Gonorrhoea: past, present and future

Gonorrhoea is an ancient disease of humans, with symptoms resembling gonorrhoea reportedly described in ancient Chinese and Middle Eastern records dating as far back as 3500 BC¹. There is also reference to urethral discharge, believed to be gonorrhoea, in the book of Leviticus in the Old Testament of the Bible (Leviticus 15:1-3). The name gonorrhoea is credited to Greek physician Galen (AD 130-200), which means the flow of semen, derived from the Greek words ’gonos’ (semen) and ’rhoia’ (to flow)¹. In the 16th century, as STIs were recognised as being more common in prostitutes, gonorrhoea became known as ‘the clap,’ likely in reference to the old Le Clapiers district of Paris where prostitutes were housed. It was not until 1879, however, that the bacteria responsible for gonorrhoea was identified and named Neisseria gonorrhoeae after Albert Neisser the German microbiologist who first isolated the bacteria (Figure 1). Over time, gonorrhoea has been described extensively in scientific literature, as well as in essays such as ‘Boswell’s Clap’ that describe James Boswell’s nineteen episodes of gonococcal urethritis between 1760–1790 based on his detailed diary accounts², and news articles describing its antibiotic resistance status, including ‘Man has ’world’s worst’ super-gonorrhoea’ (BBC News, UK, 28 March 2018).

Figure 1.  Neisseria gonorrhoeae (Ng) under the microscope. (A) Light microscope image of Ng colonies on an agar plate (×4 magnification). Opaque and translucent colonies are seen due to phase variation of opacity (Opa) proteins. (B) Light microscope image of Gram-stained Ng (×100 magnification). Scanning electron micrograph of Ng microcolonies on the surface of urethral epithelial cells, acquired at (C) ×5000 magnification (scale bar represents 5 µm) and (D) ×17 000 magnification (scale bar represents 1 µm).

The WHO estimates that more than 1 million STIs occur every day³. There are an estimated 87 million gonorrhoea infections occurring each year³ and N. gonorrhoeae has been prioritised as an urgent public health threat by the WHO⁴, CDC⁵ and Australian National AMR Strategy⁶. STI surveillance systems vary widely within and across WHO regions, which means that current figures likely underestimate the burden of gonorrhoea due to limitations in diagnosis and reporting. Several systems currently exist in Australia for the surveillance of N. gonorrhoeae infections, including state-level reporting via the Notification of Communicable Diseases, as well as the Australian Gonococcal Surveillance Programme (AGSP) conducted by the National Neisseria Network (NNN). These systems provide incidence, demographic, and antimicrobial resistance data to inform clinical and public health responses to continue towards gonorrhoea control. Rates of gonorrhoea have continued to increase in Australia over the last 10 years, with an 80% increase between 2013 to 2017⁷. Rates of gonorrhoea are particularly high in gay and bisexual men (GBM), Australia’s First Peoples and younger populations (19–29 years) and there has been a recent resurgence of gonorrhoea in urban heterosexuals⁷. In 2019 there were 34 265 gonococcal infections notified in Australia⁸.

The gold standard for N. gonorrhoeae diagnosis remains culture due to its high specificity and the ability to perform antibiotic sensitivity tests to guide treatment. However, culture yields are highly dependent on bacterial loads, storage and transport of specimens. This impacts extragenital site sampling where culture rates could be as low as 64% in pharyngeal infections⁹. In addition, the intimate and invasive nature of obtaining urethral and cervical samples limit its utility for widespread screening and testing programmes. Since 2002 nucleic acid amplification tests (NAATs) have been preferred as the screening tool for N. gonorrhoeae infection. NAATs have demonstrated superior detection rates with 97–99% sensitivity, and outperform culture by up to 2-fold for rectal and 5-fold for pharyngeal gonorrhoea infections¹⁰. NAATs have also been pivotal in improving access and uptake of gonorrhoea screening programmes, with a high level of acceptability and effectiveness for detecting gonorrhoea infection¹¹. Multiplex NAATs testing are also being developed, so that samples can be tested for up to nine different pathogens including Chlamydia trachomatis, Trichomonas vaginalis and Mycoplasma genitalium¹². Concomitant infection of N. gonorrhoeae with these infections occur in up to 30% of cases. Finally, NAAT tests have the ability to deliver a result in a matter of hours. A study in the UK demonstrated that the rapid turnaround of results would reduce time to diagnosis by more than 8 days leading to potential reduction in transmission¹³.

