuals of the same race and/or ethnicity) and disassortative mixing by risk group (that is, the tendency to connect with individuals with a different risk level), gender and disparities in economic status and access to services, as well as the intrinsic characteristics of the pathogen 24 , 26 , 27 , 28 , 29 , 30 .

Other reasons for the recent increase in gonorrhoea incidence in many high-resourced settings include changes in sexual behaviour in the era of antiretroviral treatment for HIV infection (that is, because of the availability of antiretroviral treatment and the perception that HIV infection is no longer life-threatening in the short term, people are less cautious and have sex with new and casual partners without using condoms), increased electronic connectivity (for example, the use of dating apps for meeting sex partners), increased number of casual unknown partners, larger sexual networks, increased travel and variable access to services 30 , 31 . Another factor to be taken into consideration is the increasing use of drugs in sexual networks, particularly common among MSM and female sex workers. Finally, certain key populations are at higher risk of and disproportionately affected by STIs, including gonorrhoea; such populations include MSM, migrants, young people and sex workers.

Incidence and prevalence

The aforementioned factors, mostly in combination, probably substantially contributed to the varying increases in gonorrhoea case rates in the past 5–10 years, even in countries with more comprehensive health systems. For example, in the USA and in the European Union/European Economic Area (EU/EEA), both socioeconomic status and ethnic background have been observed to highly correlate with gonococcal infection rates. In the USA in 2017, the rate of reported cases of gonorrhoea was approximately eight times higher among black populations than among white populations. Higher rates were also noted among American Indians and Alaskan Natives, Native Hawaiians and individuals with Hispanic heritage, whereas the rate among individuals with Asian heritage was half the rate among white individuals 30 , 31 . In the USA, the number of gonorrhoea cases increased by 67% from 2013 ( n  = 333,510) to 2017 ( n  = 556,413) 32 . The proportion of gonococcal isolates cultured from MSM increased from 3.9% in 1989 to a high of 38.5% in 2017, reflecting epidemiological changes and possibly changes in the health care-seeking behaviour of men with gonorrhoea as well as improved reporting of sexual orientation in the USA 30 , 31 .

In the EU/EEA, the number of reported gonorrhoea cases has increased by >200% since 2008, from 29,434 cases in 2008 (with an incidence of 7.85 per 100,000 population) to 89,239 cases in 2017, with the highest numbers of cases in the UK, France, the Netherlands and Spain 33 . Of note, higher prevalence in these countries might be in part accounted for by the availability of comprehensive sexual health systems, frequent testing and/or surveillance. The highest incidence of gonorrhoea in the EU/EEA is in young adults (15–24 years of age) 33 . MSM accounted for ~25–30% of all the cases in the EU/EEA during recent years — 30% of the reported gonorrhoea cases (57% of the cases reporting sexual orientation) in Europe in 2017 (ref. 33 ); however, over the past decade, substantial increases also occurred among heterosexual men, men with no sexual orientation reported and women. In the UK, MSM experienced substantial increases in reported STIs in 2017. Of the 50,032 new nonviral STI diagnoses in MSM in 2017, 43% were gonococcal infections and, between 2016 and 2017, gonococcal infection diagnoses increased by 21% 34 .

The geographical setting in which people live also seems to have a role in the prevalence of gonococcal infection, probably reflecting differences in the access to information regarding STIs, availability, accessibility and quality of health-care services, and social factors such as the effect of stigma on health-care-seeking behaviours. Observations showed that the prevalence of gonorrhoea in women aged 15–24 years in clinical or community settings in South Africa was ~4.6%, whereas in southern Africa and eastern Africa the prevalence was 1.7%. Furthermore, in the same study, the prevalence in a high-risk population in eastern Africa, mostly sex workers, was 8.2% 35 .

In low-income settings, syndromic management of STIs is mainly performed, and no comprehensive aetiology-based surveillance systems enable accurate assessment nationwide of increases or decreases in gonorrhoea prevalence in the general population or in subpopulations. However, even in many high-income settings, for example in Europe, the surveillance data should be interpreted with caution as the surveillance systems, testing, methodologies and quality assurance are not standardized across countries and remain weak in several settings 33 , 36 . Finally, whole-genome sequencing (WGS) will revolutionize our understanding of the epidemiology of gonorrhoea and the geographical and temporal spread of AMR and antimicrobial susceptible N. gonorrhoeae strains in different populations and subpopulations, including at-risk groups (see Outlook, below).

Gonorrhoea in MSM on pre-exposure prophylaxis

Another topical area of interest is the observation of rapid increases in the incidence of gonorrhoea, and other STIs, in high-resourced settings among MSM taking pre-exposure prophylaxis (PrEP) for the prevention of HIV infection. Some published data reported that MSM using PrEP can be ~25 times more likely to acquire a gonococcal infection than MSM not using PrEP 37 . A multisite open-label study of just under 3,000 gay and bisexual men using PrEP, conducted in Australia between 2016 and 2018, showed a significant increase in the incidence of STIs (including gonorrhoea, Chlamydia trachomatis infection and syphilis) during a follow-up period of 1.1 years. Younger age, greater number of sex partners and group sex participation were associated with a greater risk for an STI, whereas inconsistent or no condom use with casual partners was not 38 . A systematic review commissioned by the WHO in 2018–2019 identified 88 STI studies, primarily in MSM in high-income countries, which found that STI prevalence was high in people prior to starting PrEP, and STI incidence varied by setting and population included in the review. However, pooled STI incidence generally remained high during follow-up when taking PrEP 39 , 40 . However, notably, individuals on PrEP are monitored more closely and tested more frequently for STIs than non-PrEP users. When both populations were controlled for frequent monitoring, as in the PROUD study, no statistically significant differences in STI rates were found between men taking PrEP and the control group 41 . Thus, it would seem that the reduced risk for and fear of HIV infection has led some PrEP users, especially young MSM, to reduce condom use and/or increase other risky sexual behaviours and, therefore, to place themselves at increased exposure to other STIs, including gonorrhoea. However, given the conflicting conclusions from different population studies on this point, more observations and studies are needed to identify the factors behind these contradictory conclusions, as well as to detail the risk factors and elements that may be responsible for the findings of increased STI risk in some populations and to better understand the ideal monitoring and screening intervals of individuals taking PrEP.

Mechanisms/pathophysiology

The bacterium N. gonorrhoeae

Growth and metabolism.

N. gonorrhoeae is a fastidious organism that is sensitive to many environmental factors such as oxygen, nonphysiological temperatures, desiccation and the presence of toxic substances (such as many fatty acids), among others 42 ; thus, the bacterium does not survive for long outside the human host, and is difficult to culture (Box  1 ). Many strains have incomplete biosynthetic capabilities for amino acids, presumably because amino acids and other important nutrients are readily obtained from the human host. Iron (which is essential for bacterial growth) is acquired from the host by binding iron-containing host proteins such as transferrin, lactoferrin and haemoglobin at the bacterial surface and stripping these molecules of iron that is then delivered to the bacterial cytoplasm 43 . Owing to the broad range of oxygen levels within different niches of the male and female urogenital tracts, it is possible that N. gonorrhoeae encounters aerobic, microaerobic, and anaerobic conditions within the host, and the bacteria are able to grow in all these conditions 44 .

Box 1 Models to study Neisseria gonorrhoeae pathogenesis

Much of the information concerning Neisseria gonorrhoeae pathogenesis has come from studying the physiological and genetic properties of the organism, including determination of growth and nutrient requirements and surface-exposed molecules, with in vitro bacterial cultures. However, these experimental conditions do not always mirror in vivo conditions and, therefore, cell culture models can be useful to learn about the interactions between the bacterium and the host, particularly how N. gonorrhoeae attaches to and is internalized into eukaryotic cells. These studies have mainly used immortalized transformed human cell lines, but have occasionally used newly harvested human primary cells 1 , as cell lines do not always replicate the properties of tissues. Primary cultures are difficult to isolate and maintain and are considerably heterogeneous, whereas tissue explants enable the study of the interactions of the organism with different cell types in a complex tissue. Compared with other primary tissues, fallopian tube tissue is relatively easy to obtain from hysterectomies and is a clinically relevant tissue environment 70 , particularly for modelling pelvic inflammatory disease 212 .

Animal models are useful to study colonization, growth and immune response in a host. Of note, because N. gonorrhoeae is restricted to the human host, the bacterial proteins have evolved highly specific interactions with human molecules, rendering early mouse models of limited value. Despite this limitation, female mice treated with 17β-oestradiol (to promote prolonged colonization and/or infection) have become a standard in the field 193 . Transgenic mouse models expressing human receptors for N. gonorrhoeae are in development and will have greater utility in the future 194 , 195 , although no existing mouse model totally mimics a natural human infection. In the 1960s, primate models were examined and chimpanzees reportedly developed symptomatic gonorrhoea 213 , but chimpanzees are no longer used for biomedical research in the USA and rarely elsewhere, although new primate models might be developed in the future. The human challenge model is the most relevant existing model 214 . Only men can participate, as they have a lower risk of complications from infection than women. This model has only been used to investigate initial colonization determinants, and its utility is limited owing to small cohorts per study, the requirement for treatment as soon as symptoms develop and being only applicable to men.

Using WGS, it has been shown that the modern gonococcal population is not as old as previously thought and has been shaped by antimicrobial treatment of STIs as well as other infections, leading to the emergence of two major genomic lineages, one multidrug-resistant and one multidrug-susceptible, with different evolutionary strategies 45 . N. gonorrhoeae has a single circular chromosome between ~2.1 and 2.3 megabase pairs ( ∼ 2,200–2,500 protein-coding sequences), which exists as diploid, homozygous, chromosomes 46 , 47 . In addition, N. gonorrhoeae can acquire additional DNA via horizontal genetic transfer (HGT), the noninherited external acquisition of new genetic material from another bacterium. HGT occurs mainly by type IV pilus-mediated DNA transformation (uptake of DNA from the environment and subsequent incorporation into the genome). N. gonorrhoeae is naturally competent for transformation during its entire life cycle, but transformation only occurs at high frequency between cells of N. gonorrhoeae and other Neisseria species. Approximately 80% of isolates carry a chromosomal insertion called the gonococcal genetic island, which has genes similar to those carried on the conjugal plasmid (that is, genes involved in conjugation — the DNA transfer between bacteria by cell-to-cell contact). However, in N. gonorrhoeae these conjugation gene products act to secrete chromosomal DNA into the medium that is then available for DNA transformation. Pilus-mediated DNA transformation provides efficient transport of DNA into the bacterial cell and DNA uptake sequences are highly represented in Neisseria genomes ( ∼ 1,900–2,000 copies per genome) 48 , 49 . This efficient transformation is one reason why AMR determinants efficiently spread from cell to cell. Notably, this ability of N. gonorrhoeae to transfer DNA between strains makes clonal analysis difficult because alleles are not stably linked and led to the creation of the multilocus sequence typing system to characterize bacterial lineages by the DNA sequence type of several defined and more conserved housekeeping genes 50 . Multilocus sequence typing systems are now available for many different bacterial species 51 . Furthermore, this reassortment of alleles suggests that mixed-strain gonorrhoea infections are common 52 , 53 , although widely unrecognized, as most clinical laboratories analyse and save single colonies when culturing isolates, probably underestimating the incidence of mixed infections. Ideally, multiple colonies should be tested.

Nearly all gonococcal strains contain a cryptic plasmid (with no defined functions); many contain a plasmid encoding a penicillinase (mostly TEM-1 or TEM-135 β-lactamase), which results in high-level penicillin resistance, and conjugative plasmids, which sometimes carry tetM causing high-level tetracycline resistance, although these plasmids are not as prevalent as reported for many other bacterial species 16 , 54 . Several penicillinase-encoding plasmids of different size have been described in N. gonorrhoeae and named according to their epidemiological origin, such as the widely spread and most common African, Asian and Rio/Toronto plasmids. Different conjugative gonococcal plasmids carrying tetM have also been described, the most common being the American tetM plasmid and the Dutch tetM plasmid 16 , 54 . In addition, several double-stranded and single-stranded bacteriophage gene islands have been annotated within the N. gonorrhoeae genome, but no isolated bacteriophage that can infect and lyse the bacteria has been found 55 .

Colonization determinants

N. gonorrhoeae shares many colonization determinants with other human-restricted Neisseria species that rarely cause infection. The factors required to establish a host niche include the type IV pilus, the opacity protein family (Opa proteins), the porin PorB, efflux pumps and metal transport systems (Fig.  3 ). N. gonorrhoeae probably has to compete with the resident microbiota for colonization, but little is known about how different resident commensal organisms may limit or cooperate with N. gonorrhoeae during colonization.

Neisseria gonorrhoeae is a Gram-negative bacterium, frequently encountered as diplococci (individual cells are ∼ 0.6–1 µm in diameter), with a characteristic cell envelope consisting of a cytoplasma membrane (the inner membrane), a periplasmic space containing the peptidoglycan cell wall 244 and the outer membrane containing lipo-oligosaccharide (LOS), which is similar to lipopolysaccharide (LPS) of other Gram-negative bacteria, except it does not have the polymeric O-antigen characteristic of LPS. The type IV pilus is a long, thin fibre that reaches far outside of the cell envelope, mainly composed of many copies of one protein, pilin. Type IV pilus assembly requires a complex molecular machine, called the assembly apparatus, that sits within the cell envelope to produce the fibre on the outside of the cell 245 . The pilus is a dynamic structure that can be retracted by the assembly apparatus, which generates one of the largest physical forces on record by a biological machine 246 . The Opa proteins are a family of integral outer membrane proteins whose expression is stochastically controlled 247 . Each N. gonorrhoeae isolate carries ~11 opa genes, and expression of each is controlled by independent molecular events that turn on or off the expression of each opa gene. A single bacterial cell may express none of the Opa proteins, a single Opa, or a combination of several. There is a correlation between patterns of Opa expression and bacteria isolated from females during menses 248 , and increased numbers of Opa proteins are expressed during human volunteer infections 249 . The outer-membrane-localized porin (PorB) allows small molecules to enter the periplasm and the reduction modifiable protein (Rmp) is associated with PorB and elicits antibodies that block the binding of anti-PorB antibodies 250 . The five efflux pump systems (FarA–FarB–MtrE, NorM, MtrC–MtrD–MtrE, MacA–MacB–MtrE and MtrF) have varying substrate specificity and many roles in pathogenesis, including removing toxic molecules encountered during infection and exporting antimicrobials (acting as resistance determinants). The three iron-scavenging complexes (LpbA–LpbB, HpuA–HpuB and TbpA–TbpB) are required to obtain iron from the host. Adapted from ref. 5 , Springer Nature Limited.

Gonococcal pili are required for efficient mucosal colonization (typically of nonciliated columnar epithelia) and carry out many functions, including initial adherence to host cells and tissues, self-adherence and adherence to other N. gonorrhoeae cells, a means to crawl along mucosal surfaces called twitching motility, protection from PMNL killing mechanisms 56 , and HGT by DNA transformation 57 . Clinical isolates of N. gonorrhoeae are always piliated, but quickly lose pilus expression in laboratory culture through a variety of mechanisms, showing that pilus expression is under strong selective pressure during infection.

The Opa proteins mainly act as adhesins that bind to a variety of receptors found on many different cells and tissues 58 and mediate more intimate attachment and initiation of microcolony formation. Most Opa proteins bind to one or more human carcinoembryonic antigen-related cell adhesion molecules (CEACAMs), a family of surface-exposed proteins. Opa proteins only bind to human forms of these proteins, and a few Opa proteins also bind to heparan sulfate proteoglycans. Although some Opa–CEACAM interactions lead to cell signalling events, such as induction of the oxidative burst from PMNLs, most Opa interactions seem to be important for adherence to cells and tissues 59 .

All Gram-negative bacterial porins (transmembrane channel proteins) act to allow small molecules access to the periplasm. The N. gonorrhoeae porin (PorB) is one of the most abundant proteins in the outer membrane; it increases attachment, is then translocated to the host cell mitochondria and impairs the ability of phagocytes to kill the bacteria. Other important properties include resisting the action of complement factors, modulating apoptosis, invasion of host cells and involvement in AMR 60 , 61 , 62 , 63 .

N. gonorrhoeae expresses up to five efflux pump systems: MtrC–MtrD–MtrE, MacA–MacB–MtrE, NorM, FarA–FarB–MtrE and MtrF 64 , 65 , 66 . These export pumps have varying narrow or extensive substrate specificity and have many roles in pathogenesis, including removing toxic molecules encountered during infection, such as fatty acids and cationic peptides, and removing antimicrobials from the cell (that is, acting as AMR determinants). Finally, there are three iron acquisition systems in the envelope of N. gonorrhoeae , and each can strip iron from a human protein that is designed to sequester iron from pathogenic organisms. There is an acquisition system for transferrin (TbpA–TbpB), one for lactoferrin (LbpA–LbpB) and one for haeme (HpuA–HpuB), which can be found, for example, in haemoglobin 43 .

Infection dynamics

All bacteria that live in or on people need to colonize and grow, whether they are commensal organisms that rarely cause harm or frank pathogens. The pathogenesis field defines colonization and growth determinants as virulence determinants even though they are often found also within organisms that do not cause overt pathology. However, for a pathogenic organism to do damage, it usually needs to colonize specific anatomical sites and grow (except when pathogenesis occurs through production of a toxin away from the site of infection).

Transmission

N. gonorrhoeae infects the mucosal epithelium of the male and female urogenital tracts, the rectum, pharynx or conjunctiva 12 . N. gonorrhoeae is mainly transmitted through unprotected vaginal, anal or oral intercourse. During vaginal sex, transmission rates from men to women are higher than from women to men 67 . Ejaculate from infected men contains millions of bacteria, effectively injecting the organism into the receiving anatomical site. How the organism is effectively transmitted from vaginal, rectal or oral/pharyngeal locations to the male urethra is not completely understood. Of note, N. gonorrhoeae infection amplifies the risk for acquisition and transmission of HIV and several other STIs 68 , 69 ; all the underlying mechanisms are not completely understood, but probably involve factors such as inflammation, destruction of the mucosa and discharges. Furthermore, women with N. gonorrhoeae infection can effectively transmit the infection to their children during birth (intrapartum), but not during pregnancy; the neonate’s conjunctiva is highly exposed during transit of the birth canal, and N. gonorrhoeae infection of the conjunctiva results in ophthalmia neonatorum.

Host defences against infection act at many levels. N. gonorrhoeae has no ability to persist on or to penetrate the skin, and it requires a mucous membrane for colonization. Many barriers in mammalian cells limit transit of organisms into the body, including the ciliary action of some epithelia. Peptidoglycan fragments and lipo-oligosaccharide (LOS) released by N. gonorrhoeae can disrupt the ciliary action of the epithelium and may promote colonization 70 , 71 . Once colonization is established, innate and adaptive immune responses act to block or limit the growth of an organism. However, as a host-restricted organism that has co-evolved with its human host, N. gonorrhoeae has intricate mechanisms to limit the action of these host defence systems.

Innate immune systems

Resident tissue macrophages are one of the first cells that N. gonorrhoeae encounters during infection 72 (Fig.  4 ). Whether macrophages have a role in limiting N. gonorrhoeae infection is not clear, but macrophages, dendritic cells and epithelial cells may all be responsible for producing the chemokines and cytokines induced during infection. Some of these host effectors are responsible for inducing the massive PMNL response that manifests as the purulent exudate characteristic of symptomatic urethral gonorrhoea. N. gonorrhoeae can survive the various antimicrobial functions of PMNLs including phagocytosis, the release of reactive oxygen species, cationic peptides and antimicrobial enzymes, metal sequestration and PMNL extracellular traps 73 . N. gonorrhoeae can also modulate the apoptosis of epithelial cells, macrophages, T cells and PMNLs, but as both the inhibition and enhancement of apoptosis has been reported, the relevance of apoptosis modulation to infection remains controversial 74 , 75 . In addition, the role of PMNLs during N. gonorrhoeae infection also remains controversial. PMNLs probably influence infection by killing some of the bacteria but enabling the spread of others 73 .

