Levels of evidence (I-IV) and grades of recommendation (A-C) are defined at the end of the "Major Recommendations" field.
Changes Since 2005 Guideline
- Nucleic acid amplification tests (NAATs) can be used for both anogenital and pharyngeal specimens. Supplementary testing is required for reactive tests from low prevalence populations and for specimens from the rectum or pharynx.
- First-line treatment is now ceftriaxone 500 mg intramuscularly immediately plus azithromycin 1 g orally immediately.
- Test of cure is recommended for all cases.
- A patient information leaflet is available (see website).
- There is a link for reporting cephalosporin treatment failures to the Health Protection Agency (HPA).
- This guideline should be read in conjunction with the Health Protection Agency Guidance for gonorrhoea testing in England and Wales (2010) and the British Association for Sexual Health and HIV (BASHH) guidelines on testing for sexually transmitted infections (STIs)/gonorrhoea .
- The diagnosis of gonorrhoea is established by the detection of N. gonorrhoeae at an infected site.
- 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 (x1000) of Gram-stained genital specimens allows direct visualization of N. gonorrhoeae as monomorphic Gram-negative diplococci within polymorphonuclear leukocytes. It offers good sensitivity (90%–95%) in men with urethral discharge and is recommended to facilitate immediate diagnosis in symptomatic men (level of evidence III; grade C recommendation). Microscopy of urethral smears in asymptomatic men is less sensitive (50%–75%). Microscopy should be done on men with rectal symptoms. In women, microscopy has poor sensitivity for the identification of gonococcal infection: 37%–50% for endocervical smears and 20% for urethral smears. Microscopy is not recommended for urethral smears in women or for detecting asymptomatic rectal infection because of low sensitivity (level of evidence III; grade C recommendation). Microscopy is not appropriate for diagnosing gonorrhoea in pharyngeal specimens.
- Detection of N. gonorrhoeae can be achieved by NAATs or culture. NAATs are generally more sensitive than culture and offer testing on a wider range of specimen types. NAATs show high sensitivity (>96%) in both symptomatic and asymptomatic infection. They show equivalent sensitivity in urine and urethral swab specimens from men and in vaginal and endocervical swabs from women. The test sensitivity in female urine is significantly lower and urine is not the optimal specimen in women (level of evidence II; grade B recommendation).
- Persons undergoing testing for genital tract gonorrhoea are usually also tested for infection with C. trachomatis. NAATs are the standard test methodology for C. trachomatis testing and commercial tests offer dual capability to also test for N. gonorrhoeae on the same sample. When testing for genital tract infection, a dual NAAT for both pathogens maximizes sensitivity and operational ease of specimen collection, transport and processing.
- NAATs are significantly more sensitive than culture for detecting N. gonorrhoeae in the rectum and pharynx although are not yet licensed for use at these sites. Commercially available NAATs differ in their cross-reactivity to commensal Neisseria species which may be present at significant levels at these sites, particularly in the pharynx. At present it is recommended that reactive specimens from the rectum and pharynx are confirmed by supplementary testing, i.e., using a different molecular target (level of evidence III; grade C recommendation).
- Culture continues to offer a specific, sensitive and cheap diagnostic test at genital sites. It allows confirmatory identification and antimicrobial susceptibility testing, which is of increasing importance as antimicrobial resistance to N. gonorrhoeae continues to evolve. Selective culture media containing antimicrobials are recommended to reduce contamination (level of evidence II; grade B recommendation).
- Whatever the testing approach adopted, positive test results should give a positive predictive value of >90%. In areas of low gonorrhoea prevalence the use of NAATs may require supplementary testing to confirm the diagnosis. Clinicians need to be familiar with the test performance of NAATs and be able to interpret results in their clinical setting.
A first pass urine is the preferred sample for NAAT testing. Microscopy and culture require a urethral/meatal swab specimen. The collection and testing of rectal and pharyngeal swab specimens should be directed by sexual history, symptoms at these sites and also considered in men who receive oral–anal or digital–anal contact.
Vaginal or endocervical swab specimens are equally sensitive for detecting N. gonorrhoeae by NAAT testing. Culture requires an endocervical and urethral swab specimen for maximum sensitivity. Urine is a suboptimal sample for the detection of N. gonorrhoeae in women. The collection and testing of rectal and pharyngeal swab specimens should be directed by sexual history, symptoms at these sites and also considered in women who are sexual contacts of gonorrhoea.
- For culture, direct plating of genital samples and use of transport media with prompt laboratory plating both give acceptable results (level of evidence IV).