The outcome of N. gonorrhoeae infection varies by site of infection and by sex¹⁴. Symptomatic infections predominantly affect the genito-urinary tract with 90% of penile infections presenting with purulent discharge or dysuria, whilst approximately 50% of cervical infections present with changes in vaginal discharge, intermenstrual or post coital bleeding. Complications of N. gonorrhoeae can occur leading to epididymo-orchitis and pelvic inflammatory disease subsequently leading to an increased risk of infertility and ectopic pregnancy. Rarely, haematogenous spread can occur causing skin lesions, arthritis and tenosynovitis (disseminated gonococcal infection). Extragenital N. gonorrhoeae infections also occur leading to pharyngitis, proctitis and uveitis, though asymptomatic pharyngeal and rectal infections are common. Though gonorrhoea remains a curable infection, treatments have changed rapidly over time to overcome emerging drug-resistant N. gonorrhoeae (Figure 2). The future effectiveness of antibiotic treatment has been significantly compromised by the fact that N. gonorrhoeae has developed resistance to all classes of antibiotics used to treat it¹⁵. Worldwide, penicillin, ciprofloxacin and cefixime are no longer recommended first-line treatments. Instead dual antibiotic combination of ceftriaxone and azithromycin are preferred, though there is increasing concern of azithromycin resistance. In 2018, ’Super gonorrhoea’ resistant to all routine antibiotics, including the recommended dual therapy of intramuscular ceftriaxone/oral azithromycin, was reported in the UK¹⁶ and Australia¹⁷.

Figure 2.  Timeline of Neisseria gonorrhoeae antibiotic treatments and antibiotic resistance. The recommended antimicrobials for treatment of N. gonorrhoeae since the 1930s are shown below the timeline. The evolution of resistance in N. gonorrhoeae is shown above the timeline. Adapted from Unemo and Shafer¹⁵.

This century, scientists have made significant advances in understanding gonococcal biology, as well as its mechanisms for causing disease and evading the immune system. Most importantly, they have also discovered new approaches to prevent and treat the infection, many of which are in final stages of development. Currently there are three new antibiotics in clinical trials and there are also several other novel drugs or treatment methods in development or preclinical settings (Table 1)¹⁸. Novel diagnostics and genotyping technologies are also being developed for rapid detection of mutations to guide antibiotic therapy¹⁹.

Table 1.  Antimicrobials and vaccines under development for Neisseria gonorrhoeae (Ng).

It is widely considered that vaccination will be the best long-term solution to gonorrhoea. However, gonococcal vaccine development is challenging. N. gonorrhoeae infection does not protect against subsequent infection, therefore there are no correlates of protection from natural immunity to guide vaccine development¹⁴. Four gonococcal vaccine candidates have been tested in human clinical trials (all pre-2000) but none provided any protection against N. gonorrhoeae infection¹⁴. However, several new vaccine antigens are currently in preclinical development (Table 1)^14,20. Considerable funding from the US National Institute of Health (NIH) was recently allocated for creation of large collaborative research groups, aiming to deliver a gonococcal vaccine into clinical trials within 5 years.

The feasibility of a gonococcal vaccine was supported by recent findings from a retrospective study that showed decreased N. gonorrhoeae rates following vaccination with an outer membrane vesicle (OMV)-based vaccine (MeNZB) licenced to protect against the closely related bacteria Neisseria meningitidis²¹. MeNZB was estimated to have a vaccine effectiveness of 31% against N. gonorrhoeae²¹. Mathematical modelling has indicated that a gonococcal vaccine with 30% efficacy would be expected to halve gonorrhoea prevalence within 20 years²². The MeNZB vaccine was succeeded by a multicomponent meningococcal serogroup B vaccine – 4CMenB (tradename Bexsero), that in addition to the MeNZB OMVs, contains additional recombinant antigens. 4CMenB has been shown to induce cross-reactive antibodies to N. gonorrhoeae in humans²³, and is now in clinical trials to investigate its efficacy against gonorrhoea. One of these studies is underway in a population at high risk of contracting N. gonorrhoeae in Australia (MenGO; ANZCTR Identifier: 12619001478101). Two additional efficacy studies will commence shortly in Australia (GoGoVax; ClinicalTrials.gov Identifier: NCT04415424) and United States (NCT04350138), with estimated completions dates in 2023.

The discovery of antibiotics ushered a new age in medicine, allowing treatment of many bacterial infections that plagued mankind, including millennia old gonorrhoea. However, the gonococcus was able to acquire resistance to new antibiotics as quickly as they were developed and we have reached the point where strains resistant to ‘last line of defence’ antibiotics have emerged, prompting urgent action. Currently there are several new antibiotics and vaccine antigens being investigated at all stages of the clinical development pipeline, which will hopefully deliver new treatments and a cure for the clap.

The authors declare no conflicts of interest.