Initial adhesion of Neisseria gonorrhoeae to the epithelium requires type IV pili and, then, Opa proteins for more intimate adhesion. The bacteria can then proliferate on the epithelial surface and invade underlying tissues via transcytosis. N. gonorrhoeae also releases peptidoglycan fragments, outer membrane vesicles (OMVs) and lipo-oligosaccharide (LOS), thereby activating Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain-containing protein signalling in tissue-resident dendritic cells and macrophages. In response to bacterial stimulation, these cells produce chemokines and cytokines (for example, IL-1, IL-6, IL-8, IL-17 and tumour necrosis factor (TNF)) that can recruit polymorphonuclear leukocytes (PMNLs); however, the bacteria can often survive phagocytosis, antibacterial factors released during degranulation or NETosis (that is, cell death mediated by neutrophil extracellular traps (NETs)). N. gonorrhoeae has many ways to prevent complement killing by the membrane attack complex; for example, the LOS can be modified by sialic acid, when the precursor substrate, CMP-NANA, is supplied by the host, to enhance complement resistance 251 . Sialylated LOS binds C3b and promotes its inactivation to iC3b via factor I, whereas the outer-membrane-localized porin (PorB) binds factor H and C4BP, thereby hiding the bacteria from complement recognition. When complement activity is inhibited (for example, by mutation or owing to immune suppressive treatment), systemic N. gonorrhoeae infections are prevalent. Whether the resistance to complement is also important in localized sites of colonization is not known. C4BP, C4b-binding protein; NLR, nucleotide-binding oligomerization domain-containing protein (NOD)-like receptor. Adapted from ref. 5 , Springer Nature Limited.

The classical and alternative complement pathways act to kill many organisms, and N. gonorrhoeae has evolved ways to avoid both pathways during uncomplicated infections 76 . Indicative of its extreme host restriction and evolution, N. gonorrhoeae remains sensitive to animal complement system components 61 . N. gonorrhoeae uses several mechanisms to limit complement-mediated killing by blocking deposition or activity of several complement factors 61 (Fig.  4 ). People with complement deficiencies are at increased risk of DGI, showing that the complement system helps to limit gonococcal survival in the blood stream 77 . Increased incidence of DGI and other disseminated Neisseria spp. infections was observed when patients were treated with eculizumab, a complement inhibitor, but this study did not report altered rates of uncomplicated gonorrhoea 78 . Whether complement effectively functions at mucosal sites of colonization is not fully known.

Adaptive immunity

As an organism that has co-evolved with its sole host for centuries, and possibly throughout all recorded time, the colonization determinants of N. gonorrhoeae are exquisitely adapted to life within humans. By contrast, the human adapted immune system has variable components (B cells and T cells) that can change to limit infection. N. gonorrhoeae is generally thought to be immunosuppressive 79 , although there are suggestions that any immunosuppression is incomplete. Many studies show that antigonococcal antibodies are found in people with active or previous infection, demonstrating a humoral immune response 80 . In addition, the existence of three, independent, antigenically variable surface antigens (type IV pilus, Opa proteins and LOS) also provides evidence that there are potentially protective responses directed against these antigens that necessitate the complex variations 81 . These antigens can all vary during infection and colonization; for example, the surface-exposed antigenic epitopes of pili will vary and pilus expression can be lost, the number and type of expressed Opa proteins will vary (Fig.  3 ), and the type of sugars on the LOS molecule can change. Although some of this surface variation alters some functional properties of N. gonorrhoeae , the most important function of antigenic variation is immune avoidance, which enables reinfection presumably even with the same gonococcal strain, as protective immunity to N. gonorrhoeae capable of preventing subsequent infections has never been recorded. Extensive surface molecule variation by N. gonorrhoeae also prevents these molecules from being considered viable vaccine candidates. A more detailed examination of immune suppression and responses during human infection is needed.

Host damage

N. gonorrhoeae is not a very disruptive pathogen, as it is well adapted to its human host and rarely lethal. It does not produce any exotoxins that can destroy host cells, but does secrete peptidoglycan fragments, outer membrane vesicles (OMVs) and LOS that are toxic to mammalian cells and can specifically inhibit the ciliated cells on fallopian tube tissues 70 , 71 . Moreover, when PMNLs are recruited to sites of infection, PMNL antimicrobial products are released that can damage the tissue. All of these factors contribute to the damage and scarring of the fallopian tube tissue that is characteristic of PID. These factors can also cause damage at other sites of infection, particularly during DGIs in which, in addition to fever, dermatitis, infectious arthritis and (less frequently) septicaemia, endocarditis and meningitis can occur.

Diagnosis, screening and prevention

Clinical presentation and diagnosis.

The incubation period for urogenital gonorrhoea ranges from ~2 days to 8 days 82 . The clinical manifestations of gonorrhoea are variable and differ markedly in men and women 12 . At least 90% of men with gonococcal urethritis are symptomatic, presenting with obvious urethral discharge and dysuria, a fact that permits the application of syndromic diagnosis (based on a set of symptoms and signs that are characteristic of a clinical manifestation) in many settings as both a time-saving and cost-saving measure. For men with symptomatic urethritis, Gram stain may be used to support symptom evaluation. By contrast, laboratory-based diagnostic tests have a more important role for gonococcal detection in asymptomatic men, women and in patients of all genders for extragenital (rectal and pharyngeal) infections, which are mostly asymptomatic or present with nonspecific symptoms. Although ~40% of women with gonococcal cervicitis may report abnormal vaginal discharge, this symptom is unreliable for syndromic diagnosis of gonorrhoea, as many other equally or more common genitourinary infections in women (for example, bacterial vaginosis, trichomoniasis and vaginal candidiasis) may cause the same symptoms.

Microbiological diagnosis of gonorrhoea can be challenging, as many regions do not have a laboratory-based diagnostic capability and rely on syndromic management algorithms to guide empirical antimicrobial treatments 14 . Microbiological diagnosis is performed by the detection of Gram-negative diplococci in stained smears using microscopy, culture of N. gonorrhoeae and/or nucleic acid amplification tests (NAATs) detecting N. gonorrhoeae DNA or RNA.

Traditional diagnostic methods

In resource-limited settings, light microscopy of Gram-stained samples is often the only method available to diagnose infection with N. gonorrhoeae presumptively (Table  1 ). The sensitivity and specificity of the Gram stain, which tests for the presence of characteristic Gram-negative diplococci within PMNLs, can vary substantially between studies and depends upon the specimen; the highest sensitivity and specificity were reported with urethral swab samples from symptomatic males (89% to >98% and >95%, respectively) 6 , 13 , 83 , 84 , 85 , whereas the sensitivity was as low as 40–50% in urethral specimens from asymptomatic males, and in endocervical or urethral specimens from women 13 , 83 , 84 . This difference can probably be explained by a reduced bacterial load, particularly in these urethral samples, and by the presence of many other bacterial species in the endocervical samples. Gram stain is not suitable for the diagnosis of N. gonorrhoeae from pharyngeal specimens (because other Neisseria species with similar morphology are prevalent in the oral and nasopharyngeal cavity) or rectal specimens (which have a sensitivity ≤40%) 82 , 83 , 84 . A methylene blue staining method is an alternative to the Gram stain, and similar high sensitivity and specificity were reported for diagnosing gonococcal urethritis in men 86 .

Prior to the introduction of NAATs, culture (Table  1 ) of the organism was the gold standard and this remains the only diagnostic method available in some settings as it is a low-cost method. Culture also remains recommended for test-of-cure for treatment failure, in cases of sexual abuse and to evaluate PID 13 , 85 , 87 . Furthermore, complete AMR testing can only be accomplished if N. gonorrhoeae is cultured 83 , 85 , 87 , 88 . Culture performance is dependent upon factors such as anatomical site of the cultured sample, method of specimen collection, media and conditions used to transport the sample to the diagnostic centre 83 , 87 , 89 , nonselective and/or selective culture media 84 , 85 , 89 , 90 , conditions of incubation 82 , 85 and species confirmatory tests. Cultures obtained too soon after exposure (<48 h) may give false-negative results 13 , and a repeated culture sample some weeks later is sometimes considered. Culture of urogenital specimens usually has a sensitivity ranging from 72% to 95%, but can have a sensitivity of 95–100% in settings with extensive experience in appropriate specimen handling and culture 83 , 84 . However, the sensitivity of culturing pharyngeal and rectal specimens is much lower.

Presumptive identification of cultured N. gonorrhoeae isolates is frequently accomplished by typical colony appearance on selective media, Gram-stained microscopy and the oxidase test, which detects the presence of cytochrome oxidase 82 , 84 , 85 . For definitive N. gonorrhoeae identification, immunological tests frequently targeting PorB 85 , 91 , 92 , 93 , sugar utilization tests or other biochemical tests 6 , 85 , 91 , 94 , NAATs or mass spectrometry (that is, matrix-associated laser desorption ionization time of flight (MALDI-TOF mass spectrometry)) 6 , 95 , 96 , 97 are frequently performed. These tests differentiate N. gonorrhoeae from species such as N. meningitidis , Neisseria lactamica , Neisseria cinerea, Neisseria subflava or other genera that may occasionally grow on even the selective culture media and may be present particularly in the pharynx but also at other sites 85 . Finally, DNA extraction from cultured isolates is also currently the best method to obtain DNA for genomic analysis, as clinical specimens often either do not contain sufficient concentrations of DNA, or contain too much DNA from other bacterial species or human cells. Furthermore, methods for genomic DNA purification from clinical specimens have not been sufficiently developed or standardized 98 .

NAATs are currently recommended for gonorrhoea diagnosis in most high-income countries 13 , 82 , 87 , 99 . NAATs are now the preferred diagnostic test because specimen collection is noninvasive (urine or self-collected particularly vaginal swabs); viable organisms are not required for detection, permitting less stringent transportation and storage methods 85 , 100 ; most have superior sensitivity with maintained high specificity (which vary between NAATs and anatomical site tested) compared with culture; they produce more rapid results (many later generation NAAT platforms allow for high throughput and automation); and many can simultaneously detect other STI-associated pathogens (particularly C. trachomatis ) 13 , 85 , 87 , 101 . Initially, a number of in-house, PCR-based NAATs were used locally and continue to be used as confirmatory tests or for diagnosis in resource-limited settings 93 , 102 , 103 , 104 . In-house NAATs generally target conserved regions of genes such as the porA pseudogene, opa genes, gyrA (encoding DNA gyrase subunit A) , cppB (encoding cryptic plasmid protein B) and the methyltransferase genes of N. gonorrhoeae 102 . Few reports have compared the performance of such in-house NAATs with culture or commercially available NAATs 102 . In high-income countries, in-house NAATs have largely been replaced with commercial NAATs that have been comprehensively validated and received regulatory approval from the US FDA 13 , 87 , 101 (Table  2 ).

In 2019, the first two NAATs (Aptima Combo 2 assay and Xpert CT/NG) for gonococcal detection received FDA approval also for extragenital specimens such as rectal and pharyngeal infection 105 , and licensing for additional NAATs is in progress. Several studies indicate that many additional NAATs are more sensitive, with maintained high specificity, than culture for diagnosing N. gonorrhoeae from pharyngeal and rectal specimens (Table  2 ); however, such tests should be used only after rigorous local performance evaluations 82 , 87 , 106 , and additionally a confirmatory NAAT with a different target should be used for such specimens 82 , 85 , 87 , 100 , as other Neisseria species, which can be frequently present especially in the pharynx, could be misidentified as N. gonorrhoeae 87 , 100 . Thus, when using NAATs to detect N. gonorrhoeae , it is important to choose the test or the testing strategy so that the positive predictive value (which is calculated based on the sensitivity and specificity of the test and on the local prevalence of the pathogen, and the last two parameters substantially affect the positive predictive value) is >90% 82 , 85 .

The introduction of NAATs for N. gonorrhoeae has substantially reduced the number of cultured patient samples. FDA-approved NAATs are more expensive than culture-based methods, and are mostly used in high-income countries 13 , 82 , 87 , 99 . Pooling specimens (that is, combining up to 5–10 specimens and then retesting them separately if the pool is positive to ascertain which specimen(s) was positive) may reduce cost, especially in settings with high-volume testing and with low positivity rate. However, strict evaluation of the performance characteristics of the NAAT in the local population is crucial before implementing any pooling strategy. Time to results, hands-on time, maintenance and consumption of reagents and consumables for automated platforms vary greatly between platforms, and these parameters influence the choice of platform 107 , 108 . A major disadvantage of commercial NAATs is the inability to perform AMR testing on gonococcal specimens 14 , 85 , 102 , 109 . In many regions, >80% of gonorrhoea cases are diagnosed by NAATs and, therefore, crucial information regarding AMR and gonococcal strain biology is lost. There are no recommended molecular tests for the prediction of antimicrobial susceptibility or resistance 102 , 110 , 111 ; however, a PCR-based test that also detects ciprofloxacin susceptibility status has received the European Conformity In Vitro Diagnostic mark (Table  3 ) and several NAATs in the pipeline are also being developed to detect both N. gonorrhoeae and its ciprofloxacin susceptibility status 101 . This type of test could be important particularly in regions in which ciprofloxacin susceptible strains are still spreading and, therefore, ciprofloxacin could be used for treatment as a lower cost, oral alternative to ceftriaxone plus azithromycin, that is to spare the use of these antimicrobials and decrease the selective pressure for resistance. This concept has been tested clinically with success 101 , 112 , 113 . Notably, both the British Association for Sexual Health and HIV (BASHH) gonorrhoea guideline for the UK and the European gonorrhoea guideline for the WHO European region recommend the use of ciprofloxacin for treatment of anogenital and pharyngeal gonorrhoea if the gonococcal strain causing the infection is proven to be ciprofloxacin-susceptible using genetic or phenotypic resistance testing 82 , 114 .

Point-of-care tests (POCTs)

Development of appropriate rapid point-of-care tests (POCTs) is a high priority for the diagnosis of gonorrhoea 14 , 85 , 101 , 115 (Table  3 ). POCTs could provide a definitive, rapid diagnosis to guide specific treatment in situations where this is not currently possible, such as in settings in which only syndromic management is available, in cases where patients may not return for treatment and for screening asymptomatic patients 116 , 117 , 118 . Ideally, POCTs should meet the ‘ASSURED’ criteria, that is, be affordable, sensitive, specific, user-friendly, robust and rapid, and equipment free (or requiring minimal equipment powered by solar or battery sources) 117 , 119 , 120 . However, all diagnostic tests that provide rapid test results and correct treatment during a single clinical visit could be defined as POCTs 117 , 121 , 122 . The Gram stain is an oft-used POCT; its benefits and limitations have been described above 122 , 123 . Other POCTs developed for N. gonorrhoeae include lateral flow immunochromatographic and optical immunoassay tests based on antigen detection, as well as a near-POCT NAAT — the Xpert CT/NG assay 101 , 120 , 122 , 123 . Recent reviews of the performance of several POCTs have shown that immunochromatographic-based and optical immunoassay-based POCTs had highly suboptimal sensitivities, some as low as 12.5%, and specificities ranging from 89% to >97% 120 , 123 and, therefore, are not recommended. However, mathematical modelling has shown that the sensitivity required for POCTs to be effective may be lower in settings where there is a high risk for transmission because treatment is delayed pending testing results or patients do not return for treatment 124 . The Xpert CT/NG assay has been successfully implemented as a near-POCT in areas such as Papua New Guinea, South Africa and remote regions of Australia 6 , 101 , 115 , 125 , 126 . However, this test is expensive, needs substantial electricity, and results take ~90 min.

Screening and prevention

Screening general populations for gonococcal infections is not indicated. However, screening or opportunistic testing can be considered for individuals at higher risk of gonococcal infection. These populations include the sexually active youth, sexual contacts of individuals having a suspected gonococcal infection, MSM, individuals with new or multiple sexual partners, individuals with HIV infection or a history of STIs, sex workers and their sexual partners, and women (≤35 years of age) and men (≤30 years of age) at initial admission to a correctional facility 6 , 13 , 83 , 127 , 128 . The US Centers for Disease Control and Prevention guidelines recommend annual screening for gonorrhoea of all sexually active females <25 years of age and older women at increased risk of infection, and screening should also be offered to young MSM 127 , 128 . More recently, in the USA, owing to observed high rates of incident infections, screening for gonorrhoea and other bacterial STIs ( C. trachomatis  infections and syphilis) has been recommended at 3–6-month intervals for individuals receiving HIV PrEP 129 . In other high-income settings, there are no screening recommendations for the general population owing to the low cost-effectiveness and low population prevalence of gonorrhoea, which results in low positive predictive values of the testing and increased probability of false positive results, which could cause considerable harm for patients and their partners. No aetiologically based screening is performed in any low-income settings.

Main prevention efforts include education regarding symptomatic and asymptomatic gonorrhoea and other STIs; promotion of safe sexual behaviours (for example, increased condom use through condom-promotion education and campaigns); behaviour change communication programmes (for example, promoting fewer unknown, casual and unprotected sexual contacts and early health-seeking behaviour); improved sexual partner notification and treatment; and expansion of targeted interventions, including screening in some settings for vulnerable populations (sex workers, MSM, adolescents and patients with STIs and their sexual partners) 130 .

Given the threat of untreatable gonorrhoea due to the spread of AMR and the high burden of gonorrhoea worldwide, the need for a gonococcal vaccine has become increasingly urgent 131 , 132 , 133 . Prior to the 1990s, four vaccine candidates progressed to clinical trials: a whole cell vaccine, a partially autolysed vaccine, a pilus-based vaccine and a PorB-based vaccine 133 , 134 , 135 ; none provided much protection from infection. Gonococcal vaccine development is complicated by the biology of the gonococcus. Limitations include the scarce adaptive immune responses to gonococcal infections, lack of known correlates of protection, antigenic variability of the potential vaccine candidate antigens, production of blocking antibodies (which upon binding their target prevent the binding of other antibodies — for example, bactericidal antibodies — to the same target or other targets in close proximity) to conserved antigens, and lack of robust, small laboratory animals for testing vaccines 132 , 134 .

However, recently, it has been noted in several countries that there was a decline in the number of gonorrhoea cases following the use of meningococcal group B OMV vaccines against N. meningitidis 136 . One of these vaccines, with the trade name MeNZB, was associated with reduced rates of gonorrhoea diagnosis and of hospitalization from gonorrhoea 136 , and it seems to provide proof-of-principle to inform the development of gonococcal vaccines 137 , 138 . Research to elucidate the specific or nonspecific antigens and mechanisms involved in the MeNZB-mediated protection against gonorrhoea is crucial. MeNZB is no longer available; however, the licensed, four-component meningococcal group B vaccine 4CMenB (trade name BEXSERO; GlaxoSmithKline) includes the same OMV as MeNZB and three recombinant meningococcal antigens (Neisserial heparin-binding antigen, factor H-binding protein and Neisseria adhesin A), which are also relatively conserved compared with their gonococcal homologues 139 . Accordingly, high coverage of the 4CMenB in the population may also decrease gonorrhoea prevalence. Recently, research has exploited OMVs from N. meningitidis expressing factor H-binding protein and found that serum bactericidal antibodies against the gonococcus were produced in mice, although sera from humans immunized with 4CMenB were not bactericidal for N. gonorrhoeae 140 . These findings, together with the immunobiology research (including on N. gonorrhoeae immune suppressive responses and how they can be overcome), antigen discovery and animal modelling, are promising for vaccine development.

Management principles

Gonorrhoea is a community-based infection and often there is limited follow-up after treatment. Prompt and effective treatment reduces complications and eliminates transmission of the infection 128 . Since there are no vaccines, and host immunity cannot prevent reinfection, eradication of infections is solely reliant upon case finding and ideally microbiological diagnosis coupled with effective antimicrobial treatment 128 . Of note, because gonorrhoea also amplifies the risk for acquisition and transmission of HIV, gonorrhoea control also contributes to global efforts to reduce HIV infections. The goal of gonorrhoea management is to quickly and accurately identify infected individuals, enabling provision of timely treatment to prevent complications and transmission of infection to sexual partners and, for pregnant women, to children at the time of birth. Factors influencing management include considerations of the clinical manifestations, the disproportionate morbidity for women (PID, infertility, ectopic pregnancy and chronic pelvic pain), and stigma associated with STIs. As the infection is most common in resource-limited settings (even in high-income nations gonorrhoea is most common among marginalized populations who may have limited resources and/or limited access to health care), costs of both diagnosis and treatment may also influence the translation of management principles into practice.