- Data are lacking on the sensitivity of a single set of tests to identify infection with N. gonorrhoeae. The use of a single endocervical or vulvovaginal NAAT sample will identify 90%–95% of women with gonococcal infection. Women infected with N. gonorrhoeae often have infection at multiple sites. A minority of men who have sex with men with gonorrhoea have infection at multiple sites, thus all exposed sites need sampling.
- To confidently exclude infection in patients who attend within three days of sexual contact, a second set of tests should be considered if epidemiological treatment with effective antimicrobial therapy is not given (level of evidence IV; grade C recommendation). Conventionally this would be 14 days after contact.
- Patients should be given a detailed explanation of their condition with particular emphasis on the long-term implications for the health of themselves and their partner(s). This should be reinforced with clear and accurate written information (level of evidence IV; grade C recommendation).
- Patients should be advised to abstain from sexual intercourse until they and their partner(s) have completed treatment (level of evidence IV; grade C recommendation); if azithromycin is used, this will be 7 days after treatment was given.
- A culture should be taken in all cases of gonorrhoea diagnosed by NAATs prior to antibiotics being given, if possible, so that susceptibility testing can be performed and resistant strains identified.
- Screening for coincident STIs should routinely be performed in patients with or at risk of gonorrhoea (level of evidence III; grade C recommendation).
Indications for Therapy (level of evidence IV; grade C recommendation)
- Identification of intracellular Gram-negative diplococci on microscopy of a smear from the genital tract
- A positive culture for N. gonorrhoeae from any site
- A positive NAAT for N. gonorrhoeae from any site. Supplementary testing is recommended if the positive predictive value of the test is <90%.
- Recent sexual partner(s) of confirmed cases of gonococcal infection
- Consider offering on epidemiological grounds following sexual assault
Uncomplicated anogenital infection in adults:
- Ceftriaxone 500 mg intramuscularly as a single dose with azithromycin 1 g oral as a single dose (level of evidence IV; grade C recommendation) (see the table below)
Table: Administration of Ceftriaxone 500 mg
Ceftriaxone is supplied as a powder which needs to be reconstituted with lidocaine solution. In the UK, it is currently available as vials of 250 mg or 1 g, the 1 g size generally being considerably more economical.
To reconstitute, mix the contents of the 1 g vial with 3.5 mL of 1% lidocaine injection BP (British Pharmacopoeia): half (2.1 mL) of the resulting solution provides 500 mg ceftriaxone.
It should be given by deep intramuscular injection.
The remaining solution can be used for up to 24 hours later, where permitted by local regulations, if it is kept in the dark at 2–80ºC (i.e. in refrigerator).
- N. gonorrhoeae has progressively exhibited reduced sensitivity and resistance to many classes of antimicrobials. Published trials of gonorrhoea treatment reflect clinical efficacy in past eras of antimicrobial sensitivity. Surveillance data in England and Wales show significant levels of N. gonorrhoeae resistance to penicillin (22% in 2009), tetracyclines (68% in 2009) and ciprofloxacin (35.3% in 2009). High-level azithromycin resistance (minimum inhibitory concentration [MIC] ≥256 mg/L) was observed in 2007 in the UK. In 2009, decreased susceptibility to cefixime (MIC ≥0.25 mg/L) was observed at 1.2% and four isolates (0.3%) with decreased susceptibility to ceftriaxone (MIC ≥0.125 mg/L) were also identified. Three UK cases of clinical cefixime failure were reported in 2011. Most resistant infections are acquired in the UK.
- The increasing recognition of multidrug resistant N. gonorrhoeae has been the driving force for the recommendation of extended spectrum cephalosporins as the preferred treatment of gonorrhoea. Concerns about the upward drift of resistance to cephalosporins justify the increased dose of ceftriaxone now recommended.
- Azithromycin is recommended as co-treatment irrespective of the results of chlamydia testing (level of evidence IV; grade C recommendation), to delay the onset of widespread cephalosporin resistance. There is some in vitro evidence of synergy between azithromycin and cephalosporins, and improved eradication of pharyngeal gonorrhoea has been reported when azithromycin was combined with cephalosporin therapy.
Clinicians using alternative regimens for the treatment of gonorrhoea are recommended to regularly review local and national trends in gonococcal antimicrobial resistance. All the agents below should be accompanied by azithromycin 1 g oral as a single dose.
