Gonorrhoea

Neisseria gonorrhoeae is a Gram-negative diplococcus infecting mucous membranes of the urethra, endocervix, rectum, pharynx and conjunctiva. Transmission occurs by the direct inoculation of infected secretions from one mucous membrane to another, usually sexually and, less commonly, perinatally. The incubation period is usually taken as being between two and five days but may be up to 10 days.

Virulence varies, as does the tendency to develop disseminated disease. The latter is conferred by the antigenic variation between subtypes. One study found that co-infection with chlamydia in women is associated with higher gonococcal organism loads, potentially increasing chances of transmission¹ .

Resistance to antibiotics also varies and can be spread rapidly by plasmid transfer of antibiotic resistance genes. Mortality associated with disseminated gonorrhoea is rare but morbidity, primarily associated with pelvic inflammatory disease (PID), is a common sequela worldwide.

Epidemiology²

In 2019, there were 468,342 diagnoses of STIs made in England, a 5% increase since 2018. The most commonly diagnosed STIs were chlamydia (229,411; 49% of all new STI diagnoses), gonorrhoea (70,936; 15%), first episode genital warts (51,274; 11%), and first episode genital herpes (34,570; 7%). There were 70,936 diagnoses of gonorrhoea reported in 2019, a 26% increase since 2018. Gonorrhoea therefore represented 6.6% of newly diagnosed STIs in genitourinary medicine (GUM) clinics. This is the largest annual number of reported cases since records began in 1918 and is a continuation of the increasing trend seen in recent years: since 2015, gonorrhoea diagnoses have risen by 71% (from 41,382 to 70,936).

While the majority of gonorrhoea diagnoses were reported in gay, bisexual and other men who have sex with men (referred to collectively as 'MSM') over the same period, diagnoses have also increased notably in women and heterosexual men. Between 2018 and 2019 increases in gonorrhoea were reported in heterosexual women (26%; from 14,167 to 17,826), heterosexual men (17%; from 13,036 to 15,253), women who have sex with women (WSW) (68%; from 87 to 146), and MSM (26%; from 26,864 to 33,853).

The rise in cases is thought to be due to a rise in men coming forward for testing as well as an increase in sexually unsafe activity. The use of new diagnostic techniques - rectal and pharyngeal testing using nucleic acid amplification testing (NAAT) - has also improved detection rates. The highest rates of gonorrhoea are amongst the young.

The largest proportional increase in gonorrhoea cases was in people aged 20-24 years (28%; from 13,623 to 17,443). Between 2018 and 2019, STI diagnosis rates remained highest among people of Black Caribbean ethnicity and rose by 9% (from 19,009 to 20,645); however, the largest proportional increase in all new STI diagnoses was in people of Asian ethnicity (16%; from 15,168 to 17,522), primarily for gonorrhoea (36%; from 2,313 to 3,136).

Urban areas reported higher prevalence rates than rural areas, London having the highest rates. Deprivation is an associated factor.

Uncomplicated gonorrhoea (affecting the lower genital tract) is a reasonably common infection, but complicated disease (affecting the upper genital tract) is rarer.

Risk factors³

• Young age.

• History of previous STI.

• Co-existent STIs - 44% of MSM with gonorrhoea had co-existing HIV infection² .

• New or multiple sexual partners.

• Recent sexual activity abroad.

• Certain sexual activities - eg, anal intercourse, frequent insertive oral sex.

• Inconsistent condom use.

• History of drug use or commercial sex work.
  

Presentation

Gonorrhoea is believed to be symptomatic in most men (90-95%) and asymptomatic in half of women.

Symptoms³

Men

• Urethral infection - discharge (>90%) and/or dysuria (>50%), asymptomatic (<10%) .

• Rectal infection - usually asymptomatic; may cause anal discharge (12%) or perianal/anal pain, pruritus or bleeding (7%).

• Pharyngeal infection - usually asymptomatic (>90%) .

Women

• Endocervical infection - frequently asymptomatic (up to 50%); increased or altered vaginal discharge is the most common symptom (up to 50%), although lower abdominal pain may also be present (up to 25%); a rare cause of intermenstrual bleeding or menorrhagia⁴ .

• Urethral infection - cause of dysuria (10-15%) without frequency.

• Rectal infection (in women, may develop by spread of infected genital secretions or anal intercourse) - usually asymptomatic.