Because gonorrhoea transmission most often is a consequence of sex with a person who is unaware of their infection, notification, testing and treatment of recent sexual partners is a crucial part of gonorrhoea management within communities 82 , 141 . Notification and referral of exposed sexual partners of individuals with STIs (by health-care providers, public health specialists or the partner themself) has been recommended since at least the 1940s 142 . However, programmes promoting notification of sexual partners have often proved resource intensive and failed to successfully lead to treatment of many sexual partners, probably in part owing to stigma and embarrassment regarding having an STI. Thus, ‘expedited partner therapy’ or ‘partner-delivered therapy’ (that is, the partner(s) of a patient with gonorrhoea receives oral, single dose antimicrobials delivered by the patient, without have being examined or tested) for gonococcal and chlamydial infections has been increasingly practiced in the USA with good results 143 . Currently, cefixime plus azithromycin is used for expedited partner therapy for heterosexual men and women 128 . However, this approach has raised concerns about the lack of clinical examination, lack of testing for additional STIs, lack of opportunities to trace ‘downstream’ sex partners, possible antimicrobial allergy or adverse events experienced by the partner(s) and AMR emergence.

Antimicrobial therapy

Syndromic management of urethral discharge in men can be relatively effective for gonorrhoea 116 . However, appropriate, local and aetiologically based studies to regularly refine the syndromic management algorithm(s) are imperative, and nevertheless some infections (for example, C. trachomatis and Mycoplasma genitalium infections) cannot be distinguished from gonorrhoea, resulting in overtreatment. Syndromic management of vaginal discharge both fails to detect and treat the substantial proportion of asymptomatic infections in women (who might continue to transmit the infection) and leads to vast overtreatment of symptomatic women who do not have gonorrhoea but who do have C. trachomatis , M. genitalium or Trichomonas vaginalis infection or bacterial vaginosis 109 , 116 .

Single-dose, directly observed systemic therapy (as topical therapy has not proved effective) that is provided in the care setting is preferred to ensure medications are delivered. Dual antimicrobial therapy (mainly parenteral ceftriaxone plus oral azithromycin) is currently recommended for empirical first-line therapy by the WHO global guidelines 109 and in most high-income countries, including European countries 82 , the USA 128 , Canada 144 and Australia 145 ; however, in some countries (for example, Japan 146 and, since 2019, the UK 114 ) ceftriaxone high-dose (1 g) monotherapy is recommended 147 , 148 , 149 . In some international and national guidelines, cefixime plus azithromycin is recommended as an alternative regimen, but only if ceftriaxone is not available or the injection is refused 82 , 128 . There is an ongoing debate among experts as to whether single or dual antimicrobial therapy should be the recommended therapy for uncomplicated gonorrhoea. The rationale for introducing dual therapy was to address the problem of C. trachomatis co-infection, which occurs in 10–40% of individuals with urogenital gonorrhoea 150 , as well as a hypothetical benefit of reducing the emergence and/or spread of AMR (particularly resistance to ceftriaxone) in N. gonorrhoeae . When possible, well tolerated oral therapy is preferred by both patients and clinicians 151 . Finally, individuals with gonorrhoea are often co-infected with other pathogens, including C. trachomatis , T. vaginalis , Treponema pallidum and/or M. genitalium and, therefore, require treatment either with agents that are also effective against these pathogens or with co-therapy.

The continuing development of AMR by the gonococcus, coupled with a diminished pipeline for the development of new antimicrobials have narrowed available therapies for gonorrhoea to a single agent that is sufficiently effective for first-line monotherapy (that is, parenteral ceftriaxone 16 , 152 ), which is frequently given together with azithromycin. If ceftriaxone is unavailable, the patient has β-lactam antimicrobial allergy or the patient is infected with a ceftriaxone-resistant gonococcal strain, therapy is challenging and highly variable, often requiring ciprofloxacin monotherapy (if the gonococcal strain causing the infection has been proven susceptible by phenotypic or genetic resistance testing 82 , 114 ), high-dose (2 g) azithromycin monotherapy, spectinomycin (together with high-dose azithromycin, particularly if pharyngeal gonorrhoea has not been excluded) or gentamicin (together with high-dose azithromycin, particularly if pharyngeal gonorrhoea has not been excluded) 82 , 128 . However, each of these alternate therapies has limitations related to gonococcal resistance, antimicrobial availability and/or patient tolerance. Progressive decreases in susceptibility of N. gonorrhoeae to ceftriaxone, as well as to other antimicrobials, create a pressing need for continued monitoring of gonococcal AMR through surveillance networks such as the WHO Global Gonococcal Antimicrobial Surveillance Programme (WHO GASP) 15 , 153 , the European GASP (Euro-GASP) 154 , 155 , 156 and the US Centers for Disease Control and Prevention Gonococcal Isolate Surveillance Project (GISP) 157 , 158 ; Euro-GASP and GISP additionally collect clinical and epidemiological data on the corresponding patients.

Practical applications

Gonorrhoea remains a global public health threat. The biological characteristics of N. gonorrhoeae and its proven propensity to develop AMR, the varied clinical manifestations of the infection that may not be obvious or pathogen-specific (particularly for women and extragenital infections), and the limited resources that are dedicated to gonorrhoea control all contribute to the limited success of present gonorrhoea control efforts. Therapy may be hindered by the lack of recommended, high-quality antimicrobials. Current main reliance on only one consistently effective antimicrobial (injectable ceftriaxone) may make effective treatment difficult. Perceptions by patients that they may be resistant or allergic to β-lactam antimicrobials, including ceftriaxone, the logistical constraints of parenteral therapy and fear/avoidance of injections may result in the use of less-effective oral therapy. Therapy is also limited in some regions by suboptimal or complete absence of surveillance of infection and particularly AMR, leading to treatment with antimicrobials that are ineffective. Although improved surveillance has increased appreciation of the threat of AMR, this surveillance is not fully representative, being insufficient or even lacking in areas where the infection is most common 15 , 153 , 159 .

On the policy level, limited health-care resources directed towards this public health problem (in low-income and middle-income nations and even in high-income nations) have created a tension between diagnostic test cost and ensuring a ready supply of medications for gonorrhoea control. The cost of paying for diagnostic testing may erode the funds available for therapy, thereby forcing public health officials to prioritize screening initiatives. In recent years, clinical microscopy (Gram stain) as a low-cost POCT has become less available, owing to the lack of availability of microscopes and adequate technical training in the methodology.

All these challenges are sometimes amplified by social factors. Stigma is a pervasive and powerful force that affects the prioritization of gonorrhoea as a public health problem and influences the behaviour of individuals with, or at risk for, gonorrhoea with regard to health care-seeking behaviour and partner notification. Stigma also affects health-care provider attitudes and practices, including evaluation of STI risk and appropriate screening 159 .

At the individual level, few individuals wish to identify themselves as being at risk for STIs, potentially inhibiting discussion of STI risk with their health-care provider, prevention measures and seeking evaluation for genitourinary symptoms and signs. Limited access to health care may also prevent or delay recommended STI screening or evaluation of symptoms when present. Finally, individuals diagnosed with gonorrhoea or other STIs may fail to notify their sex partners of their risk of infection, thereby increasing the probability of complications or continuing transmission.

Clinicians too are sometimes hindered by perceived social factors in evaluating and managing individuals with or at risk for STIs. Busy clinicians may assume that their patients are not at risk or hesitate to take sexual histories without a cue to action from their patients, such as a history of possible exposure or genitourinary symptoms or signs, worrying that to ask such questions might be offensive to patients, when data in fact indicate that, if properly presented, this is not the case 159 . Clinician reticence, along with individual embarrassment and/or shame may also hinder partner notification.

Thus, although the principles of gonorrhoea management are well known, there are numerous areas within the current management strategies that need to be improved.

Quality of life

As gonorrhoea is an STI, its diagnosis is often associated with perceptions of social stigma, shame and denial, and can lead to intense embarrassment and fear of retaliation, domestic violence or loss of relationships, including marriages 160 . In the 1960s, the sociologist Erving Goffman described stigma as “undesired differentness” and “discrediting” 161 — a finding reinforced by research findings in the 1990s showing that STI-related stigma resulted in lower testing rates for gonorrhoea 162 . More recent studies have shown that stigma in different populations contributes to a reduction in seeking testing for STIs, reluctance to notify sexual partners and lower levels of treatment compliance 163 , 164 . For example, in Bhutan, perceived stigma was identified as a key reason for high levels (>50%) of loss to follow-up among patients diagnosed with gonorrhoea 165 . Research found that common coping strategies among people with gonorrhoea in an urban American setting included denial and disengagement — although these behaviours did not greatly affect rates of partner notification 166 . These findings, specific to gonorrhoea, are illustrative of more general findings that stigma influences STI care-seeking. Research noted a reluctance to seek STI testing in young women from socioeconomically marginalized neighbourhoods in Canada, owing to “stigma and the fear of being ostracized” 167 and studies found that, among African–American men, increasing STI-related stigma was “significantly associated with…decreased odds of having been tested, [and]…decreased willingness to notify non-main partners” 168 ; these factors may contribute to the observed disparities in the distribution of STIs across the intersectional inequalities of ethnicity and gender 169 . In Tigray, Ethiopia, rates of loss to follow-up were lower among patients with low levels of STI-related stigma than in study participants reporting high levels of stigma 164 .

At the policy level, stigma around gonorrhoea probably contributes to the widespread lack of attention and resource allocation within public health global and national programmes. A recent review of the challenges and opportunities for STI control argued that stigma associated with gonorrhoea and other STIs arises, in part, from ‘condemnatory moral attitudes’ around the behaviours leading to risk of infection — in particular same-sex relationships and transactional sex 170 . Earlier research investigating gonorrhoea control in the USA in the 1970s and 1980s similarly argued that “society’s propensity to view gonorrhoea as a disease of ‘immoral’ people” directly contributed to the lack of resources and attention paid to the infection 171 . Qualitative research on the lack of political prioritization afforded to STI control in China confirmed that STIs received a lower place on the health agenda than HIV infection, as decision makers associated them with ‘immorality’ and patients were considered ‘condemnable’ 172 .

Arguably, the high levels of stigma and accompanying negative framing of gonorrhoea and other STIs exert the most substantial effect on quality of life measures associated with gonorrhoea. Perceptions of embarrassment and humiliation that a diagnosis may bring — both for the affected individuals and their sexual partners — combined with under-resourced public health control programmes, contribute to undiagnosed or poorly treated infections, thereby increasing risks of onward transmission and individual clinical complications and longer-term sequelae caused by this otherwise treatable infection.

Paradoxically, the rise of AMR in N. gonorrhoeae may, potentially, force policy-level decision makers to act to devote more attention to the prevention and control of gonorrhoea. However, it should be emphasised that interventions to tackle gonococcal AMR are only likely to succeed if they address not only questions of appropriate antimicrobial use/misuse, but also aim to decrease the global burden of gonorrhoea, which also requires reducing the perception of associated shame and stigma. Effective interventions to decrease stigma and increase patient quality of life should be directed not only at individual and community levels, but also at the political level, to identify and address the social conditions giving rise to stigma and promote institutional fairness 173 .

It is imperative to address many global issues for the successful management and control of gonorrhoea. These key priorities and research efforts span all fields, from epidemiology of the pathogen and the disease to the quality of life of patients (Box  2 ). Of note, reducing the perception of shame, humiliation and stigma that is associated with a diagnosis of gonorrhoea and with certain sexual orientations (for example, MSM) in many settings is crucial to obtain more accurate incidence and prevalence data and to decrease the global burden of gonorrhoea, which would also substantially reduce gonococcal AMR. Effective interventions to decrease STI-associated stigma should be implemented at individual and community levels, and at the social and political levels where social conditions giving rise to stigma should be identified and tackled 173 . Gonorrhoea and other STIs need to be considered and managed by individuals, the health system, the general community and at the political level in all countries in recognition of the right to health services free of discrimination and without stigma.

Box 2 Key priorities in gonorrhoea research and control

Decreasing the perception of stigma, humiliation and shame associated with gonorrhoea and other sexually transmitted infections (STIs), and ensuring that services and interventions are delivered free of discrimination, leaving no populations behind

Increasing knowledge of the incidence and prevalence of the infection and its complications and sequelae in the general population and subpopulations

Expanding global antimicrobial resistance (AMR) surveillance (phenotypic and genetic AMR testing), including surveillance of treatment failures and antimicrobial use/misuse, in combination with whole-genome sequencing and clinical and epidemiological data from patients

Improving knowledge of the natural course and pathogenesis, including genomic, physiological, pathogenic and virulence mechanisms of Neisseria gonorrhoeae in different anatomical sites and understanding the emergence, evolution, spread and biological costs or benefits (fitness) of AMR

Understanding of pharmacokinetics and pharmacodynamics of current and future therapeutic antimicrobials in urogenital and particularly extragenital sites, to inform treatment guidelines

Increasing diagnostic testing (also to detect asymptomatic gonorrhoea), increasing use of validated and quality-assured nucleic acid amplification tests and developing rapid, appropriate and affordable point-of-care tests, which should also enable simultaneous prediction of AMR or susceptibility status

Strengthening prevention (for example, increasing the use of condoms and of out-of-box approaches, such as the use of antiseptic mouthwash to prevent acquisition and transmission of pharyngeal gonorrhoea 215 )

Improving the understanding of the effects of pre-exposure prophylaxis on the prevalence of gonorrhoea and other STIs in different populations, the risk factors involved, and the ideal counselling, monitoring and screening intervals for individuals taking pre-exposure prophylaxis

Developing gonococcal vaccine(s), for which substantial progress has been made in recent years 131 , 132 , 133 , 134 , 136 , 137 , 138 , 189 , 191 , 216

Promoting early diagnosis and treatment of patients and their partners, following evidence-based international and national guidelines

Promoting responsible antimicrobial use and stewardship (both STI-related and on a population level), as excessive antimicrobial use can decrease the susceptibility of N. gonorrhoeae to therapeutic drugs, both directly (through selection of AMR in N. gonorrhoeae ) and indirectly (through selection of AMR determinants in, for example, commensal Neisseria spp. that are subsequently shared through horizontal genetic transfer with N. gonorrhoeae 217 )

Developing novel therapeutic antimicrobials and strategies to preserve the efficacy of current and future antimicrobials

The incidence of gonorrhoea is increasing, especially in high-income settings globally. However, global population-based incidence and prevalence data are extremely scarce from most settings and, even in high-income settings where surveillance is conducted in a more systematic and regular manner, the surveillance data should be interpreted with caution as the surveillance systems, diagnostic testing, methodologies and quality assurance are not standardized across countries and remain weak in several settings 33 , 36 . Additionally, the current prevalence of serious complications and sequelae due to gonorrhoea is mainly unknown and estimates are mostly based on historical data. WGS will revolutionize our understanding of the molecular epidemiology (that is, the geographical and temporal spread) of N. gonorrhoeae strains. WGS is substantially more accurate than previously used molecular epidemiological typing methods and can adequately describe the emergence, transmission and evolution of AMR gonococcal strains both geographically and temporally, as well as predict AMR with adequate accuracy 45 , 156 , 174 , 175 , 176 , 177 , 2 mg/L) Neisseria gonorrhoeae isolates in Europe from 2009 to 2014. J. Antimicrob. Chemother. 71, 3109–3116 (2016)." href="#ref-CR178" id="ref-link-section-d126509203e5547_4">178 , 179 , 180 , 181 , 182 , 183 , 184 . However, it is important to strongly emphasize that the full benefits of using WGS for both molecular and infection epidemiology can only be achieved if the WGS data are linked to phenotypical data for the gonococcal isolates and the clinical and epidemiological data for the corresponding patients with gonorrhoea. Notably, WGS of gonococcal isolates with joint analysis of clinical and epidemiological data has also already been introduced and provided increased understanding of, for example, the distribution of AMR and susceptible gonococcal strains in different populations nationally and regionally in the international Euro-GASP (which currently includes 27 European countries) 156 .

Our understanding of the pathophysiology of gonorrhoea is still limited in many areas, especially the natural course of the infection (including duration and spontaneous resolution), the dynamics of pathogenesis and infection (such as transmission, average time to detection and treatment in different populations, effects of treatment (or co-treatment for other concomitant STIs) on innate and adaptive immunity, host damage and possible host protection) and immune responses and their suppression in urogenital and particularly extragenital sites, such as the pharynx. Improving the knowledge in these areas would enable us to more effectively use mathematical modelling in the gonorrhoea and gonococcal AMR field, taking into account microbiological, genomic, evolutionary, clinical, immunological and epidemiological data 185 , as well as in vaccine development.

After the introduction of any new therapeutic antimicrobial for gonorrhoea, N. gonorrhoeae has rapidly acquired or developed decreased susceptibility or resistance to it (Fig.  1 ) via several AMR mechanisms: enzymatic destruction or modification of the antimicrobial, modification or protection of antimicrobial targets to avoid binding, increased export of the antimicrobial (for example, through the MtrC–MtrD–MtrE efflux pump) and decreased uptake of the antimicrobial (for instance, through the porin PorB) 16 . Some AMR determinants, particularly target alterations, directly cause AMR, whereas others cannot result in AMR on their own and require the presence of additional AMR determinants. The accumulation of many AMR determinants does not seem to substantially reduce the biological fitness of N. gonorrhoeae 16 , 17 , 18 , 19 , 20 , 21 , and some AMR determinants seem to even enhance the fitness of specific gonococcal strains 19 , 20 , 21 . Nevertheless, we need to substantially improve our understanding and definition of fitness as well as of compensatory mutations that could restore possible fitness cost in N. gonorrhoeae . We need detailed knowledge regarding how gonococcal AMR determinants affect the fitness of gonococcal strains, how fitness affects the emergence and spread of AMR strains and how these strains become established in the circulating gonococcal populations. Thus, we need to investigate how the fitness of AMR strains may affect the competition with wild-type antimicrobial susceptible strains (which is mainly the current fitness definition in microbiological research) and its effects on several other factors, such as transmissibility, duration of infection in different anatomical sites and proportion of symptomatic and asymptomatic infections and severe complications and sequelae in heterogeneous populations with different sexual behaviours. Further research is also needed to identify and characterize in detail known or novel AMR determinants in clinical gonococcal isolates (including their induction and selection, evolution, effect on AMR and biological fitness) and to develop and evaluate genetic AMR prediction tests that can supplement the culture-based AMR surveillance.

In many settings, mostly in less-resourced areas (in which frequently the prevalence of gonorrhoea is the highest), the diagnosis, testing, case reporting and prevention of gonorrhoea remain suboptimal. Thus, it is important to widely implement the use of cost-effective, appropriate and quality-assured NAATs. If required, these NAATs can be performed in centralized reference laboratories for cost-effectiveness and to maintain a high level of quality assurance. In addition, rapid, appropriate POCTs for the diagnosis of gonorrhoea and other STIs are urgently needed. Gonococcal POCTs should ideally simultaneously predict AMR to inform treatment. For some antimicrobials, such as ciprofloxacin, mathematical modelling has indicated that POCTs with high sensitivity to detect AMR can be more effective than NAATs and even culture to preserve the effectiveness of the antimicrobial. By contrast, POCTs detecting N. gonorrhoeae without reliable AMR detection may accelerate the spread of AMR gonococcal strains 186 . Several rapid, sensitive and specific NAAT-based POCTs for gonorrhoea are in the pipeline and will be available in the coming few years 101 , 122 , 170 , 187 (Table  3 ). Accordingly, it will soon be essential to prepare health-care systems for use of these POCTs by including them in STI training modules, management guidelines, diagnostic algorithms and regulatory frameworks. Limitations to the adoption of POCTs are considerable and include time for results; cost of the instrument; lack of required infrastructure, quality assurance and reporting criteria; supply chain issues that may discourage use; lack of clear recommendations on the inclusion of POCTs in diagnostic algorithms and regulatory frameworks, lack of training opportunities and education of health-care workers about the utility and advantages of POCTs; and worries by laboratory-based personnel that out-of-laboratory testing may infringe on job security 118 .

In an era of high prevalence of AMR in N. gonorrhoeae coupled with the widespread use of diagnostic gonococcal NAATs internationally, it is essential to retain and strengthen the ability to perform gonococcal culture, which is the only method that enables complete AMR testing, because surveillance of gonococcal AMR (preferably minimum inhibitory concentration (MIC)-based) and ideally also of cases of treatment failure is imperative. In settings where NAATs solely are used for the diagnosis of gonorrhoea, participation in organized and quality-assured national, regional and/or international GASPs is crucial.

