Gonorrhoea

Abstract

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.

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 animals⁸. 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 pathology⁹ 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 tissues¹¹. 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.

Fig. 1: Recommended empirical therapy for gonorrhoea and emergence of AMR in Neisseria gonorrhoeae.

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 UK²⁴¹. 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 age²² (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.

Fig. 2: Estimated new global cases of gonorrhoea in 2016.

Estimated numbers (in millions) of incident cases of gonorrhoea in adults (15–49 years of age) by WHO region²². 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 men²². 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 Spain³³. 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 PrEP³⁷. 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 not³⁸. 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 group⁴¹. 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 others⁴²; 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 cytoplasm⁴³. 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 conditions⁴⁴.

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 cells¹, 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 environment⁷⁰, particularly for modelling pelvic inflammatory disease²¹².

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 field¹⁹³. 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 gonorrhoea²¹³, 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 model²¹⁴. 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.

Genetics

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 strategies⁴⁵. 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 genes⁵⁰. Multilocus sequence typing systems are now available for many different bacterial species⁵¹. 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 found⁵⁵.

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.

Fig. 3: N. gonorrhoeae cell envelope structure.

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 wall²⁴⁴ 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 cell²⁴⁵. 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 machine²⁴⁶. The Opa proteins are a family of integral outer membrane proteins whose expression is stochastically controlled²⁴⁷. 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 menses²⁴⁸, and increased numbers of Opa proteins are expressed during human volunteer infections²⁴⁹. 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 antibodies²⁵⁰. 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 mechanisms⁵⁶, and HGT by DNA transformation⁵⁷. 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 tissues⁵⁸ 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 tissues⁵⁹.

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 haemoglobin⁴³.

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 conjunctiva¹². 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 men⁶⁷. 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 infection⁷² (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 traps⁷³. 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 others⁷³.

Fig. 4: N. gonorrhoeae infection.

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 resistance²⁵¹. 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 infections⁷⁶. Indicative of its extreme host restriction and evolution, N. gonorrhoeae remains sensitive to animal complement system components⁶¹. N. gonorrhoeae uses several mechanisms to limit complement-mediated killing by blocking deposition or activity of several complement factors⁶¹ (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 stream⁷⁷. 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 gonorrhoea⁷⁸. 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 immunosuppressive⁷⁹, 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 response⁸⁰. 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 variations⁸¹. 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 days⁸². The clinical manifestations of gonorrhoea are variable and differ markedly in men and women¹². 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 treatments¹⁴. 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

Microscopy

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 men⁸⁶.

Table 1 Tests for the diagnosis of Neisseria gonorrhoeae

Culture

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 results¹³, 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 sites⁸⁵. 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 standardized⁹⁸.

NAATs

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. gonorrhoeae¹⁰². Few reports have compared the performance of such in-house NAATs with culture or commercially available NAATs¹⁰². 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).

Table 2 FDA-approved and CE-IVD-approved NAATs for the detection of Neisseria gonorrhoeae

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 infection¹⁰⁵, 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 status¹⁰¹. 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.

Table 3 POCTs, near-POCTs and antimicrobial resistance tests available and in the pipeline

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 treatment¹²⁴. 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 PrEP¹²⁹. 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.

Vaccines

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. meningitidis¹³⁶. One of these vaccines, with the trade name MeNZB, was associated with reduced rates of gonorrhoea diagnosis and of hospitalization from gonorrhoea¹³⁶, 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 homologues¹³⁹. 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. gonorrhoeae¹⁴⁰. 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

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 infection¹²⁸. 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 treatment¹²⁸. 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 1940s¹⁴². 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 results¹⁴³. Currently, cefixime plus azithromycin is used for expedited partner therapy for heterosexual men and women¹²⁸. 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 gonorrhoea¹¹⁶. 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 guidelines¹⁰⁹ and in most high-income countries, including European countries⁸², the USA¹²⁸, Canada¹⁴⁴ and Australia¹⁴⁵; however, in some countries (for example, Japan¹⁴⁶ and, since 2019, the UK¹¹⁴) 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 gonorrhoea¹⁵⁰, 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 clinicians¹⁵¹. 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 screening¹⁵⁹.

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 case¹⁵⁹. 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 marriages¹⁶⁰. 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 gonorrhoea¹⁶². 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 gonorrhoea¹⁶⁵. 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 notification¹⁶⁶. 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 gender¹⁶⁹. 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 stigma¹⁶⁴.

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 sex¹⁷⁰. 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 infection¹⁷¹. 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 fairness¹⁷³.

Outlook

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 tackled¹⁷³. 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

Epidemiology

• 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

Mechanisms/pathophysiology

• 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

Diagnosis, screening and prevention

• 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 gonorrhoea²¹⁵)

• 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}

Management

• 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. gonorrhoeae²¹⁷)

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

Epidemiology

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^{45,156,174,175,176,177,178,179,180,181,182,183,184}. 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.

Mechanisms

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 data¹⁸⁵, 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.

Diagnosis, screening and prevention

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 strains¹⁸⁶. 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 security¹¹⁸.

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^{156,174,175,176,177,178,179,180,181,182,183,188,189,190,191}. 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. meningitidis¹⁹⁵.

Management

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. gonorrhoeae¹⁸³. 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 limited²¹¹ and requires substantially increased attention to inform ideal dosing regimens, and multiple dose regimens for gonorrhoea might be required.