• Pharyngeal infection - usually asymptomatic (>90%).

Signs

Men

• Mucopurulent or purulent urethral discharge. Symptoms occur in over 90% of individuals, with discharge and/or dysuria appearing two to five days following exposure⁴ . A mucopurulent urethral discharge is often present on examination.

• Epididymal tenderness/swelling or balanitis (rare).

Women

• Mucopurulent endocervical discharge (not a sensitive predictor of infection).

• Easily induced contact bleeding of the endocervix.

• Pelvic/lower abdominal tenderness (uncommon, 5%).

• Normal examination (very common).

Children

• Acute conjunctivitis in association with purulent discharge, usually bilateral, <48 hours of birth, often accompanied by chemosis and lid oedema.

• Vaginal discharge and vulval erythema (prepubertal vulvovaginal epithelium is more susceptible to infection compared with that of adult women).

Haematogenous dissemination may occur from infected mucous membranes to cause skin lesions, arthralgia, arthritis and tenosynovitis (disseminated gonococcal infection). In a study involving nearly 4,000 cisgender women attending a sexual health clinic in the UK, PID was reported in approximately 14% of those with gonorrhoea⁵ .

Differential diagnosis

• Other causes of penile or vaginal discharge - eg, chlamydia.

• Other causes of pelvic pain - eg, endometriosis, appendicitis.

• Other causes of pharyngitis, arthritis.

Investigations⁴

Follow local protocols

The diagnosis of gonorrhoea is established by the detection of N. gonorrhoeae at an infected site, either by nucleic acid amplification tests (NAATs) or by culture. The approach and method used to test for gonorrhoea will be influenced by the clinical setting, storage and transport system to the laboratory, local prevalence of infection and the range of tests available in the laboratory. No test for gonorrhoea offers 100% sensitivity and specificity.

Microscopy

• Penile urethra: microscopy of urethral or meatal swab smears has good sensitivity (90-95%) in people with discharge from the penile urethra and is recommended to facilitate immediate presumptive diagnosis in these individuals. Microscopy of penile urethral smears in those without symptoms is less sensitive (50-75%); therefore, it is not recommended in asymptomatic individuals.

• Female urethra and endocervix: microscopy has only 37-50% and 20% sensitivity compared with culture for detecting gonorrhoea from endocervical and female urethral smears. The sensitivity of cervical microscopy compared to NAATs in a more recent study was only 16% and is therefore not routinely recommended.

• Rectum and pharynx: ano-rectal smears and microscopy should be offered if rectal symptoms are present. The sensitivity of microscopy for detecting asymptomatic rectal infection is low and is not routinely recommended.

Nucleic acid amplification tests (NAATs)

NAATs are more sensitive than culture, particularly for oropharyngeal and rectal sites. NAATs show high sensitivity (>95%) in both symptomatic and asymptomatic infection. Therefore, although NAATs are not licensed for use at extra-genital sites, their use is recommended.

• Penile urethra: NAATs show equivalent sensitivity in urine and urethral swab specimens from cisgender men, although a first-pass urine specimen is the preferred sample.

• Female urethra and endocervix: self-collected or clinician-collected vulvovaginal swabs (VVS) perform better than endocervical swabs and significantly better than urine for cisgender women. VVS are therefore the recommended specimen. For people who have had a hysterectomy, there is no evidence on optimal sampling site. We suggest considering urine and VVS for NAAT with subsequent culture from that site if positive.

• Rectum and pharynx: rectal and pharyngeal sampling should be routine in all MSM (as recommended by the BASHH guideline on the sexual healthcare of MSM), be considered in women who are sexual contacts of gonorrhoea and be guided by an assessment of risk and symptoms in everyone else.

The primary role of culture is for antimicrobial susceptibility testing, which is of increasing importance as antimicrobial resistance in N. gonorrhoeae continues to evolve and spread.

Approximately 19% of patients with gonorrhoea have concurrent chlamydial infection. Therefore, testing for other STIs should be carried out in line with guidelines⁶ .

NB: Where a patient has had sexual contact with an individual with confirmed gonorrhoea within the previous three days, a further interval set of tests (usually two weeks later) should be considered if empirical treatment with antimicrobial therapy is not undertaken.

Management⁴

General

• Where a patient has tested positive for gonorrhoea, or where an individual has suggestive symptoms/is at high risk, referral to a GUM clinic or service offering an enhanced sexual health service is strongly encouraged.