WGS and other new technologies such as transcriptomics and proteomics are also informing the development of N. gonorrhoeae diagnostics and vaccines 156 , 174 , 175 , 176 , 177 , 2 mg/L) Neisseria gonorrhoeae isolates in Europe from 2009 to 2014. J. Antimicrob. Chemother. 71, 3109–3116 (2016)." href="#ref-CR178" id="ref-link-section-d126509203e5654_4">178 , 179 , 180 , 181 , 182 , 183 , 188 , 189 , 190 , 191 . For developing gonococcal vaccines, a number of promising protein antigens have been described and characterized, including proteins involved in colonization (for example, PilC, PilQ, PorB, Opa and OmpA), evasion of innate defences (for example, MtrE, SliC, Ng-ACP, MsrAB, Lst and PorB) and nutrient acquisition (for example, TbpA, TbpB, LbpA and LbpB); structural proteins (for example, BamA, BamE, NGO2054 and NGO2111); other proteins such as AniA (implicated in nitrate reduction) and MetQ (methionine transporter that promotes survival in macrophages); the 2C7 epitope (peptide mimetic of LOS epitope); and OMVs 131 , 132 , 134 . Many of the promising new vaccine targets for N. gonorrhoeae have been identified through proteomic approaches and transcriptome analysis of genes expressed during gonococcal infections 188 , 189 , 190 , 192 . Furthermore, to overcome the restrictions of the current model of female mice treated with 17β-oestradiol, new animal models for N. gonorrhoeae infection are being developed, such as transgenic mice that mimic human infections and express human cell adhesion molecules or iron-binding molecules 193 , 194 , and a transgenic mice model expressing human complement factor H is available for the closely related N. meningitidis 195 .

Currently available genetic assays have shortcomings (such as cross-reactions with nongonococcal Neisseria species in clinical, particularly pharyngeal, specimens, and suboptimal sensitivity and/or specificity) that limit their prediction of resistance or susceptibility to currently recommended therapeutic antimicrobials (except for ciprofloxacin, for which the sensitivity and specificity of NAATs are generally >95%); additionally, newly emerging AMR determinants are not detected 196 , 197 , 198 . However, future improved rapid POCTs that detect both N. gonorrhoeae and its resistance or susceptibility to several antimicrobials will guide individualized therapy at the first health-care visit and restrict the use of last-line antimicrobials 196 , 197 , 198 , 199 . Such POCTs will improve the management and control of both gonorrhoea and N. gonorrhoeae AMR. WGS can also be used for prediction of AMR and MICs of antimicrobials with reasonably high accuracy 156 , 182 , 183 , 184 . Rapid, real-time sequencing with the hand-held MinION sequencer was shown to generate fairly accurate genome sequences and be able to predict resistance to ciprofloxacin and azithromycin and decreased susceptibility or resistance to cefixime in N. gonorrhoeae 183 . The rapid development of WGS technologies with decreasing complexity and cost and faster turnaround times may make these technologies suitable for N. gonorrhoeae detection and prediction of resistance or susceptibility to therapeutic antimicrobials at the diagnostic setting, including at point-of-care.

The global issue of AMR in N. gonorrhoeae will probably continue to escalate, and we cannot rely on the last-line ceftriaxone (plus azithromycin) indefinitely. Consequently, new antimicrobials, with novel mechanisms of action, for monotherapy and/or inclusion in dual therapies for urogenital and extragenital gonorrhoea are crucially needed. Some recently developed new antimicrobials, namely, the spiropyrimidinetrione zoliflodacin 200 , 201 , 202 , 203 , 204 and triazaacenaphthylene gepotidacin 205 , 206 , 207 , will both soon be in phase III randomized clinical controlled trials for uncomplicated gonorrhoea. Additional promising novel antimicrobials in earlier development that deserve further attention for the treatment of gonorrhoea (and possibly additional STIs) are, for example, lefamulin 208 , 209 and SMT-571 (ref. 210 ). However, until novel antimicrobials are available, it is imperative to increase our knowledge regarding ideal treatment, including dosing regimens, of gonorrhoea and other STIs, such as C. trachomatis and M. genitalium infections, with the available antimicrobials ceftriaxone, azithromycin and doxycycline. Clearly, a more holistic view on the treatment of bacterial STIs and understanding the effect of any new bacterial STI treatment on other STI pathogens and the bystander microbiota is essential. Current knowledge regarding the pharmacokinetics and pharmacodynamics of the available antimicrobials in the treatment of gonorrhoea and other STIs at urogenital and particularly extragenital sites is highly limited 211 and requires substantially increased attention to inform ideal dosing regimens, and multiple dose regimens for gonorrhoea might be required.

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Acknowledgements

The authors are grateful to S. Jacobsson (Örebro University Hospital and Örebro University) and S. Perera and N. Parmar (University of Saskatchewan) for technical assistance with preparing this manuscript.

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Magnus Unemo

National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden

Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

H Steven Seifert

Departments of Medicine, Epidemiology and Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA

Edward W. Hook III

Institute for Global Health, University College London, London, UK

Sarah Hawkes

Skin and Genitourinary Medicine Clinic, Harare, Zimbabwe

Francis Ndowa

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Unemo, M., Seifert, H.S., Hook, E.W. et al. Gonorrhoea. Nat Rev Dis Primers 5 , 79 (2019). https://doi.org/10.1038/s41572-019-0128-6

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Gonorrhea - an evolving disease of the new millennium

Stuart a hill, thao l masters, jenny wachter.

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Conflict of interest: The authors declare no conflict of interest.

Please cite this article as: Stuart A. Hill, Thao L. Masters and Jenny Wachter (2016). Gonorrhea - an evolving disease of the new millennium. Microbial Cell 3(9): 371-389. doi: 10.15698/mic2016.09.524

Received 2015 Oct 9; Accepted 2016 Jan 30; Collection date 2016 Sep 5.

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Etiology, transmission and protection: Neisseria gonorrhoeae (the gonococcus) is the etiological agent for the strictly human sexually transmitted disease gonorrhea. Infections lead to limited immunity, therefore individuals can become repeatedly infected. Pathology/symptomatology: Gonorrhea is generally a non-complicated mucosal infection with a pustular discharge. More severe sequellae include salpingitis and pelvic inflammatory disease which may lead to sterility and/or ectopic pregnancy. Occasionally, the organism can disseminate as a bloodstream infection. Epidemiology, incidence and prevalence: Gonorrhea is a global disease infecting approximately 60 million people annually. In the United States there are approximately 300, 000 cases each year, with an incidence of approximately 100 cases per 100,000 population. Treatment and curability: Gonorrhea is susceptible to an array of antibiotics. Antibiotic resistance is becoming a major problem and there are fears that the gonococcus will become the next “superbug” as the antibiotic arsenal diminishes. Currently, third generation extended-spectrum cephalosporins are being prescribed. Molecular mechanisms of infection: Gonococci elaborate numerous strategies to thwart the immune system. The organism engages in extensive phase (on/off switching) and antigenic variation of several surface antigens. The organism expresses IgA protease which cleaves mucosal antibody. The organism can become serum resistant due to its ability to sialylate lipooligosaccharide in conjunction with its ability to subvert complement activation. The gonococcus can survive within neutrophils as well as in several other lymphocytic cells. The organism manipulates the immune response such that no immune memory is generated which leads to a lack of protective immunity.

Keywords: pathogenesis, antigenic variation, immune manipulation, antibiotic resistance, panmictic

INTRODUCTION

Neisseria gonorrhoeae (the gonococcus) is a Gram-negative diplococcus, an obligate human pathogen, and the etiologic agent of the sexually transmitted disease, gonorrhea. The gonococcus infects a diverse array of mucosal surfaces, some of which include the urethra, the endocervix, the pharynx, conjunctiva and the rectum 1 . In 2013, the Centers for Disease Control and Prevention (CDC) reported that there were 333,004 new cases of gonorrhea in the United States, with an incidence of 106.1 cases per 100,000 population 2 . Worldwide, 106.1 million people are infected by N. gonorrhoeae annually 3 . In most cases, the disease is a noncomplicated mucosal infection. However, in a few patients, generally with women, more serious sequelae can occur and include salpingitis (acute inflammation of the fallopian tubes), pelvic inflammatory disease (PID; an infection in the upper part of the female reproductive system), or, in rare cases, as a bacteremic infection 4 . If left untreated, these more serious complications can result in sterility, ectopic pregnancy, septic arthritis, and occasionally death. Approximately 3% of women presenting with a urogenital infection develop the most severe forms of the disease 5 . However, the occurrence of PID has significantly decreased over time 6 , 7 , 8 , with an estimated 40,000 cases of infertility in women annually 9 . Dissemination rarely occurs, but when the bacteria do cross the endothelium, they can spread to other locations in the body. Currently, a more worrying trend has emerged, in that, there now appears to be an increased risk for HIV infection in patients that are also infected with N. gonorrhoeae 10 .

Gonorrhea the disease was initially described approximately 3,500 years ago, but it was not until 1879 that Albert Neisser determined the etiologic agent of the disease 11 . The Neisseriae are usually regarded as microaerophilic organisms. However, under the appropriate conditions, they are capable of anaerobic growth 12 . In vitro cultivation of this fastidious organism has always been problematic and it was not until the development of an improved Thayer-Martin medium that early epidemiological studies could be undertaken. Subsequently, other commercial growth mediums have since been developed which has allowed for a greater understanding of the disease process.

VIRULENCE FACTORS OF N. GONORRHOEAE

Like many Gram-negative bacterial pathogens, N. gonorrhoeae possesses a wide range of virulence determinants, which include the elaboration of pili, Opa protein expression, lipooligosaccharide expression (LOS), Por protein expression and IgA1 protease production that facilitates adaptation within the host.

Type IV pili (Tfp)

Considerable attention was paid to pili stemming from the observations of Kellogg and coworkers 12 , 13 that virulent (T1, T2 organisms) and avirulent (T3, T4 organisms) strains could be differentiated on the basis of colony morphology following growth on solid medium. Subsequently, it was established that all freshly isolated gonococci possessed thin hair-like appendages (pili) which were predominantly composed of protein initially called pilin but subsequently renamed PilE 14 . The elaboration of pili is a critical requirement for infection as this structure plays a primary role in attaching to human mucosal epithelial cells 15 , fallopian tube mucosa 16 , 17 , vaginal epithelial cells 16 , 18 as well as to human polymorphonuclear leukocytes (PMN’s; neutrophils) 19 , 20 . Due to their prominent surface location, pili were initially thought to be an ideal vaccine candidate as pilus-specific antibodies were observed in genital secretions 18 . However, two prominent vaccine trials failed, with evidence indicating that pilus protein(s) underwent antigenic variation 21 .

Gonococcal pili are categorized as Type IV pili, as the PilE polypeptide is initially synthesized with a short (7 amino acid) N-terminal leader peptide, which is then endo-proteolytically cleaved 22 . The mature PilE polypeptide is then assembled at the inner membrane into an emerging pilus organelle with the PilE polypeptides being stacked in an α-helical array 23 . The PilE polypeptide consists of three functional domains based on sequence characteristics 24 . The N-terminal domain is highly conserved and is strongly hydrophobic, with this region of the protein comprising the core of the pilus structure 23 . The central part of the PilE monomer is partially conserved and structurally aligned as a β-pleated sheet. As the C-terminal domain is hydrophilic, this segment of the protein is exposed to the external environment 23 and undergoes antigenic variation which allows the bacteria to avoid recognition by the human host’s immune cells (reviewed 25 , 26 ).

Assembly of the pilus structure is complicated and involves other proteins besides PilE (e.g., the pilus tip-located adhesion, PilC) 27 as well as other minor pilus components PilD, PilF, PilG, PilT, PilP and PilQ 28 . During pilus biogenesis, and prior to assembly, the leader peptide is removed from PilE by the PilD peptidase 23 . The N-terminal domain then facilitates translocation across the cytoplasmic membrane allowing PilE subunits to be polymerized at the inner membrane 29 , 30 . As the pilus structure is assembled, it is extruded to the exterior of the outer membrane using the PilQ pore forming complex 29 , 30 , 31 . PilC is a minor protein located at the tip of pilus as well as being present at its base. The pilC gene exists as 2 homologous, but non-identical copies, pilC1 and pilC2 in most gonococcal strains, with only the pilC2 gene being expressed in piliated N. gonorrhoeae MS11 strains 27 . pilC expression is also subject to RecA-independent phase variation (on/off switching) due to frequent frameshift mutations occurring within homo-guanine tracts located within its signal peptide region 27 . PilC participates in pilus biogenesis as well as in host cell adherence, as pilC mutants prevent the formation of pili by negatively affecting their assembly process, which leads to the bacteria being unable to adhere to human epithelial cells 32 .

In addition to promoting attachment to host cells, type IV pili are also involved in bacterial twitching motility, biofilm formation, and DNA transformation 33 . N. gonorrhoeae is naturally competent for transformation in that it can take up exogenously produced Neisseria -specific DNA containing a 10-bp uptake sequence (GCCGTCTGAA; DUS) 34 . pilE mutations resulting in loss of pilus expression lead to transformation incompetence 28 , 35 . The binding and uptake of exogenous DNAs by N. gonorrhoeae requires type-IV-pili-structurally-related components, including ComP protein 36 , 37 . Despite sharing sequence similarity to PilE in the N-terminal domain, ComP was shown to be dispensable to Tfp biogenesis 36 . Instead the bacteria were unable to take up extraneous DNA; subsequent overexpression of ComP increased sequence-specific DNA binding, suggesting that ComP functions in the DNA binding step of transformation 37 . Recently, ComP has been shown to preferentially bind to DUS-containing DNAs via an electropositive stripe on its surface 38 with uptake of the DNA being facilitated by de-polymerization of the pilus structure through PilT hydrolytic activity 39 . The coordinated physical retraction and elongation of pili can lead to "twitching", a form of motility that propels the cell along a surface. Retraction is facilitated by PilT activity (an ATPase), whereas PilF protein promotes pilus elongation at the inner membrane 39 , 40 .

Por protein

The outer membrane porin protein, Por, is the most abundant protein in the gonococcus accounting for approximately 60% of the total protein content 1 . The molecular size of Por varies between strains, yet, within individual strains, it exists as only a single protein species 41 . Por has been used as the basis for serological classification of gonococci 41 with nine distinct serovars being identified 42 . Overall, there are two distinct structural classes (PorA and PorB) 42 , with the PorA subgroup tending to be associated with the more complicated aspects of the disease, whereas the PorB subgroup is more likely to be involved with uncomplicated mucosal infections 43 .

Porins allow the transport of ions and nutrients across the outer membrane and can also contribute to the survival of the bacteria in host cells 44 . Moreover, gonococcal Por protein has been shown to translocate from the outer membrane into artificial black lipid membranes 45 as well as into epithelial cell membranes, following attachment of the bacteria 46 . Por can also transfer into mitochondria of infected cells which leads to the formation of porin channels in the mitochondrial inner membrane, causing increased permeability 47 . This causes the release of cytochrome c and other proteins, leading to apoptosis of infected cells 48 . However, Por-induced apoptosis remains controversial. In direct contrast to events with the gonococcus, Neisseria meningitidis Por, which also interacts with mitochondria, apparently protects cells from undergoing apoptosis 49 . Interestingly, mitochondrial porins and Neisseria PorB share similar properties, with both protein species being capable of binding nucleotides and exhibiting voltage-dependent gating 50 . Por protein also modulates phagosome maturation by changing the phagosomal protein composition through the increase of early endocytic markers and the decrease of late endocytic markers, which ultimately delays phagosome maturation 51 .

Opacity-associated protein (Opa)

Opa proteins are integral outer membrane proteins and cause colonies to appear opaque due to inter-gonococcal aggregation when viewed by phase-contrast microscopy 52 , 53 , 54 . Opa proteins belong to a multigene family with a single gonococcal cell possessing up to 12 opa genes that are constitutively transcribed 55 , 56 . Each gene contains conserved, semivariable and 2 hypervariable regions, with the hypervariable segments of the proteins being located on the outside of the outer membrane 55 . Opa protein expression can undergo phase variation due to changing the numbers of pentameric repeat units (-CTCTT-) that are located within the leader peptide encoding region, which results in on/off switching of expression 57 . A single cell is capable of expressing either none to several different Opa proteins 57 , 58 .

Unlike pili, Opa expression is not required for the initial attachment of gonococci to the host. However, as an infection proceeds, Opa expression varies 58 , and Opa-expressing bacteria can be observed in epithelial cells and neutrophils upon re-isolation from infected human volunteers 59 , 60 . The invasive capacity of N. gonorrhoeae is determined by the differential expression of Opa 61 . Individual Opa proteins bind to a variety of receptors on human cells through their exposed hypervariable regions. The binding specificity for human receptors falls into two groups: OpaHS which recognize heparin sulfate proteoglycans 62 , 63 ; and, OpaCEA which recognize the carcinoembryonic antigen cell adhesion molecule (CEACAM) family that is comprised of the various CD66 molecules 64 , 65 , 66 , 67 . CEACAMs are the major receptors of Opa proteins and are expressed on many different cell types including epithelial, neutrophil, lymphocyte and endothelial cells 68 .

Lipooligosaccharide (LOS)

As with all Gram-negative bacteria, gonococci possess lipopolysaccharide in the outer membrane. Gonococcal LPS is composed of lipid A and core polysaccharide yet lacks the repeating O-antigens 1 . Accordingly, gonococcal LPS has been designated as lipooligosaccharide (LOS). Due to its surface exposure, gonococcal LOS is a primary immune target along with the major outer membrane protein Por 69 , 70 , 71 . Gonococcal LOS is also toxic to fallopian tube mucosa causing the sloughing off of the ciliatory cells 72 . The LOS oligosaccharide composition is highly variable both in length and in carbohydrate content. Consequently, heterogeneous LOS molecules can be produced by a single cell. However, distinct forms of LOS may be a prerequisite for infection in men 73 . The most common carbohydrates associated with isolated LOS molecules are lacto-N-neotetraose (Galβ(1-4)GlcNAcβ(1-3)Galβ(1-4)Glc) and digalactoside Galα(1-4)Gal and switching from one form to another occurs at high frequency 74 through phase variation of glycosyl transferases 75 , 76 . The variable oligosaccharide portions of LOS can also mimic host glycosphingolipids, thus promoting bacterial entry 74 . In addition, gonococcal LOS can also be sialylated which renders the bacteria resistant to serum killing 77 , 78 , 79 , 80 . Consequently, gonococcal LOS contributes to gonococcal pathogenicity by facilitating bacterial translocation across the mucosal barrier as well as by providing resistance against normal human serum 81 , 82 .

IgA protease

Immunoglobin A (IgA) protease is another virulence factor in N. gonorrhoeae 83 . Upon release from the cell, the protein undergoes several endo-proteolytic cleavages, leading to maturation of the IgA protease 84 . During an infection, the mature protease specifically targets and cleaves IgA1 within the proline-rich hinge region of the IgA1 heavy chain. The human IgA2 subclass is not cleaved by gonococcal IgA protease since it lacks a susceptible duplicated octameric amino acid sequence 85 . Neisseria IgA protease also cleaves LAMP1 (a major lysosome associated membrane protein), which leads to lysosome modification and subsequent bacterial survival 86 . Furthermore, iga mutants are defective in transcytosis of bacteria across an epithelial monolayer 87 .

PATHOGENESIS

Neisseria gonorrhoeae primarily colonizes the urogenital tract after sexual contact with an infected individual 88 . The gonococcus can exist as both an extracellular and intracellular organism, with the bulk of its genes being devoted to colonization and survival, due to the fact that it cannot survive outside of a human host 89 . Transmission is generally a consequence of sexual intercourse. Upon arrival into a new host, micro-colony formation commences on non-ciliated columnar epithelial cells approximately 1 to 2 hours post-infection 90 , 91 . Once the micro-colonies achieve a cell density of approximately 100+ diplococci, cytoskeletal rearrangement and host protein aggregation occurs, which leads to pilus-mediated attachment of the gonococcus to the CD46 host cell-surface receptor (Fig. 1) 89 , 92 . Once bound, the pilus structures on some organisms are retracted through PilE depolymerization 39 which promotes tighter contact with the host cells through Opa binding to the CEACAM receptors (Fig. 1) 65 , 66 . Upon CEACAM binding, actin polymerization and rearrangement is induced within the host cell which results in bacterial engulfment, transcellular transcytosis and release of the bacteria into the subepithelial layer (Fig. 1) 68 , 93 .

Figure 1. FIGURE 1: Schematic representation of a Neisseria gonorrhoeae infection.

1) Piliated, Opa-expressing gonococci interact with the mucosal epithelium. The thin, hair-like pilus appendages provide the initial contact with receptors on the surface of the mucosal cells.

2) Pili are then retracted which allows for more intimate, Opa-mediated attachment of the bacteria with the CD66 antigens located on the mucosal cells.

3) Following Opa-mediated attachment, the bacteria are engulfed and are internalized into the mucosal cells.

4) Following internalization, some bacteria can transcytose to the basolateral side of the mucosal epithelium.

5) Depending upon which Opa protein is being expressed, gonococci can also reside and survive inside of neutrophils.

6) Following transcytosis, gonococci can enter the bloodstream where heavy sialylation of lipooligosaccharide renders the bacteria serum resistant. This figure is based on 98 .

In vivo , the coordinated expression of pili and Opa varies considerably 94 . Organisms isolated from the male urethra generally co-express pili and one of several Opa proteins 58 . However, in women, Opa expression varies depending upon the stage of the menstrual cycle and whether or not the patient is taking oral contraceptives 94 . At mid-cycle, bacteria isolated from the cervix express Opa, whereas those isolated during menses tend to be Opa negative 17 . Moreover, organisms isolated from infected fallopian tubes are almost universally Opa negative, even though Opa expressing organism can be isolated from the cervix of the same patient 17 . These observations can perhaps be explained by the fact that cervical secretions during menstruation contain more proteolytic enzymes than during the follicular phase. Consequently, non-Opa expressing cells may be selected due to the extreme sensitivity of Opa proteins to trypsin-like enzymes. However, with the recent studies demonstrating Opa interactions with CECAM receptors, it has been observed that fallopian epithelial tube cell cultures do not appear to express CECAM receptors 95 . Nonetheless, in the absence of these receptors, gonococci were found to still adhere and invade. Consequently, CECAM expression, or the lack of it, possibly allows for in vivo phenotypic selection of distinct gonococcal populations on various tissues 96 . Overall, Opa expression does appear to increase gonococcal fitness within the female genital tract 97 . Generally, Opa expression is absent in most re-isolates from female disseminated infections.

Inflammation

The hallmark symptom of a non-complicated gonorrhea infection is a massive recruitment of neutrophils to the site of infection leading to the formation of a pustular discharge. Initially, Opa protein expression was suspected to be intimately involved in PMN stimulation 20 , 99 , 100 , 101 . Subsequently, it was shown that following attachment of gonococci to the mucosa, the pro-inflammatory cytokines IL-6 and TNF-alpha as well as the chemokine IL-8 are released leading to the recruitment of neutrophils 102 . In addition, upon arrival at the sub-epithelial layer, gonococci release LOS and lipoproteins which further stimulate cytokine production 103 as these outer membrane components are detected by Toll-like receptors (TLRs) on immune cells 104 . Host cells also respond to bacterial peptidoglycan fragments within outer membrane vesicles via cytoplasmic NOD-like receptors (NLRs) which also contribute to the secretion of additional pro-inflammatory cytokines 105 .

Despite the active recruitment of PMNs to a site of infection, gonococci can survive the oxidative and non-oxidative defense mechanisms (Fig. 1) 106 . Survival appears to correlate with gonococci selectively triggering Th17-dependent host defense mechanisms by modulating expression of IL-17 107 . Gonococci also must combat considerable oxidative stress by elaborating a number of different enzymes during the inflammatory response in order to detoxify superoxide anions (O2•−), hydrogen peroxide (H 2 O 2 ), and hydroxyl radicals (HO•) 108 , 109 . Gonococci must remove H 2 O 2 because in the presence of ferrous ions the Fenton reaction is initiated (Fe 2+ + H 2 O 2 → Fe 3+ + OH . + OH − ) which yields additional hydroxyl radicals 110 , 111 . Catalase is used by the gonococcus to eliminate H 2 O 2 (which significantly increases the organism’s ability to resist in vitro neutrophil killing) 112 in conjunction with a periplasmic cytochrome c peroxidase (Ccp) 110 . Normally, superoxide ions are removed by superoxide dismutase enzymes (SOD) which convert superoxide to H 2 O 2 and water. However, the majority of N. gonorrhoeae strains have no measurable SOD activity 108 , 109 , 110 , 111 , suggesting that oxidants may be removed via an alternative mechanism. It appears that N. gonorrhoeae utilize manganese ions (Mn 2+ ) to combat reactive oxygen species accumulation. Manganese accumulates within the cell through the Mn uptake system (MntABC), with Mn(II) and Mn(III) both scavenging superoxide and hydrogen peroxide molecules non-enzymatically. Furthermore, Mn(II)-pyrophosphate and Mn(III)-polyphosphate complexes are also effective in eliminating hydroxyl radicals that are formed via the Fenton reaction 110 .

The need for iron

Despite the problems associated with the Fenton reaction, iron is a vital nutrient, with pathogens expending considerable resources on scavenging the element from their human host. This becomes even more complicated during an infection, as the host responds to inflammation by limiting iron availability, as well as by decreasing free iron within the bloodstream 113 . Even though humans keep their iron sequestered in iron-protein complexes such as transferrin, lactoferrin, haemoglobin, and ferritin, the Neisseria are capable of scavenging iron from both transferrin and haemoglobin 114 , and express receptors for both transferrin and lactoferrin that provide a selective advantage within the host 115 . Because Neisseria do not produce siderophores, they must directly extract iron from transferrin. To achieve this, the iron transport system consists of two large surface proteins, transferrin binding protein A (TbpA) and transferrin binding protein B (TbpB), with both of these proteins being found in all clinical isolates of pathogenic Neisseria 116 . TbpA is an outer membrane transporter essential for iron uptake that binds both apo- and iron-containing transferrin with similar affinities, whereas TbpB, a surface-exposed lipoprotein, only associates with iron-bound transferrin 117 . As the affinity of the bacterial receptor for iron is similar to transferrin’s affinity, this enables the gonococcus to compete with the host for this necessary nutrient 118 . Subsequently, it was shown that the expression of the transferrin receptor was absolutely required for gonococcal infectivity 119 .

Serum resistance

Bactericidal antibody-mediated killing was found to vary greatly between patients presenting genital infections 120 . Subsequently, it was soon recognized that gonococcal surface components were the primary targets of antibody-dependent complement killing, with LPS-specific antibodies being the most effective at inducing bactericidal responses 121 . Two forms of serum resistance were initially described; stable and unstable serum resistance 77 , 122 . Unstable serum resistance is due to the modification of gonococcal LOS through the addition of sialic acid molecules to terminal galactose residues using cytidine 5’-monophosphate N-acetylneuraminic acid (CMP-NANA) which is abundant in human serum, as well as in various mucosal secretions and within professional phagocytes. Sialic acid transfer uses the conserved outer membrane-located enzyme 2,3-sialyltransferase 79 . Sialylation of LOS mediates both the entry of gonococci into host mucosal cells as well as influencing bacterial resistance to killing by complement 82 . Gonococcal cells harboring lightly sialylated LOS molecules are able to invade host epithelial cells more efficiently than heavily sialylated-LOS variants. However, lightly sialylated-LOS expressing cells are more susceptible to complement-mediated killing, whereas, heavy sialylation of LOS renders the bacteria resistant to normal human serum by masking the target sites for bactericidal antibodies 78 , 80 which prevents the functional activation of the complement cascade (Fig. 1) 81 .

In contrast, stable serum resistance appears to be caused through the faulty insertion of the C5b-C9 membrane attack complex in serum resistant strains 123 , 124 , 125 . Accompanying this defect in deposition, blocking antibody is also thought to cause the C3 complement component to be loaded onto a different site on the outer membrane such that it again hinders bactericidal killing 126 . Clearly, complement resistance is important for organisms causing a disseminated infection, but its value is less clear for those organisms causing a mucosal infection. However, seminal plasma does contain an inhibitor of complement activation suggesting that there is some complement activity at the mucosa 127 .

As indicated previously, the major outer membrane protein, Por, exists in two forms, Por1A and Por1B, with Por1A-expressing gonococci being most often associated with disseminated infections 42 , 43 . Por1A-expressing gonococci also bind complement factor H more efficiently, and, as factor H down-regulates alternative complement activation, such binding helps explain serum resistance in these disseminated strains 128 . Furthermore, it also helps explain species-specific complement evasion 129 . Por protein also influences activation of the classical complement pathway, as Por binds to the C4b-binding protein, which again down-regulates complement activation 130 . Consequently, as factor H and C4b-binding sites on the Por proteins impede functional complement deposition these may need to be modified in vaccine preparations as this may help alleviate problems associated with serum resistance 131 .

Active immunity

It has long been known that gonorrhea does not elicit a protective immune response and nor does it impart immune memory. Consequently, individuals can become repeatedly infected. Nonetheless, specific antibodies are generated within the genital tract that inhibit adherence to the mucosal epithelium, yet their persistence appears to be short-lived 18 , 132 . Overall, the immune response to an uncomplicated genital infection remains modest 133 .

The general unresponsiveness to an infection appears to stem from the organism being able to manipulate the host cell response. Transient decreases in T-cell populations occur within the bloodstream and appear to reflect Opa protein interactions with CD4 + T-cells which suppresses T-cell activation 134 . Moreover, in contrast to Opa-mediated interactions with CEACAM antigens on other cell types, Opa-CEACAM1 T-cell interactions do not appear to cause the internalization of bacteria into the T-cells. This then leads to a dynamic re-cycling response with the T-cells that ultimately suppresses an immune response 135 . Likewise, Opa-CEACAM1 interactions on B lymphocytes also inhibit antibody production 133 , 136 . Even with dendritic cells, Opa-CEACAM1 interactions do not stimulate internalization 136 . Instead, engulfment by dendritic cells is mediated through LOS interaction with DC-SIGN antigens. Consequently, as LOS molecules vary in composition, this allows the gonococcus a further opportunity for immune evasion 137 . LOS molecules often activate immune cells through interaction with Toll-like receptors. However, LOS deacylation can moderate an immune response following interaction with its cognate Toll-like receptor leading to B-cell proliferation where antibody production is down-regulated 138 .

Recently, an artificial estradiol-induced mouse infection model has been developed for gonococcal infections that allows for in vivo assessment 139 . However, major differences exist between the human and mouse female genital tract. For example, the pH of the mouse vagina is higher, there is no comparable menstral cycle, fewer anaerobic commensal bacteria are present, and as the mice need to be treated with antibiotics, this aspect dramatically changes the resident flora 140 . Nonetheless, the mouse infection model has yielded several interesting observations. Using the model, gonococci have been shown to moderate the murine innate immune response by stimulating IL-17 release from TH17 cells which subsequently effects other cells 107 . In conjunction with transforming growth factor beta (TGF-beta), this coupled cytokine presence suppresses Th1/Th2 adaptive responses 141 . Therefore, as the genital tract is rich in TGF-beta, gonococci naturally inhabit an immunosuppressive environment 142 . Again, LOS and Opa expression play a major role in these responses, as LOS drives the Th17 response with Opa negatively impacting the Th1/Th2 responses 142 . Further manipulation of the host response is also seen with gonococcal activation of IgM-specific memory B-cells in a T-independent manner. Consequently, this elicits a non-specific polyclonal immunoglobulin response without generating specific immunologic memory to the gonorrhea infection 143 . Recently, human CEACAM transgenic mouse models have been developed for studying gonococcal in vivo infections 144 , 145 . With these more refined models, gonococci were shown to readily infect and cause inflammation in the transgenic animals and that Opa-CEACAM interactions dramatically reduced exfoliation of the murine mucosal surface. As gonococci bind to human CR3 (hCR3) integrin to invade cervical cells and that human factor H bridges the interaction between the bacteria and hCR3, then future transgenic mouse models, expressing both hCR3 and human factor H, may further mimic a bona fide gonococcal infection in vivo .

Antigenic variation

Neisseria gonorrhoeae can survive either as an extracellular organism, or, alternatively, as an intracellular organism within a variety of different cell types. Which state the organism enters depends largely on which surface components are expressed and whether these components are chemically modified or not. N. gonorrhoeae can modulate expression, or, the chemical character of its surface components either by phase variation, or, by antigenic variation 25 . Generally, phase variation is a consequence of frame-shifting within a gene which leads to random switching between on/off states, whereas antigenic variation leads to changes in the chemical composition of some structural component. Therefore, each gonococcal cell can differentially express distinct surface antigens, in various chemical forms, which hinders recognition by host antibodies, facilitates multiple lifestyles 25 and helps explain the lack of efficacious vaccines to protect against a gonorrheal infection 21 .

From genome analysis, 72 putative genes were identified that have the capacity to undergo phase variation 146 . Consequently, the stochastic expression of various surface components leads to the emergence of micro-populations that allows colonization within unique environmental niches 147 . Pilus expression can undergo on/off switching due to frameshifting either within the pilE gene 35 , or, within the pilC gene 27 . Similarly, LOS variation depends upon frameshifting within various glycosyl transferase genes which leads to the random acquisition of various sugar moieties on a varying LOS molecule 75 , 76 . Opa expression relies exclusively on phase variation, as a series of pentameric repeats (-CTCTT-) reside towards the 5' end of each opa gene 57 . Consequently, the addition or subtraction of a repeat(s) will bring each individual opa gene either in or out of frame. As expression of individual Opa proteins influence the cellular tropism of the organism with regards to internalization into either mucosal or lymphocytic cells, opa phase variation allows variable gonococcal populations to be established that have the potential to internalize into whatever cell becomes available 56 , 61 . Consequently, phase variation confers a degree of fitness on the organism for a specific environment, yet provides little with respect to bona fide immune evasion.

Antigenic variation on the other hand confers remarkable immune evasion. Antigenic variation occurs extensively within the pil system as well as in some other minor systems ( maf and fha ) 26 . Gonococci possess multiple variable pil genes; some are deemed silent ( pilS ) and serve as storage loci for variable pil sequence, and act in conjunction with a single expression locus, pilE , which encodes the PilE polypeptide. Recombination frequently occurs between pilE and an individual pilS leading to changes in the chemical composition of PilE. It is estimated that PilE can assume 108 chemical forms 148 which helps thwart an efficacious immune response due to its prominent surface location. Therefore, despite the fact that anti-pilus antibodies can be detected within the genital tract such antibodies do not recognize heterologous strains thus allowing for reinfection of an individual 18 .

It is in the coordinated variation of these various surface components that allow gonococci to develop adaptive strategies where the organism can exist either externally or internally during an infection (Fig. 1). When gonococci reside externally, the organisms are generally piliated, with PilE undergoing antigenic variation which negates the various antibody clearing strategies. When coupled with the appropriate LOS composition, these organisms can also become heavily sialylated, which impedes serum killing, thus facilitating extra-cellular growth. In contrast, internalization into host cells requires the retraction of pili causing the cells to become non-piliated. When coupled with phase variation of Opa expression and a non-sialylatable LOS phenotype, the gonococcus can translocate across the mucosal epithelium at an initial stage of the infection and ultimately reside internally within various cell types 25 . Eventually, infected host cells will undergo apoptosis, releasing bacteria back onto the mucosal lining, where in the presence of seminal plasma the appropriate cell surface reappears to facilitate transit into a new host 149 .

Vaccine development

Vaccine development for sexually transmitted diseases has long been a goal of the scientific community 150 , 151 . However, given the extensive antigenic variation displayed by N. gonorrhoeae , coupled with suppression and manipulation of the host immune response, progress has been severely impeded. Nonetheless, in the mouse infection model, if Th1 responses can be induced, an infection will clear and immune memory can be established 152 . Consequently, incorporating Th1-inducing adjuvants within any vaccine preparation may be crucial for success in this endeavor.

Two outer membrane proteins have come under considerable scrutiny as potential vaccine components; pilus constituents and the major outer membrane protein, Por. Because anti-pili antibodies were detected in vaginal secretions following an infection 18 , this led to the early development of a parenteral pilus vaccine. Unfortunately, administration of this vaccine afforded partial protection only to homologous strains. Moreover, it also showed poor immunogenicity and did not stimulate an adequate antibody response at the site of infection 21 , 153 , 154 . Consequently, other antigens were explored as potential vaccine candidates. As neisserial Por proteins can serve as adjuvants to B-cells, as well as stimulate Por-specific circulating Th2-cells that appear to migrate to mucosal surfaces, Por has come under considerable scrutiny 155 , 156 . Por is also capable of stimulating dendritic cells where activation depends on Toll-like receptor 2. Therefore, as Por composition is relatively stable, this protein has become a promising vaccine candidate, especially if Th1-inducing adjuvants and Toll-like 2-inducing adjuvants can be included within any "designer" vaccine preparation 157 , 158 , 159 .

However, a problem exists in the development of any vaccine in that antibodies within normal human serum bind to the gonococcal outer membrane protein Rmp with binding apparently, having important consequences with regard to serum resistance for the organism 160 , 161 . The presence of cross-reactive Rmp antibodies also facilitates transmission 161 and women with Rmp antibody titers appear at an increased risk for infection 162 . As the Rmp protein is in close association with Por protein 163 it would appear to be imperative that Rmp protein is excluded from any Por-based vaccine preparation. Nonetheless, a quiet optimism now pervades the field that an anti-gonococcal vaccine may be around the corner 152 .

MOLECULAR EPIDEMIOLOGY - A HISTORICAL REVIEW

Auxotyping and serotyping - 70’s through the early 80’s.

As public health decisions regarding transmissible pathogenic diseases rely heavily on epidemiological surveillance, it became necessary to accurately identify and characterize the different circulating strains of N. gonorrhoeae 164 . Initially, isolates were typed through growth responses on chemically defined media 165 , 166 or by serotyping using common protein antigens or lipopolysaccharide 41 , 42 , 43 , 167 . Consequently, the identification of different auxotypes allowed different N. gonorrhoeae strains to be typed with respect to disease severity 168 , 169 . Subsequent Por-based serotyping allowed isolates to initially be grouped into two structurally related forms 41 , 44 , 170 , which was then further refined using enzyme-linked immunosorbant assays to eventually define nine different Por-based serotypes 171 .

Attempts were then made to differentiate isolates that caused uncomplicated, localized infections and those that caused disseminated gonococcal infections (DGI) 172 . DGI phenotypes included an increased sensitivity to penicillin 173 , unique nutritional requirements 168 coupled with serum resistance which led to increased virulence of DGI isolates 172 . Subsequently, it has been shown that the majority of DGI isolates belonged to two distinct serotypes 43 , 174 .

The emergence of antibiotic-resistant strains of N. gonorrhoeae identified a need to determine modes of antibiotic resistance among strains in order to monitor the development of new resistance genes, the lateral transfer of resistance genes, or the spread of resistance strains among the population. Early genetic mapping identified several genes involved in antibiotic resistance 175 . Through epidemiologic studies and characterization of penicillinase-producing N. gonorrhoeae (PPNG), it was determined that two indeendent strains of PPNG arose in geographically separate populations; both carried the resistance gene on distinct plasmids, with one strain (linked to the Far East) being more prevalent than the strain linked to West Africa 176 . Analysis of PPNG strains demonstrated that their introduction into the United States was due to returning military personnel from the Far East. Travel also contributed to global spread of these strains, as patients would encounter penicillin-resistant β-lactamase-producing N. gonorrhoeae following rendezvous with overseas prostitutes, which would in turn often transmit them to local prostitutes, thereby continuing their spread 169 , 177 .

Such analysis of clinical isolates indicated that distinct reservoirs of infection could be detected based upon sexual preference. Studies revealed that homosexual men had a lower incidence of asymptomatic urethral infections and DGIs, yet more frequently acquired infections by strains that were more resistant to penicillin G, which at the time, accounted for the high failure rate of this antibiotic for rectal infections 178 . Also, reservoirs for certain PPNG outbreaks could be traced back to female prostitutes, as these strains were largely absent from the homosexual community. Further epidemiological studies were able to identify gonococci that were exclusively present in both heterosexual men and women, or within homosexual male communities, thus defining sources of infection between male and female partners, prostitution and/or same sex partners 169 .