• Emergency medical admission may be required if there is evidence of disseminated gonorrhoea or severe PID.

• Allow time to provide a detailed explanation of the condition and its long-term implications for the patient and their partner's/partners' health, reinforced with written information. Advise on safer sexual practices for the future.

• Advise patients to avoid unprotected sexual intercourse until seven days after both they and their partner(s) have completed treatment.

• Advise routine screening for other STIs in all patients with or at risk of gonorrhoea. Co-infection with other STIs, particularly chlamydia, is common.

• Partner notification should preferably be performed by a trained health adviser. For male patients with symptomatic urethral infection, all partners with whom they have had sexual contact in the previous two weeks or their last partner (if longer than two weeks). With asymptomatic infection or infection at other sites, sexual partners of the preceding three months should be notified. These partners should receive a full STI screen and receive empirical treatment for gonorrhoea and chlamydia in advance of results.

• Patients should be followed up to check compliance with treatment, to make sure symptoms have resolved, to explore the risk of re-infection and to further partner notification and health promotion.

Medication

• Ceftriaxone 1 g intramuscularly as a single dose is given when sensitivity to antimicrobials is unknown.

• Ciprofloxacin 500 mg orally as a single dose when sensitivities are known. Gonorrhoea is a serious infection and the potential benefit of using ciprofloxacin in people with susceptible infection will outweigh the potential risks.

A test of cure (with culture >72 hours or with NAAT >2 weeks following antibiotic treatment) is recommended in all cases.

Alternative treatments may be given because of allergy, needle phobia or other absolute or relative contra-indications. In patients with penicillin allergy there is ample evidence to allow the safe use of all but a few early generation cephalosporins (eg, cefalexin, cefaclor and cefadroxil), and third-generation cephalosporins such as cefixime and ceftriaxone have been shown to have low cross-allergy with penicillins.

Alternatives include:

• Cefixime 400 mg orally as a single dose plus azithromycin 2 g orally. Only advisable if an intramuscular injection is contra-indicated or refused by the patient. Resistance to cefixime is currently low in the UK.

• Gentamicin 240 mg intramuscularly as a single dose plus azithromycin 2 g orally. RCTs have examined the efficacy and safety of gentamicin for the treatment of gonorrhoea, prescribing gentamicin in combination with 1 g of azithromycin⁷ . Microbiological cure (negative NAAT two weeks after treatment) was achieved in 91% of urogenital infections. Another randomised trial used a 2 g dose of azithromycin in combination with gentamicin⁸ . This found 100% clearance of infection; however, few extragenital infections were included and culture was used to confirm clearance (ie it is likely to overestimate the effectiveness).

Pregnancy and breastfeeding

• Ceftriaxone 1 g intramuscularly as a single dose.

• Azithromycin 2 g as a single oral dose. However, the manufacturer of azithromycin advises use only if adequate alternatives are not available.

Pharyngeal infection

• Ceftriaxone 500 mg intramuscularly with azithromycin 1 g orally as a single dose.

• Oral cefixime (400 mg loading dose, followed by 200 mg twice a day for three days) plus azithromycin 1 g orally as a single dose can be used where intramuscular injections are contra-indicated or refused (off-label use).

• Ciprofloxacin 500 mg orally or ofloxacin 400 mg orally (if N. gonorrhoeae known to be quinolone-sensitive) is an option for patients in whom cephalosporins are contra-indicated.

Pelvic inflammatory disease⁶
Ceftriaxone 1 g intramuscularly as a single dose in addition to the regimen chosen to treat PID (see the BASHH PID guideline).

Gonococcal epididymo-orchitis
Ceftriaxone 1 g intramuscularly as a single dose.

Gonococcal conjunctivitis
Systemic treatment is recommended as the cornea may be involved and the eye is relatively avascular:

• Wash the eye with saline/water.

• Ceftriaxone 1 g intramuscularly as a single dose

• There is a lack of evidence to guide treatment options if there is a history of penicillin anaphylaxis or established cephalosporin allergy. Treatment should be based on antimicrobial susceptibility results where available.

Children

Ophthalmia neonatorum (neonatal conjunctivitis)⁹

• During the first year of life, gonorrhoea can cause ophthalmia neonatorum, pharyngitis, rectal infections and pneumonia. Signs develop within two to five days following birth, because exposure to infection tends to have occurred during delivery.