"Core group" hypothesis - late 70’s through the 80’s

As previous gonorrheal infections provide little to no immunity to subsequent infections, an alternative model for gonorrhea transmission was proposed, t suggesting that all cases of the disease are caused by a core group of individuals 179 . This "core group" hypothesis, was later reinforced by the emergence and spread of PPNG from the Far East 169 , 179 and through clinical investigations in the United States 180 , 181 . The persistence of isolates within a community was proposed to be due to a number of factors including the tendency for these strains to cause asymptomatic infections, or, alternatively, to have long incubation times prior to the onset of symptoms, which provided support to the theory that a core group of transmitters, most likely prostitutes, transmit the disease to many sexual partners 169 . Epidemiological studies revealed that a substantial group of individuals (33%) admitted to continual sexual engagement even with the knowledge of potential exposure, or, worse, even after the onset of symptoms, and that men with new or multiple sex partners were more likely to contract gonorrhea 182 , 183 . Consequently, five sociological trends were identified that assisted the rise of gonorrhea infections: 1) frequent changes in sex partners, 2) increased population mobility, 3) increasing gonococcal resistance to antibiotics, 4) decreased condom, diaphragm and spermicide use, and 5) increasing the use of oral contraceptives 184 .

Linkage disequilibrium - 1993

With the widespread use of serological typing, coupled with the desire for vaccine development, the classification and characterization of gonococcal strains invariably focused on investigating surface exposed antigens 185 . However, the combination of auxotyping and serotyping proved to be unreliable, as these techniques did not always provide adequate resolution 186 . As most pathogens are clonal with a disposition towards linkage disequilibrium, this property generally allows for classification based upon nucleotides that are present at variable sites, which in turn allows the serology, pathogenicity, host specificity and the presence of virulence genes to be mapped 185 , 187 . However, panmictic microorganisms, such as the gonococcus, that undergo mutation and frequent recombinational exchanges, do not allow stable clones to emerge due to the randomization of alleles within a population. Consequently, this complicates epidemiological characterization. Also, as surface-exposed antigens that are used for serotyping also tend to evolve rapidly due to strong diversifying selection placed on them by the host immune system, this further compounds the problem 185 . Given the above problems, it became necessary to index genes that only undergo neutral variation in order to investigate population structure, which led to analysis being focused on housekeeping genes involved in central metabolism 188 . Consequently, novel methods of molecular typing were then devised to define outbreaks based on either local or global epidemiology 164 .

Multilocus enzyme electrophoresis (MLEE) - 90’s

The advent of multilocus enzyme electrophoresis (MLEE) allowed for the presence or absence of linkage disequilibrium within a population to be monitored via deviations between multiple chromosomal alleles 188 , 189 , 190 , 191 . Indeed, this approach allowed for global epidemiological studies and permitted the identification of strains with an increased tendency to cause disease 164 . Statistical analysis performed on the electrophoretic types of 227 global N. gonorrhoeae isolates provided evidence of a panmictic population structure, as no single pair of alleles was statistically significant for linkage disequilibrium. Additionally, it was determined that the genetic variability of isolates obtained from the same geographic location was as great as that found between all geographic locations that were analyzed. Consequently, it was concluded that the propensity for individual hosts to carry more than one genotype of N. gonorrhoeae , combined with natural competence for DNA transformation, promoted the highly panmictic nature of this pathogen 189 .

Multilocus sequence typing (MLST) - 90’s

However, MLEE had limitations as it could only detect a small proportion of mutations through differences in electrophoretic mobility 164 , 185 . Therefore, nucleotide sequencing of the core gene set was then introduced leading to multilocus sequence typing (MLST) 164 . This proved to be extremely effective at detecting relationships between identical or closely related isolates by characterizing them on the basis of sequence variation 164 , 192 . While MLST typing could be readily applied to N. meningitidis isolates, it was initially thought that clinical isolates of N. gonorrhoeae could not be used, as gonococcal housekeeping genes appeared to be homologous 164 , 185 , 193 . Also, as frequent recombination occurred within the organism, it was initially believed that the genetic relatedness of distant isolates may become obscured 194 . However, recombinant exchanges must accrue over long time periods for relationships to be masked, and as the field of molecular epidemiology is only concerned with very short evolutionary time scales, any correlations drawn are unlikely to be skewed by recombination 192 . Therefore, MLST studies did show that N. gonorrhoeae isolates could be typed using the same methods applied to N. meningitidis 164 and N. lactamica 18 , 195 . It was through comparison of MLST data among the Neisseriae , that it was postulated that minimal interspecies recombination actually occurs among the housekeeping genes 186 .

eBURST - 2000’s

Typically, MLST allelic profiles were placed into a matrix of pairwise differences which allows for detection of identical or closely related isolates. However, these do not provide the necessary information on the evolutionary descent of genotypic clusters, nor do they identify the founder genotype 192 . Additionally, in bacterial species such as N. gonorrhoeae that undergo frequent recombination, any relatedness that may be implied through the use of pairwise differences is highly suspect and most likely may not be phylogenetically relevant 196 . To account for these concerns, the BURST (based upon related sequence types) algorithm was designed to analyze microbial MLST data by assigning defined sequence types (STs) to lineages which allowed the identification of a putative founder genotype 197 .

The program was further refined with the development of the eBURST algorithm, which differentiates large MLST datasets based on isolates with the most parsimonious descent pattern from the probable founder, and allows for the identification of clone diversification yet also provides insight into the emergence of clinically relevant isolates 192 . Initially, eBURST was used for analysis of quinolone-resistant N. gonorrhoeae (QRNG) 198 . Previous epidemiological studies of quinolone resistance strains of N. gonorrhoeae could not determine if distinct isolates arose due to variation of an original strain or if multiple strains were concomitantly introduced into a specific geographic location 198 , 199 , 200 , 201 . eBURST analysis determined the total number of QRNG strains that entered a country, the divergence of loci, and the time period during which the founder strains evolved 198 . With the combination of MLST and eBURST analysis, disease isolates could now be defined with regard to distribution, population structure, and evolution 202 . Consequently, the origins of pathogenic strains could now be determined as well as how bacterial populations respond to antibiotics and vaccines through analysis of recent evolutionary changes 203 .

CHEMOTHERAPY

Neisseria gonorrhoeae is rapidly evolving and has developed resistance to all previous and current antimicrobials. The recent emergence of multidrug resistant gonococcal isolates in Japan 204 , France 205 , and Spain 206 has provoked major concerns in public health circles worldwide, especially as drug resistance is spreading rapidly 207 . Consequently, we may be entering an era of untreatable gonorrhea. Medications such as penicillin, and later, the fluoroquinolines, have each been used to treat gonorrhea in the past, however, resistance to these antimicrobial agents quickly developed, leaving limited options for gonococcal treatment 208 . Currently, third generation extended-spectrum cephalosporins (ESCs); which include ceftriaxone (injectable form) and cefixime (oral form) are being prescribed. However, resistance to ESCs has also emerged with resistant isolates having been reported in 17 different countries 209 , 210 .

The recent emergence of the first N. gonorrhoeae "superbug" strain in Japan (H041, which was later assigned to MLST ST7363) has been shown to exhibit extremely high-level resistance to all ESCs, including cefixime (MIC= 8 µg/ml), and ceftriaxone (MIC= 2-4 µg/ml) as well as to almost all other available therapeutic antimicrobials 204 . Since the isolation of the H041 strain, other extensive drug resistance (XDR) strains have also been isolated in Quimper, France (F89 strain) 205 as well as in Catalonia, Spain 206 , and both share considerable genetic and phenotypic similarity to the Japanese H041 strain. Unfortunately, transmission of these strains is augmented by the fact that XDR strains have been isolated from commercial sex workers, homosexual men, sex tourists, long distance truck drivers, and people undergoing forced migration, suggesting that these strains have the potential to spread globally 207 .

N. gonorrhoeae are exceptional bacteria that can rapidly evolve to promote adaptation and survival within different niches of the human host. This is facilitated by their natural competence which allows DNA uptake from the environment via transformation, as well as by engaging in bacterial conjugation. Consequently, gonococci can acquire various different types of antimicrobial resistance (AMR), which include drug inactivation, modification of drug targets, changing bacterial permeability barriers, and increasing efflux properties 208 , 209 . The acquisition of AMR genes was initially thought to occur within commensal Neisseria spp. that reside in the pharynx, as pharyngeal organisms are often exposed to antimicrobials, with the fixed mutations then being transferred to gonococci that mingle with the commensal bacteria 211 . Neisseria can also obtain AMR through spontaneous mutations, although such events are comparatively rare. Many resistance determinants originate through the accumulation of chromosomal mutations, with only two known plasmid-borne genes having been described; penicillin resistance associated with the blaTEM plasmid 212 , 213 , 214 and tetracycline resistance associated with the tetM plasmid 215 . Penicillinase-producing strains of Neisseria gonorrhoeae were first isolated in Southeast Asia and in sub-Saharan Africa 176 . However, less than one percent of gonococcal clinical isolates in the US contain the β-lactamase gene, indicating that the major mechanism of penicillin resistance appears to result from accumulation of chromosomal mutations over time 214 . Interestingly, the N. gonorrhoeae tetM conjugative plasmid 216 is not only self-transmissible but is also responsible for transfer of the β-lactamase plasmids to other gonococci, other Neisseria spp., and E. coli 217 , 218 .

Chromosomal-mediated resistance to penicillin, as well as to other ESCs, generally involves modification of the penicillin binding proteins (PBP) coupled with mutations that enhance the efflux and decrease the influx of antimicrobials. Penicillin-resistant gonococcal strains typically contain 5 to 9 point mutations in the penA gene which encodes PBP2, the primary lethal target of the β-lactam antimicrobials 219 , 220 . Penicillin and ESC minimum inhibitory concentrations (MICs) can also be elevated in strains carrying mtrR and penB mutations which increase efflux and decrease influx of the antimicrobials, respectively 204 , 205 . Surprisingly, synergy between mtrR and penB mutations appears to have very little impact on resistance to cefixime which is mainly conferred by penA mosaic alleles 221 .

Once acquired, resistance determinants contributing to decreased susceptibility or resistance to certain antibiotics are stably carried within Neisseria populations even when the antibiotic is withdrawn from treatment regimens 208 . The persistence of resistance determinants also suggests that these factors do not cause a negative impact on the biological fitness of the gonococcus. In fact, antibiotic resistance can be linked with enhanced fitness as demonstrated with the MtrCDE efflux system that contributes to gonococcal virulence and survival during an infection 222 , 223 . This efflux pump can recognize and expel not only hydrophobic antibiotics such as penicillin, ESCs, macrolides, tetracycline, and ciprofloxacin 224 , 225 , 226 , but also antimicrobial compounds from the innate host response such as antimicrobial peptides, bile salts, and progesterone, allowing the bacteria to survive within host cells 227 .

Future directions

Due to the lack of an efficacious vaccine, control of gonococcal infections relies on appropriate antibiotic treatment, coupled with prevention, proper diagnosis, and epidemiological surveillance. Recently, novel dual antimicrobial therapy, e.g. ceftriaxone and azithromycin 228 , 29 or gentamicin and azithromycin 230 combination treatment, has been evaluated for treatment of uncomplicated gonorrhea. However, the emergence of concomitant resistance to the available antimicrobials has again compromised such an approach 207 , 208 , 228 , 231 .

Previously developed antibiotics, including gentamicin, solithromycin, and ertapenem, are also now being considered as clinical isolates show a high degree of sensitivity to these antibiotics in vitro 232 , 233 . The carbapenem, ertapenem, is potentially an option for ceftriaxone -resistant N. gonorrhoeae as these strains display relatively low MICs when treated with this agent 234 . However, regimens with ertapenem are only applicable if ertapenem and ceftriaxone do not share the same resistance mechanism such as strains carrying certain penA , mtrR , and penB mutations which coincided with increased carbapenem MICs 209 , 234 . Consequently, using these antimicrobials may only provide a short-term solution for combating multidrug-resistant gonorrhea 207 .

To counteract this problem, new antibiotics are being developed for anti-gonococcal therapy. The novel macrolide-family of antibiotics, such as bicyclolides modithromycin (EDP-420) and EDP-322, display high activity against azithromycin-, ESC-, and multidrug-resistant gonococcal isolates in vitro . However, these macrolide drugs appear to cause some cross-resistance with high-level azithromycin resistance 235 . The tetracycline derivatives, glycylcycline tigecycline and fluorocycline eravacycline (TP-434), have also been shown to be effective against ceftriaxone-resistant gonococci in vitro , yet, concerns remain regarding their usage and effectiveness 236 , 237 . Recently, new broad-spectrum fluoroquinolones, such as avarofloxacin (JNJ-Q2) 238 , delafloxacin, sitafloxacin 239 , and WQ-3810 240 , have displayed high potency against multidrug-resistant gonococcal isolates in vitro including ciprofloxacin-resistant strains. Finally, the lipoglycopeptide dalbavancin and 2-acyl carbapenems, SM-295291 and SM-369926, are among potential antimicrobials that can be used in gonorrhea treatment to a limited extent 241 .

Current research has centered on exploring novel antimicrobials or compounds designed to inhibit new targets. Among these newly developed agents are a protein inhibitor (pleuromutilin BC-3781), a boron-containing inhibitor (AN3365) 242 , efflux pump inhibitors, which enhance susceptibility to antimicrobials, host innate defense components and toxic metabolites 226 , 243 , non-cytotoxic nanomaterials 244 , host defense peptides- LL-37 (multifunctional cathelicidin peptide) 245 , molecules that mimic host defensins, LpxC inhibitors 246 , species-specific FabI inhibitors (MUT056399) 247 , and inhibitors of bacterial topoisomerases (VT12-008911 and AZD0914) both of which target alternative sites other than the fluoroquinolone-binding site 248 . Importantly, all these compounds possess potent in vitro activity against multidrug-resistant gonococcal strains 208 , 249 . The novel spiropyrimidinetrione antibacterial compound (AZD0914) which inhibits DNA biosynthesis 250 appears to be extremely promising, as no emerging resistance has been observed in diverse multidrug-resistant gonococcal isolates 235 . Consequently, AZD0914 is being seriously considered for its potential use as future oral treatment for gonococcal infections especially as it lacks cross-resistance exhibited by other fluoroquinolone antibiotics 251 .

Ideally, the future treatment for gonorrhea will rely on individually-tailored regimens as clinical isolates will hopefully be rapidly characterized by novel phenotypic AMR tests and rapid genetic point-of-care antimicrobial resistance tests. Unfortunately, no commercial molecular diagnostic kit is currently available to detect AMR determinants in gonococci, with the current genetic assays lacking sensitivity and specificity 249 , 252 . Meanwhile, healthcare initiatives need to be immediately undertaken to postpone the further widespread dissemination of ceftriaxone-resistant N. gonorrhoeae strains. These measures should include conducting AMR surveillance on global, national, as well as local scales, identifying treatment failures, monitoring the susceptibility of gonococcal isolates to prescribed antibiotics, and using appropriate and effective antibiotics with optimized quality and doses in gonorrhea treatment regimens 209 .

Funding Statement

Dedicated to the memory of John Swanson.

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• PMID: 32644329
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Neisseria gonorrhoeae , an obligate human pathogen, is a sexually transmitted disease that causes consequential worldwide morbidity both in resource-abundant and resource-limited nations, and its diagnosis and treatment require costly expenditures annually. Like other sexually transmitted infections (STIs), gonorrhea disproportionately impacts young adult populations. An ancient disease with biblical references (Hebrew Bible; Leviticus 15:1-3), gonorrhea has many slang references, including “the clap,” which likely derived from the name of the ancient Parisian red-light district Les Clapiers.

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Management of Gonorrhea in Adolescents and Adults in the United States

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Sarah Kidd, Kimberly A. Workowski, Management of Gonorrhea in Adolescents and Adults in the United States, Clinical Infectious Diseases , Volume 61, Issue suppl_8, December 2015, Pages S785–S801, https://doi.org/10.1093/cid/civ731

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Gonorrhea is the second most commonly reported notifiable disease in the United States and is associated with serious health sequelae, including pelvic inflammatory disease, infertility, and ectopic pregnancy. Treatment for gonorrhea has been complicated by antimicrobial resistance. Neisseria gonorrhoeae has developed resistance to each of the antimicrobials that were previously recommended as first-line treatment regimens, and current treatment options are severely limited. This article summarizes the key questions and data that were discussed at the Sexually Transmitted Diseases (STD) Treatment Guidelines Expert Consultation meeting in April 2013, and the rationale for the 2015 Centers for Disease Control and Prevention STD treatment guidelines for gonococcal infections in adolescents and adults. Key issues addressed include whether to change the dosage of ceftriaxone and azithromycin used in the recommended dual treatment regimen, whether to continue to list dual treatment with cefixime and azithromycin as an alternative treatment regimen, and management of gonococcal infections in persons with severe cephalosporin allergy or suspected treatment failure.

Gonorrhea, a sexually transmitted infection, is the second most commonly reported notifiable disease in the United States [ 1 ], with a total of 333 004 new cases reported to the Centers of Disease Control and Prevention (CDC) in 2013 [ 2 ]. However, because many infections are never diagnosed or reported, the true burden of gonococcal infection is likely significantly higher. It is estimated that >800 000 new gonococcal infections occur in the United States each year [ 3 ]. Although the national gonorrhea rate has declined substantially from its peak in 1975 (464.1 cases per 100 000 population) and reached an all-time low in 2009 (98.1 cases per 100 000), the rate subsequently increased each year during 2010–2012, and plateaued at 106.1 cases per 100 000 population in 2013 [ 2 ]. High gonorrhea rates continue to be observed in certain demographic groups and geographic areas. In particular, adolescents aged 15–19 years (337.5 cases per 100 000 population), young adults aged 20–24 years (500.5 cases per 100 000 population), non-Hispanic blacks (426.6 cases per 100 000 population), and residents of the Southern United States (128.6 cases per 100 000 population) bear the highest burden of disease [ 2 ].

Timely and effective treatment is an essential component of gonorrhea control programs. It reduces transmission in the community by shortening the duration of infection and decreases the risk of serious health sequelae, including pelvic inflammatory disease, infertility, and ectopic pregnancy [ 4 ]. Unfortunately, treatment for gonorrhea has been complicated by antimicrobial resistance. Neisseria gonorrhoeae has progressively developed resistance to each of the antimicrobials that were previously recommended as first-line treatment regimens, and current treatment options are severely limited [ 5 ]. In 2013, the CDC hosted a meeting with expert consultants to review the most recent data on gonococcal antimicrobial susceptibility, review the most recent data on treatment effectiveness, and make recommendations for the management of gonorrhea in adolescents and adults in the United States. This paper summarizes the evidence discussed at the meeting and the rationale for the 2015 CDC Sexually Transmitted Diseases (STD) treatment guidelines for gonococcal infections in adolescents and adults.

The CDC hosted a STD Treatment Guidelines Expert Consultation meeting in April 2013, where >60 experts in the fields of STD, infectious disease, epidemiology, and medicine discussed the latest developments in STD clinical and preventive services. In preparation for the meeting, 9 key questions on the management of gonococcal infections were developed based on input solicited from partners at state and local health departments and expert consultants. To address the key questions, a PubMed search for relevant articles published since 2008 (previous treatment guidelines meeting) through 9 March 2013 was conducted using the search terms “(gonorrhea or gonorrhoeae or gonorrrhoea or gonococcus or gonococcal) AND (treatment or therapy or resistance or antibiotics or failure)” and was restricted to abstracts or articles written in English. References listed in the retrieved articles were also searched for other relevant articles and abstracts. Additional data on national or regional gonococcal susceptibility were obtained from reports published on the websites of internationally recognized public health agencies and directly from the US Gonococcal Isolate Surveillance Project (GISP). GISP is a sentinel surveillance system, located in 25–30 cities throughout the United States, that monitors gonococcal antimicrobial susceptibility among urethral isolates obtained from men with urethritis [ 6 ]. Relevant data from these articles and reports were reviewed, summarized, and presented to a group of expert consultants at the April 2013 meeting. Preliminary answers to the 9 key questions and proposed recommendations were drafted based on available evidence or, when data were insufficient, expert opinion. Below is a list of key questions discussed, a summary of the data available for each question, and an overview of the discussion and recommendations resulting from each question.

In July 2013, the results of a clinical trial evaluating 2 new dual treatment regimens for gonorrhea were presented at an international conference and subsequently published [ 7 , 8 ]. In September 2013, a subset of the expert consultants met to discuss the data from the trial, and amended the proposed recommendations based on the new evidence. These data and revised recommendations are included in the following discussion.

Key Question 1. Are There Any Data to Suggest That There Should Be a Change in the Recommended Dosage of Ceftriaxone or Azithromycin for the Treatment of Uncomplicated Urethral, Cervical, or Rectal Gonococcal Infections?

At the time of the 2013 guidelines meeting, the CDC recommendation for treatment of uncomplicated gonococcal infection of the cervix, urethra, and rectum was dual treatment with ceftriaxone 250 mg intramuscularly as a single dose and either azithromycin 1 g orally as a single dose or doxycycline 100 mg orally twice daily for 7 days; azithromycin was preferred over doxycycline as the second antimicrobial, owing to the high prevalence of tetracycline resistance among gonococcal isolates in the United States [ 2 , 9 ]. However, other countries have recommended higher doses of ceftriaxone and/or azithromycin than those recommended by the CDC [ 10–12 ].

Ceftriaxone Clinical Effectiveness Data

The CDC has traditionally used the criteria of ≥95% effectiveness, and a lower 95% confidence interval (CI) bound of ≥95% effectiveness, for recommended treatment regimens [ 13 , 14 ]. According to summed data from clinical trials published in the 1980s and early 1990s, the effectiveness of ceftriaxone 250 mg for uncomplicated urethral, cervical, and rectal gonococcal infections is 99.2% (95% CI, 98.8%–99.5%) (Table 1 ) [ 21 ]. There are no new clinical trial data on the efficacy of ceftriaxone 250 mg. A literature review identified 2 recent studies assessing the clinical effectiveness of ceftriaxone at higher doses: one evaluated ceftriaxone 500 mg and one evaluated ceftriaxone 1 g. The evaluation of ceftriaxone 500 mg reported a cure rate of 90% in 100 patients with urethral or cervical infection [ 16 ]. However, this study did not use standard bacteriologic criteria to confirm gonococcal infection and treatment failure, and these results should be interpreted with caution. The evaluation of ceftriaxone 1 g demonstrated a cure rate of 100% in 48 patients with urethral or cervical gonococcal infection [ 17 ].

Clinical Effectiveness Data for the Treatment of Uncomplicated Gonococcal Infections of the Urethra, Cervix, or Rectum

Abbreviations: CI, confidence interval; IM, intramuscularly; IV, intravenously; MIC, minimum inhibitory concentration; PO, orally.

a Failure defined as persistence of symptoms with presence of gram-negative diplococci and pus on day 5 following treatment; no comment on evaluation for reexposure.

Ceftriaxone Susceptibility Data

In general, for an antimicrobial to meet the ≥95% clinical effectiveness criterion, ≥95% of gonococcal infections must be susceptible to the antimicrobial. Accordingly, although the correlation between in vitro resistance and clinical treatment failure is imperfect, in the past the CDC has changed treatment guidelines when the prevalence of resistance to a recommended antimicrobial reached ≥5% in the population [ 14 ]. The in vitro minimum inhibitory concentration (MIC) breakpoints that correspond to cefixime and ceftriaxone resistance have not been defined, but the Clinical and Laboratory Standards Institute (CLSI) defines decreased susceptibility to ceftriaxone as an MIC ≥0.5 µg/mL [ 23 ]. The proportion of GISP isolates with decreased susceptibility to ceftriaxone has remained <0.1% (Table 2 ). While increases in cephalosporin MICs were observed worldwide during 2000–2010 [ 9 , 24–26 ], ceftriaxone MICs in the United States during 2011–2013 were similar to ceftriaxone MICs during 1987–2000, when the majority of the ceftriaxone clinical trials were conducted (Table 2 ).

Ceftriaxone Minimum Inhibitory Concentrations in the Gonococcal Isolate Surveillance Project, United States, 1987–2013

Source: Gonococcal Isolate Surveillance Project, unpublished data.

Abbreviations: MIC 50 , minimum concentration needed to inhibit 50% of isolates; MIC 90 , minimum concentration needed to inhibit 90% of isolates.

Worldwide, a total of 4 isolates with very high ceftriaxone MICs (MICs 1–4 µg/mL) have been identified (Table 3 ) [ 33 , 37 , 38 , 42 , 43 ]. The first of these was associated with a pharyngeal infection and ceftriaxone 1 g treatment failure. The other 3 were associated with urethral or rectal infections that were treated with antimicrobials other than ceftriaxone. No other isolates with ceftriaxone MICs in this range or higher have been reported.

Cefixime Treatment Failures, Ceftriaxone Treatment Failures, and Additional Reports of High-Level Cefixime or Ceftriaxone Resistance

Abbreviations: IM, intramuscularly; IV, intravenously; MIC, minimum inhibitory concentration; PO, orally.

a Pretreatment and posttreatment isolates from 2 of these cases had discordant antibiograms, suggesting that these 2 cases were reinfections, not treatment failures.

b One urethral infection originally treated with cefixime 400 mg and doxycycline also failed retreatment with cefixime 400 mg PO × 1.

c One rectal infection originally treated with cefixime 400 mg PO × 1 also failed retreatment with cefixime 800 mg PO × 1.

d This rectal infection, originally treated with cefixime 800 mg, also failed retreatment with cefixime 400 mg PO × 1 plus doxycycline 100 mg PO twice daily × 7 days.

Case Reports of Ceftriaxone Treatment Failures

There have been no reported cases of ceftriaxone treatment failure for urethral, cervical, or rectal infection, and no reported cases of ceftriaxone treatment failure at any anatomic site in the United States (Table 3 ). While ceftriaxone treatment failure for pharyngeal infection has been reported at MICs as low as 0.016 µg/mL [ 36 ], pharyngeal infection is known to be more difficult to eradicate, and treatment failure at this site does not necessarily indicate antimicrobial resistance [ 22 ].

Pharmacokinetic Estimates of Ceftriaxone Effectiveness

A pharmacodynamic modeling study published in 2010 predicted that treatment failures with ceftriaxone 250 mg would be likely at ceftriaxone MICs of 0.125–0.25 µg/mL [ 44 ]. However, clinical data on the ceftriaxone MIC breakpoint that is correlated with treatment failure for urethral, cervical, or rectal infection are lacking.

Rationale for Dual Treatment

Prior to the 2010 STD treatment guidelines, administration of a second antimicrobial was recommended for patients with gonococcal infection to provide treatment for Chlamydia trachomatis infection, which frequently co-occurred with gonococcal infection [ 45 ]. Since the publication of the 2010 treatment guidelines, dual treatment that included either azithromycin or doxycycline has been recommended for all patients with gonococcal infection, regardless of the presence of chlamydial coinfection [ 46 ]. The primary rationale for recommending dual treatment is that it may enhance treatment effectiveness and prevent further transmission of a resistant organism. In addition, coadministration of 2 antimicrobials with different mechanisms of action may also hinder the development of resistance.

Recent recommendations have stated that azithromycin was preferred over doxycycline as the second antimicrobial owing to the high prevalence of tetracycline resistance among gonococcal isolates in the United States [ 9 , 47 ]. In 2013, 23.7% of GISP isolates were resistant to tetracycline [ 2 ].

Azithromycin Clinical Effectiveness Data

Based on summed data from clinical trials, monotherapy with azithromycin 1 g cures 97.6% of uncomplicated gonococcal infections of the urethra, cervix, or rectum (95% CI, 95.7%–98.9%), and monotherapy with azithromycin 2 g cures 99.2% of these infections (95% CI, 97.3%–99.9%) (Table 1 ) [ 14 ]. For urethral and cervical infections, a more recent review estimated that the clinical effectiveness of azithromycin 1 g was 96.5% (95% CI, 94.3%–97.6%) if retrospective studies were excluded and 97.0% (95% CI, 95.2%–97.9%) if retrospective studies were included [ 15 ]. The same review estimated that azithromycin 2 g cured 99.0% (95% CI, 97.5%–99.6%) of urethral or cervical infections.

Azithromycin Susceptibility Data

Azithromycin MICs among US GISP isolates appear to have slightly increased from the early 1990s, when the majority of azithromycin clinical studies were conducted, to 2011–2013 (Table 4 ). However, interpretation of these data is complicated by the use of a new media formulation beginning in 2005, which may have resulted in a one-dilution increase in azithromycin MIC results [ 48 ].

Azithromycin Minimum Inhibitory Concentrations in the Gonococcal Isolate Surveillance Project, United States, 1992–2013

In 2005, the Gonococcal Isolate Surveillance Project began using a new media formulation for azithromycin susceptibility testing, which resulted in a one-dilution increase in azithromycin MICs.

The MIC breakpoint that defines resistance or that correlates with clinical treatment failure has not been defined for azithromycin, and CLSI has not established an MIC breakpoint that defines decreased susceptibility to azithromycin. In GISP, isolates with azithromycin MICs ≥2 µg/mL are considered to have elevated MICs [ 6 ]. The percentage of GISP isolates with elevated azithromycin MICs has remained <1% (Table 4 ). However, of concern, sporadic cases of high-level azithromycin resistance (MICs ≥256 µg/mL) have been identified in the United Kingdom, Italy, Argentina, Hong Kong, and the United States [ 49–54 ].

Case Reports of Azithromycin Treatment Failures

There have been multiple reports of azithromycin treatment failures since the 1990s, but these are infrequently associated with higher azithromycin MICs and so do not necessarily indicate failure due to antimicrobial resistance [ 32 , 55–60 ]. Urethral and cervical infection treatment failures have been associated with pretreatment azithromycin MICs of 0.06–0.5 µg/mL following treatment with azithromycin 1 g and MICs of 0.25–1 µg/mL following treatment with azithromycin 2 g.

Other Considerations for Azithromycin Dosing

Other considerations for azithromycin include the ease with which N. gonorrhoeae develops resistance to macrolides when given as monotherapy. Most recently, a case report documented the rapid emergence of resistance (MIC increased from 1 µg/mL to 8 µg/mL) following a single 2-g dose of azithromycin [ 60 ].

In addition, when considering increasing the dual treatment dose of azithromycin from 1 g to 2 g as part of a dual treatment regimen, a tradeoff exists between the possible benefit of increasing the cure rate and the risk of increasing the frequency or severity of adverse effects. Depending on formulation, studies using azithromycin 2 g as a single dose report vomiting in 0.7%–7.0% of patients and gastrointestinal symptoms in up to 24.4%–35.3% [ 61–63 ]. In comparison, azithromycin 1 g as a single dose is generally associated with fewer and milder gastrointestinal symptoms, and studies using a 1-g dose report any adverse effect in <10% of patients [ 55 , 56 , 59 ].

Recommendations

The available clinical data indicate that ceftriaxone 250 mg is effective in approximately 99% of uncomplicated urethral, cervical, and rectal gonococcal infections. There are no clinical data to support the administration of ceftriaxone at higher doses than 250 mg. Therefore, dual treatment for gonorrhea that includes ceftriaxone at the 250-mg dose is recommended for the treatment of uncomplicated urethral, cervical, and rectal gonococcal infections.

When azithromycin 1 g is given as part of a dual treatment regimen with ceftriaxone, development and subsequent transmission of azithromycin resistance is unlikely. Therefore, based on the effectiveness of azithromycin 1 g and the increased adverse effects associated with the 2 g dose, azithromycin 1 g should be used when given as part of a dual treatment regimen with ceftriaxone.

Last, given the prevalence of tetracycline resistance among US GISP isolates, doxycycline is no longer recommended for use as the second antimicrobial for treatment of gonococcal infections. The recommended regimen for uncomplicated urethral, cervical, or rectal gonococcal infection is dual treatment with ceftriaxone 250 mg intramuscularly as a single dose and azithromycin 1 g orally as a single dose.

Key Question 2. Should Cefixime or Any Oral Cephalosporin Continue to Be Recommended as an Alternative Treatment for Urethral, Cervical, or Rectal Gonococcal Infections?

In 2012, CDC treatment guidelines were updated so that cefixime was no longer recommended as first-line treatment for gonorrhea [ 9 ]. This change was made based on observations that the overall percentage of GISP isolates with elevated cefixime MICs (MIC ≥0.25 µg/mL) had increased from 0.1% in 2006 to 1.5% during January–August 2011. Of particular concern was that the percentage of isolates with elevated cefixime MICs in the West increased from 0.2% to 3.2%, and the percentage among gay, bisexual, and other men who have sex with men (collectively referred to as MSM) in the West increased from 0.1% to 4.5%. Although the cefixime MIC breakpoints that correlate with clinical treatment failure have not been defined, there was concern that this pattern indicated early stages of the development of clinically significant gonococcal resistance to cefixime, and the rising cefixime MICs would soon result in declining effectiveness of cefixime. Additionally, there was concern that, as cefixime became less effective, its use might hasten the development of resistance to ceftriaxone. Although cefixime was no longer included as part of the recommended treatment regimen, CDC continued to list dual treatment with cefixime 400 mg orally as a single dose and either azithromycin 1 g orally as a single dose or doxycycline 100 mg orally twice daily for 7 days as an alternative regimen for gonococcal infections of the urethra, cervix, or rectum when ceftriaxone is not available.

Cefixime Clinical Effectiveness Data

Based on summed data from clinical trials published in the 1980s and 1990s, the effectiveness of cefixime 400 mg for urethral, cervical, and rectal gonococcal infections is 97.5% (95% CI, 95.4%–98.8%) [ 14 ]. The only recent data on cefixime effectiveness come from a retrospective analysis of gonococcal infections at any anatomic site (urethral, cervical, rectal, or pharyngeal) that were treated with a variety of cefixime-based regimens (cefixime 400 mg or 800 mg; some patients also received either azithromycin or doxycycline) (Table 1 ) [ 20 ]. Overall, in this analysis cefixime-based regimens cured 93.2% of gonococcal infections among patients who returned for test of cure, but cefixime effectiveness varied depending on cefixime MIC. Among patients who returned for test of cure, cefixime-based regimens successfully cured 98.1% of infections associated with a cefixime MIC <0.12 µg/mL, but only 75.0% of infections associated with a cefixime MIC ≥0.12 µg/mL (relative risk of treatment failure, 13.1 [95% CI, 2.9–59.7]). The authors also performed a secondary analysis to account for possible bias resulting from limiting the analysis to patients who returned for test of cure. If all patients who were treated were included in the analysis and it was assumed that no treatment failures occurred among those who did not return for tests of cure, cefixime-based regimens cured 99.1% of infections associated with a cefixime MIC <0.12 µg/mL, and 88.1% of infections associated with a cefixime MIC ≥0.12 µg/mL (relative risk of treatment failure 13.8 [95% CI, 2.9–64.5]).

Cefixime Susceptibility Data

The MIC breakpoint that corresponds to cefixime resistance and treatment failure has not been defined, but CLSI defines decreased susceptibility to cefixime as a cefixime MIC ≥0.5 µg/mL [ 23 ]. The proportion of US GISP isolates with decreased susceptibility to cefixime (MIC ≥0.5 µg/mL) has remained ≤0.1% (Table 5 ). In contrast, the proportion of GISP isolates with elevated cefixime MICs (MIC ≥0.25 µg/mL) has increased from 0.1% during 2001–2005 to 0.9% during 2011–2013. The proportion of isolates with MICs ≥0.125 µg/mL, the MIC threshold associated with increased risk of treatment failure [ 20 ], increased from 0.7% during 2001–2005 to 2.7% in 2011–2013.

Cefixime Minimum Inhibitory Concentrations in the Gonococcal Isolate Surveillance Project, United States, 1992–2013

a Cefixime susceptibility testing was not conducted during 2007–2008.

Case Reports of Cefixime Treatment Failures

Globally, cefixime treatment failures following treatment with cefixime 400 mg have generally been associated with cefixime MICs of 0.12–4 µg/mL [ 20 , 30–34 ] (Table 3 ). However, at least one study has reported cefixime treatment failures at MICs as low as ≤0.03 µg/mL [ 20 ].

Recommendation

Clinical data from a recent retrospective analysis and from documented cefixime treatment failures suggest that gonococcal infections with cefixime MICs ≥0.125 µg/mL are associated with a higher risk of treatment failure compared to those with MICs <0.125 µg/mL. Given the increase in cefixime MICs observed in the last decade, ceftriaxone is clearly preferable to cefixime for the treatment of gonococcal infections. However, there are no data to suggest that the clinical effectiveness of dual treatment with cefixime and azithromycin for urethral, cervical, and rectal gonococcal infections is <95% in the United States. Recognizing that there are circumstances where ceftriaxone is not available or where an injection is not possible, and that treatment with a cefixime-based dual treatment regimen is preferable to no treatment, dual treatment with cefixime 400 mg orally as a single dose and azithromycin 1 g orally as a single dose will continue to be an alternative regimen for the treatment of uncomplicated urethral, cervical, and rectal gonococcal infections when ceftriaxone is not available.

Key Question 3. Should Dual Treatment With Cefixime and Azithromycin Be Recommended for Expedited Partner Therapy (EPT)? Are There Any Data to Support Use of Azithromycin 2 g Over Azithromycin 1 g in Combination With Cefixime for EPT?

The 2012 update to CDC gonorrhea treatment guidelines recommended that EPT be considered for heterosexual partners of a patient with gonorrhea if they cannot be linked to evaluation and treatment in a timely fashion. In this scenario, EPT using dual treatment with cefixime 400 mg orally as a single dose and azithromycin 1 g orally as a single dose would be delivered to the partner by the patient, a disease investigation specialist, or through a collaborating pharmacy. The legal status of EPT varies by state. EPT has been shown to reduce the rate of reinfection among index patients and increase rates of partner treatment in clinical trials [ 64 ]. However, EPT requires an oral regimen, and given recent concerns about the continued effectiveness of cefixime, some have questioned whether the advantages of EPT outweigh the potential increased risk of treatment failures associated with a cefixime-based dual treatment regimen.

In practice, EPT must be prescribed without knowing the partner's complete history of sexual exposure, and there are no population data or estimates of the proportion of partners that are infected at different anatomic sites. It is therefore important to consider the effectiveness of an EPT regimen for urethral, cervical, and rectal infections, as well as pharyngeal infections. The previous question addressed the data on cefixime effectiveness for urethral, cervical, and rectal infections and concluded that dual treatment with cefixime and azithromycin should continue to be listed as an alternative treatment regimen in situations when ceftriaxone is not available (see Key Question 2). For pharyngeal infections, older summed clinical trials data estimate that monotherapy with cefixime 400 mg cures 92.3% (95% CI, 74.9%–95.7%), while ceftriaxone 250 mg cures 99.0% (95% CI, 94.4%–100%) of gonococcal infections of the pharynx (Table 6 ) [ 21 ]. More recent data on the effectiveness of cefixime for pharyngeal infections, and all data on the effectiveness of dual treatment regimens for pharyngeal infections, are limited to retrospective studies among the relatively small subset of persons who returned for test of cure. However, some retrospective data suggest that the effectiveness of dual treatment with an oral cephalosporin (either cefixime 400 mg or cefpodoxime 400 mg) in combination with azithromycin 1 g (93.0%) is comparable to the effectiveness of ceftriaxone 125–250 mg monotherapy (90.9%) or dual treatment with ceftriaxone 125–250 mg and either azithromycin 1 g or doxycycline (88.7%) [ 65 ].

Clinical Effectiveness Data for the Treatment of Uncomplicated Gonococcal Infections of the Pharynx

Data on the comparative effectiveness of azithromycin 1 g vs azithromycin 2 g as monotherapy, as well as their potential adverse effects, are reviewed elsewhere (see Key Question 1 for urethral, cervical, and rectal infections, and Key Question 7 for pharyngeal infections). There are no data comparing the effectiveness of dual treatment with cefixime and azithromycin 1 g vs dual treatment with cefixime and azithromycin 2 g for gonococcal infections at any anatomic site (Tables 1 and 6 ).