• Babies with true conjunctivitis (ie signs of conjunctival inflammation as opposed to a simple 'sticky eye') should be referred by GPs for same-day hospital assessment.

• Gram-stain conjunctival exudates followed by culture are the investigations of choice. Treatment should be prompt to prevent corneal ulceration and permanent visual loss - usually parenteral benzylpenicillin or cephalosporin, in combination with saline lavage and topical antibiotic (eg, erythromycin, azithromycin).

• Both parents should be screened.

Co-infection with chlamydia¹⁰

Treatment for confirmed or suspected chlamydial co-infection should follow the current guideline for the management of chlamydia. If an individual has already received azithromycin 2 g for the treatment of gonorrhoea then this should be sufficient to treat chlamydia and no further doses of azithromycin are required.

Disseminated gonococcal infection

• Ceftriaxone 1 g intramuscularly or intravenously every 24 hours; or

• Cefotaxime 1 g intravenously every eight hours; or

• Ciprofloxacin 500 mg intravenously every 12 hours (if the infection is known to be susceptible); or

• Spectinomycin 2 g intramuscularly every 12 hours.

Therapy should continue for seven days but may be switched 24-48 hours after symptoms improve to one of the following oral regimens guided by sensitivities:

• Cefixime 400 mg twice daily; or

• Ciprofloxacin 500 mg twice daily; or

• Ofloxacin 400 mg twice daily.
  

Sexual abuse

• Consider the possibility of sexual abuse in those underage and vulnerable. Follow local child protection guidance and seek expert advice.

• After the neonatal period, it is thought that genital and pharyngeal gonorrhoea are almost always due to sexual abuse by an infected adult. However, there are cases, particularly of conjunctivitis, that appear to have been acquired non-sexually. All cases of gonorrhoea post-infancy must be investigated thoroughly.

Complications³

Men

• Gonococcal urethritis may cause urethral scarring and stricture, resulting in bladder-outflow obstruction.

• Local spread causing acute epididymitis, prostatitis, seminal vesiculitis, penile lymphangitis, peri-urethral abscess and infection of Tyson's and Cowper's glands.

Women

The main concerns of PID are infertility and peri-hepatitis caused by ascending infection.

• Bartholin's abscess (usually multiple pathogens).

• PID - thought to occur in 10-20%, causing infertility, chronic pelvic pain and ectopic pregnancy.

• Peri-hepatitis (Fitz-Hugh Curtis syndrome).

• In pregnancy it may be associated with premature labour and miscarriage.

• Corneal scarring and severe sight impairment from neonatal ophthalmic infection.

General

• Haematogenous dissemination (uncommon - <1%) causing:
  

  • Skin lesions (papules, bullae, petechiae and necrotic skin lesions).

  • Arthralgia, arthritis and tenosynovitis of the ankles, wrists, hands and feet (reactive arthritis).

  • Meningitis, endocarditis or myocarditis, with risk of death or permanent sequelae (extremely rare).

• Increased risk of acquiring and transmitting HIV infection.

Prognosis

Where treatment is rapidly received for a recently acquired gonorrhoeal infection, prognosis is good with full recovery as normal. Continuing symptoms are more likely to be due to re-infection than persistence of the original infection. However, the emergence of a new multidrug-resistant strain ('superbug') is causing increasing global public health concern.

The risk of infertility increases with repeated episodes.

Prevention

• Promotion of safer sex methods.

• Consistent use of condoms reduces the risk of acquiring gonorrhoea and other STIs.

• Testing for those sexually active and at risk of acquiring gonorrhoea - in the UK there is no current evidence base to support widespread unselected screening for gonorrhoea and only very limited evidence for selective community screening. Localised interventions targeted on high-risk groups (inner-city residents, GUM attendees, military personnel, prisoners and MSM) are more likely to be cost-effective and beneficial than unselected screening.

• Quicker partner referral and treatment can substantially reduce re-infection rates. Novel partner notification technologies like accelerated partner therapy may be helpful but need further evaluation.

• Progress in the area of vaccine research has been slow but recent development of a murine model facilitated advances in this field.

National guidelines recommend that¹⁰ :

• Male patients with symptomatic urethral infection should notify all sexual partners from the preceding two weeks or their last partner if longer than two weeks.

• People with infection at other sites or asymptomatic infection should contact all partners within the preceding three months.

• Partners should be offered testing and treatment.