EPT increases rates of partner treatment and reduces reinfections among index patients. Although there are concerns about the effectiveness of cefixime-based regimens for the potential treatment of pharyngeal infection when used as EPT, these are outweighed by concerns that failure to use EPT will result in fewer partners receiving treatment. Based on these considerations, as well as the data presented in Key Question 2 that support continued use of dual treatment with cefixime and azithromycin as an alternative regimen for urethral, cervical, and rectal infections in settings where ceftriaxone is not available, dual treatment with cefixime 400 mg orally as a single dose and azithromycin 1 g orally as a single dose will continue to be recommended for EPT.

Key Question 4. Are There Any Other Drugs or Drug Regimens Besides Those Listed in the 2012 Update to the Treatment Guidelines That Can Be Recommended as First-line or Alternative Treatment for Gonorrhea?

At the time of the guidelines meeting, a literature search of studies published since 2008 did not identify any clinical trials for novel gonorrhea treatment regimens (Table 1 ). A systematic review of previously published clinical trials of gentamicin calculated that intramuscular gentamicin 240 mg or 280 mg had a pooled cure rate of 91.5% (95% CI, 88.1%–94.0%) [ 18 ] for urethral or cervical infection, lower than the CDC clinical effectiveness criterion. In addition, 2 studies assessed the clinical effectiveness of intramuscular spectinomycin 2 g for urogenital infection, and reported cure rates of 94% and 96.7% [ 16 , 19 ]. These data are consistent with older summed clinical trials data which estimate that the clinical effectiveness of spectinomycin is 98.2% (95% CI, 97.6%–99.9%) for urethral, cervical, and rectal gonococcal infections [ 21 ]. However, spectinomycin has poor efficacy against pharyngeal infection (51.8% [95% CI, 38.7%–64.9%]) (Table 6 ) [ 21 ], and is not currently available in the United States.

Following the guidelines meeting, the results of a clinical trial evaluating 2 new dual treatment regimens (dual treatment with gemifloxacin 320 mg orally as a single dose and azithromycin 2 g orally as a single dose, or dual treatment with gentamicin 240 mg intramuscularly as a single dose and azithromycin 2 g orally as a single dose) were published [ 8 ]. For urethral and cervical infections, this trial demonstrated that dual treatment with gemifloxacin and azithromycin cured 99.5% of infections (lower 95% CI bound, 97.6%) and dual treatment with gentamicin and azithromycin cured 100% of infections (lower 95% CI, bound 98.5%). Dual treatment with gemifloxacin and azithromycin also cured 15 of 15 pharyngeal and 5 of 5 rectal infections; dual treatment with gentamicin and azithromycin cured 10 of 10 pharyngeal and 1 of 1 rectal infections. Gastrointestinal adverse events were common with both regimens. Overall, 7.7% of patients given dual treatment with gemifloxacin and azithromycin and 3.3% of patients given dual treatment with gentamicin and azithromycin vomited within 1 hour of medication administration, necessitating retreatment with a different regimen.

Since 2008, there have been many published studies of in vitro activity of various agents against N. gonorrhoeae . Few agents have showed enough promise to warrant clinical trials. Notable agents tested in vitro include solithromycin [ 69 , 70 ], delafloxacin and other novel quinolones [ 71–75 ], ertapenem [ 76 ], and novel carbapenems [ 77 ]. Of these, only solithromycin and delafloxacin have progressed to phase 3 clinical trials (ClincalTrials.gov identifiers NCT02210325 and NCT02015637, respectively).

Based on data that became available after the treatment guidelines meeting, 2 new dual treatment regimens (dual treatment with gemifloxacin 320 mg orally as a single dose and azithromycin 2 g orally as a single dose, or dual treatment with gentamicin 240 mg intramuscularly as a single dose and azithromycin 2 g orally as a single dose) may be considered as alternative treatment options, but gastrointestinal adverse events may limit their use. Because of limited data on the effectiveness of these regimens for rectal and pharyngeal infections, and because of the frequency of gastrointestinal adverse events associated with these regimens, dual treatment with cefixime 400 mg orally as a single dose and azithromycin 1 g orally as a single dose is the preferred alternative regimen for urethral, cervical, and rectal infections if ceftriaxone is not available and the patient is not allergic to cephalosporins.

Key Question 5. What Regimen Should Be Recommended for Persons Who Fail Treatment With the Recommended Regimen (Dual Treatment With Ceftriaxone 250 mg and Azithromycin 1 g)?

Few ceftriaxone treatment failures have been identified worldwide (Table 3 ). Therefore, only minimal clinical experience is available to guide treatment recommendations for treatment failures following the recommended regimen. All documented ceftriaxone treatment failures have been pharyngeal infections, and have successfully resolved with either repeated or higher doses of ceftriaxone, dual treatment with ceftriaxone 250 mg and azithromycin 1 g, or single-dose azithromycin 2 g [ 36–41 ]. Urethral or rectal infections associated with high ceftriaxone MICs (1–2 µg/mL) resolved after treatment with either gentamicin, a course of levofloxacin followed by a multiday course of azithromycin, or a course of doxycycline.

When available, antimicrobial susceptibility results may guide treatment decisions. Other regimens recently demonstrated to have high clinical effectiveness, such as dual treatment with gemifloxacin and azithromycin or dual treatment with gentamicin and azithromycin (see Key Question 4) [ 8 ], may be of use in the management of ceftriaxone treatment failures.

Because the majority of suspected treatment failures are actually reinfections, persons with suspected treatment failure following treatment with the recommended regimen (dual treatment with ceftriaxone 250 mg intramuscularly as a single dose and azithromycin 1 g orally as a single dose) should usually be re-treated with the same regimen. However, in situations with a higher likelihood of treatment failure than reinfection, clinicians should (1) culture relevant clinical specimens and obtain antimicrobial susceptibility testing of any N. gonorrhoeae isolates, and advise the laboratory to retain the isolate(s) for possible further testing; (2) consult an infectious disease specialist, an STD/HIV Prevention Training Center clinical expert, the local or state health department, or CDC for advice on obtaining cultures, obtaining antimicrobial susceptibility testing, and treatment; and (3) report the case to CDC via the state or local health department. Clinicians may consider treating these patients with either dual treatment with gemifloxacin 320 mg orally as a single dose and azithromycin 2 g orally as a single dose, or dual treatment with gentamicin 250 mg intramuscularly as a single dose and azithromycin 2 g orally as a single dose. Clinicians should also obtain a test of cure at the relevant anatomic site 7–14 days after retreatment. Culture is the recommended test for test of cure, preferably with simultaneous nucleic acid amplification test (NAAT). Antimicrobial susceptibility testing should be performed if N. gonorrhoeae is isolated. All sex partners from the preceding 60 days should be evaluated promptly with culture and presumptively treated with the same regimen as the patient.

Key Question 6. What Regimens Should Be Recommended for the Treatment of Uncomplicated Urethral, Cervical, or Rectal Infection in Persons With Severe Cephalosporin Allergy?

At the time of the treatment guidelines meeting, the only available treatment option for patients with severe cephalosporin allergy that met CDC clinical effectiveness criteria was monotherapy with azithromycin 2 g [ 9 , 46 ]. Following the treatment guidelines meeting, the results of a clinical trial demonstrating the effectiveness of dual treatment with gemifloxacin 320 mg orally as a single dose and azithromycin 2 g orally as a single dose or dual treatment with gentamicin 240 mg intramuscularly as a single dose and azithromycin 2 g orally as a single dose were published (see Key Question 4) [ 8 ].

Given new data on the clinical effectiveness of 2 new dual treatment regimens (see Key Question 4) and the theoretical benefit of dual treatment using antimicrobials with different mechanisms of action (see Key Question 1), azithromycin 2 g is no longer recommended as an alternative regimen for persons with severe cephalosporin allergy. Dual treatment with gemifloxacin 320 mg orally as a single dose and azithromycin 2 g orally as a single dose, or dual treatment with gentamicin 240 mg intramuscularly as a single dose and azithromycin 2 g orally as a single dose are potential therapeutic options for these patients.

Key Question 7. Are Current Recommendations Sufficient for Pharyngeal Gonococcal Infection?

At the time of the guidelines meeting, the current (2012) recommendation for uncomplicated gonococcal infections of the pharynx was dual treatment with ceftriaxone 250 mg intramuscularly as a single dose and either azithromycin 1 g orally as a single dose or doxycycline 100 mg orally twice daily for 7 days [ 9 ]. Azithromycin was preferred over doxycycline as the second antimicrobial because of the high prevalence of tetracycline resistance among GISP isolates. There were no alternative regimens listed for treatment of pharyngeal infection.

Clinical Effectiveness Data

Gonococcal infections of the pharynx are more difficult to eradicate than infections of the urethra, cervix, or rectum [ 29 ], and few antimicrobial regimens reliably cure >90% of gonococcal pharyngeal infections (Table 6 ). According to summed data from clinical trials published in the 1980s and 1990s, ceftriaxone 250 mg eradicates 99.0% (95% CI, 94.4%–100%) of pharyngeal infections [ 21 ]. Prospective clinical trials data on azithromycin effectiveness for pharyngeal infections are particularly sparse. Older summed clinical trials data have estimated that the clinical effectiveness of azithromycin 1 g is 100% (95% CI, 29.2%–100%) and the effectiveness of azithromycin 2 g is 100% (95% CI, 82.3%–100%), but these estimates were based on only 3 and 19 infections, respectively [ 13 , 21 ]. A more recent systematic review found that azithromycin 1 g cured 100% (7/7) and azithromycin 2 g cured 97.5% (39/40) of pharyngeal infections [ 15 ].

Review of the literature published since 2008 identified just 2 new prospective clinical trials with data on pharyngeal infections. A clinical trial of ceftriaxone 1 g demonstrated 100% effectiveness in 25 of 25 patients [ 17 ]. In a second trial, dual treatment with gemifloxacin 320 mg and azithromycin 2 g cured 100% (15/15) of pharyngeal infections and dual treatment with gentamicin 240 mg and azithromycin 2 g cured 100% (10/10) pharyngeal infections [ 8 ]. Unfortunately, gastrointestinal adverse events were commonly associated with both dual treatment regimens, potentially limiting their routine use (see Key Question 4).

Several retrospective analyses have attempted to describe the effectiveness of various regimens for the treatment of gonococcal infections of the pharynx [ 65 , 67 , 68 ] (Table 6 ). Overall, dual treatment regimens that include either ceftriaxone or cefixime and azithromycin compare favorably to other regimens evaluated in these analyses. However, interpretation of these data is complicated by limitations associated with retrospective studies; data were restricted to the subset of patients who returned for test of cure, and there were relatively small numbers of infections evaluated for some treatment regimens. In addition, most of these analyses did not report whether patients had been reexposed between treatment and test of cure, so it is possible some apparent treatment failures in these studies were actually reinfections.

Case Reports of Ceftriaxone Treatment Failure

Pharyngeal infection treatment failures following treatment with ceftriaxone 250–500 mg monotherapy have been reported from Australia [ 36 , 40 ], Sweden [ 39 ], and Slovenia [ 41 ], and were associated with ceftriaxone MICs 0.03–0.25 µg/mL (Table 3 ). In addition, a pharyngeal infection treatment failure following treatment with ceftriaxone 1 g monotherapy was documented in Japan in 2009 and was associated with ceftriaxone MICs of 2–4 µg/mL [ 37 , 38 ].

There are insufficient data to suggest that any treatment regimen for gonococcal infections of the pharynx is more effective than dual treatment with ceftriaxone 250 mg and azithromycin 1 g. There are no data comparing the effectiveness of azithromycin 1 g vs 2 g when used in combination with ceftriaxone for treatment of pharyngeal infections. Although newer dual treatment regimens (ie, dual treatment with gemifloxacin and azithromycin or dual treatment with gentamicin and azithromycin) appear promising, there are insufficient data on the effectiveness of these regimens for pharyngeal infections, and the adverse effects associated with these regimens may limit their use in practice. Therefore, dual treatment with ceftriaxone 250 mg intramuscularly as a single dose and azithromycin 1 g orally as a single dose is the recommended regimen for uncomplicated infections of the pharynx.

Key Question 8. Are Current Treatment Recommendations Sufficient for Disseminated Gonococcal Infection?

At the time of the guidelines meeting, the recommended treatment regimen for disseminated gonococcal infection (DGI) without evidence of meningitis or endocarditis was ceftriaxone 1 g given intramuscularly or intravenously every 24 hours [ 46 ]. This regimen was to be continued for 24–48 hours after clinical improvement begins, at which time therapy could be switched to oral cefixime 400 mg twice daily to complete at least 1 week of antimicrobial therapy.

There are no recent studies published on the treatment of DGI. No treatment failures have been reported following treatment with the above regimens.

Given the absence of data on the topic, DGI recommendations are based on expert opinion. Owing to growing concerns over gonococcal antimicrobial resistance, all persons with suspected DGI should have relevant clinical specimens collected for gonococcal culture, and if positive, gonococcal antimicrobial susceptibility testing. Treatment for DGI should be guided by the results of antimicrobial susceptibility testing. Pending antimicrobial susceptibility results, treatment decisions should be made on the basis of clinical presentation. The duration of treatment for DGI has not been systematically studied and should be determined in consultation with an infectious disease specialist.

For DGI without meningitis or endocarditis, the recommended treatment is ceftriaxone 1 g intramuscularly or intravenously every 24 hours plus azithromycin 1 g orally as a single dose. Clinicians may consider switching to an oral agent 24–48 hours after substantial improvement, but choice of oral antimicrobial should be guided by the results of antimicrobial susceptibility testing. The total duration of antimicrobial treatment should be at least 7 days.

For gonococcal meningitis or endocarditis, the recommended treatment is ceftriaxone 1–2 g intravenously every 12–24 hours and azithromycin 1 g orally in a single dose. Parenteral treatment for meningitis should be continued for 10–14 days. Parenteral treatment for endocarditis should be continued for at least 4 weeks.

Key Question 9. Should a Test of Cure Be Performed After Treatment for Gonococcal Infection? If so, Then What Test Should Be Used for Test of Cure and How Soon After Treatment Should Test of Cure Be Performed?

In the 2012 update to the gonorrhea treatment guidelines, test of cure was recommended for (1) persons treated with an alternative regimen and (2) persons with suspected treatment failure following treatment with the recommended regimen [ 9 ]. For persons treated with an alternative regimen, test of cure using culture or NAAT was recommended 1 week after completion of treatment. For patients with suspected treatment failure, culture and antimicrobial susceptibility testing was recommended to document persistent infection and guide therapy, and test of cure was recommended 1 week after completion of retreatment.

Use of Culture Versus NAAT for Test of Cure

The use of culture for test of cure facilitates antimicrobial susceptibility testing. However, the sensitivity of NAATs for detection of N. gonorrhoeae is superior to culture [ 78–84 ]. In practice, gonococcal culture is not readily available, and it is likely that NAATs will be used for test of cure in most settings.

Timing of Test of Cure

Test of cure using NAATs is complicated by the fact that residual nucleic acid from nonviable bacteria can be detected by NAATs for a period of time after successful treatment. There are few data on the duration of persistent N. gonorrhoeae nucleic acid after successful treatment. One study, using a ligase chain reaction (LCR) test that is no longer marketed in the United States, found the median time to a negative urine LCR test was 1 day for men and 2 days for women [ 85 ]. In this study, >90% of tests were negative on day 5 after treatment, but 18% of patients continued to have intermittent shedding of gonococcal nucleic acids after their first negative test. A second study, using an in-house porA pseudogene polymerase chain reaction test, asked persons with urogenital gonorrhea to return for test of cure 4–7 days after treatment and found that 84% (16/19) of those who returned during this interval had a negative test [ 86 ]. Of patients with positive tests of cure, 2 had a negative test when they returned on day 11, and one did not return until day 19, at which time his test was negative. The third and most recent study with data on test of cure evaluated the APTIMA Combo 2 Assay and evaluated MSM who returned for test of cure 3–21 days after treatment [ 87 ]. In this study, tests of cure were positive in no (0/95) urethral infections, 7.4% (10/135) of rectal infections, and 5.2% (7/134) of pharyngeal infections. All positive rectal tests of cure were among persons who were tested within 14 days of treatment; all positive pharyngeal tests of cure were among persons who were tested within 10 days of treatment. Together, these results suggest that residual DNA typically clears from the urogenital site within 7 days, but may persist for longer at extragenital sites.

Culture or NAAT can be used for test of cure. In practice, it is likely that NAATs will be used for test of cure in most settings. If a NAAT test of cure is positive, every effort should be made to obtain confirmatory culture before retreatment, and all positive test of cure cultures should undergo antimicrobial susceptibility testing.

Given the evidence that dual treatment with the alternative treatment regimen (cefixime 400 mg and azithromycin 1 g) is most likely ≥95% effective for treatment of urethral, cervical, or rectal infections (see Key Question 2) as well as concerns about a low positive predictive value of NAAT tests of cure, routine test of cure for persons diagnosed with urogenital or rectal gonorrhea who are treated with the alternative regimen is not recommended. However, because of concerns over cefixime's effectiveness at the pharyngeal site (see Key Question 3), test of cure is recommended for persons diagnosed with pharyngeal infection who are treated with the alternative regimen. Test of cure is also recommended for persons with suspected treatment failure at any anatomic site of infection.

Based on the limited data on appropriate timing of test of cure using NAATs, test of cure should be performed 14 days after treatment in the setting of pharyngeal infections treated with the alternative regimen and 7–14 days after retreatment in the setting of suspected treatment failure.

Further research is needed to inform future recommendations for the optimal management of gonorrhea. Research priorities identified at the 2013 meeting included (1) evaluation of novel oral antimicrobials or novel combinations of antimicrobials for treatment of gonorrhea; (2) pharmacokinetic models for ceftriaxone and azithromycin in the treatment of gonorrhea at urethral, cervical, rectal, and pharyngeal sites; and (3) evaluation of transport media for gonococcal culture, to facilitate access to gonococcal culture and antimicrobial susceptibility testing.

Dual treatment with ceftriaxone 250 mg intramuscularly as a single dose and azithromycin 1 g orally as a single dose is recommended for the treatment of uncomplicated gonorrhea of the urethra, cervix, rectum, or pharynx. For urethral, cervical, and rectal infections, dual treatment with cefixime 400 mg orally as a single dose and azithromycin 1 g orally as a single dose may be used as an alternative regimen when ceftriaxone is not available. Owing to the high prevalence of tetracycline resistance in the United States, doxycycline is no longer recommended as a second antimicrobial in either the first-line or alternative dual treatment regimen. Test of cure will continue to be recommended for persons with pharyngeal infection who receive an alternative treatment regimen, but is no longer recommended for persons with urethral, cervical, or rectal infection who are treated with the alternative regimen. Based on recent data demonstrating the effectiveness of 2 new dual treatment regimens (dual treatment with either gemifloxacin 320 mg orally as a single dose and azithromycin 2 g orally as a single dose, or dual treatment with gentamicin 240 mg intramuscularly as a single dose and azithromycin 2 g orally as a single dose), these regimens may be considered for persons with cephalosporin allergy or for those persons who fail treatment following the recommended regimen. Monotherapy with azithromycin 2 g orally as a single dose is no longer recommended for patients with cephalosporin allergy. Further research to identify new antimicrobials or new combinations of antimicrobials for the treatment of gonorrhea, particularly oral regimens, is urgently needed.

Acknowledgments.  We thank Hunter Handsfield, Ned Hook, Bob Kirkcaldy, Fred Sparling, and Jonathan Zenilman for providing their input on the key questions and their assistance in the development of the treatment guidelines.

Supplement sponsorship.  This article appears as part of the supplement “Evidence Papers for the CDC Sexually Transmitted Diseases Treatment Guidelines,” sponsored by the Centers for Disease Control and Prevention.

Potential conflict of interest.  Both authors: No reported conflicts.

Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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Beymer MR , Llata E , Stirland AM et al.  . Evaluation of gonorrhea test of cure at 1 week in a Los Angeles community-based clinic serving men who have sex with men . Sex Transm Dis 2014 ; 41 : 595 – 600 .

• ceftriaxone
• azithromycin
• gonococcal infection
• centers for disease control and prevention (u.s.)
• treatment failure
• antimicrobials
• treatment guidelines

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