- Cefixime 400 mg oral as a single dose (level of evidence 1b; grade A recommendation). Only advisable if an intramuscular injection is contraindicated or refused by the patient. Observations in Asia have raised serious concerns over the adequacy of the 400 mg cefixime dose for the treatment of genital tract gonorrhoea. Repeated treatment failures have been reported with cefixime and other oral extended spectrum cephalosporins.
- Spectinomycin 2 g intramuscularly as a single dose (level of evidence 1b; grade A recommendation). Spectinomycin was not being manufactured in 2010 so may be difficult to obtain. See BASHH website (www.bashh.org ) for further details.
- Other single dose cephalosporin regimens, notably cefotaxime 500 mg intramuscularly as a single dose (level of evidence Ib; grade A recommendation) or cefoxitin 2 g intramuscularly as a single dose plus probenecid 1 g oral. Alternative injectable or oral cephalosporins offer no advantage in terms of efficacy and pharmacokinetics over ceftriaxone or cefixime.
- Cefpodoxime is an alternative oral third generation cephalosporin that as a single dose of 200 mg orally is licensed for the treatment of uncomplicated gonorrhoea. Published trial data are limited, but in view of its less favourable pharmacokinetics than cefixime and suboptimal efficacy against pharyngeal infection, it should be used with caution at a dose of 400 mg (level of evidence II; grade C recommendation).
- Quinolones cannot generally be recommended for the treatment of gonorrhoea because of the high prevalence of quinolone resistance worldwide. When an infection is known before treatment to be quinolone sensitive, ciprofloxacin 500 mg orally as a single dose or ofloxacin 400 mg orally as a single dose have proven efficacy (level of evidence Ib; grade A recommendation).
- High-dose azithromycin (2.0 g as a single dose) has shown acceptable efficacy in clinical trials, but was associated with high gastrointestinal intolerance. The clinical efficacy of azithromycin does not always correlate with in vitro sensitivity testing and high-level azithromycin resistance has been observed in the UK. A single dose of azithromycin 1.0 g alone is not recommended as treatment for gonorrhoea (level of evidence II; grade C recommendation).
- The alternative treatment regimens listed do not comprise all effective treatment regimens, but reflect clinical practice in the UK.
Treatment of Complicated Infections
Gonococcal Pelvic Inflammatory Disease (PID)
Ceftriaxone 500 mg intramuscularly immediately followed by oral doxycycline 100 mg twice daily plus metronidazole 400 mg twice daily for 14 days (see National Guideline Clearinghouse [NGC] summary of the BASHH guideline Management of acute pelvic inflammatory disease).
Ceftriaxone 500 mg intramuscularly plus doxycycline 100 mg twice daily for 10–14 days (see the NGC summary of the BASHH guideline 2010 United Kingdom national guideline for the management of epididymo-orchitis).
A three-day systemic regimen is recommended as the cornea may be involved and is relatively avascular (level of evidence IV; grade C recommendation). The eye should be irrigated with saline/water:
- Ceftriaxone 500 mg intramuscularly daily for three days
- For non-anaphylaxis allergy: ceftriaxone as above
- If history of penicillin anaphylaxis or established cephalosporin allergy: spectinomycin 2 g intramuscularly immediately daily for three days or azithromycin 2 g oral immediately plus doxycycline 100 mg twice daily for one week plus ciprofloxacin 250 mg daily for three days (level of evidence IV; grade C recommendation).
Disseminated Gonococcal Infection (grade C recommendation)
- Ceftriaxone 1 g intramuscularly or intravenous every 24 hours or cefotaxime 1 g intravenous every eight hours or ciprofloxacin 500 mg intravenous every 12 hours (if the infection is known to be sensitive) 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: cefixime 400 mg twice daily, ciprofloxacin 500 mg twice daily or ofloxacin 400 mg twice daily.
Third-generation cephalosporins such as cefixime and ceftriaxone show negligible cross-allergy with penicillins. Contraindications to the administration of ceftriaxone are hypersensitivity to any cephalosporin or previous immediate and/or severe hypersensitivity reaction to a penicillin or other beta-lactam drug. Recommended treatments for patients giving a history of such hypersensitivity:
- Spectinomycin 2 g intramuscularly as a single dose (level of evidence Ib; grade A recommendation) with azithromycin 1 g oral as a single dose or
- Azithromycin 2.0 g oral as a single dose (level of evidence Ib; grade B recommendation) or
- Ciprofloxacin 500 mg orally as a single dose when the infection is known or anticipated to be quinolone sensitive
Pregnancy and Breastfeeding
Pregnant and breastfeeding women should not be treated with quinolone or tetracycline antimicrobials. Azithromycin: manufacturer advises use only if adequate alternatives are not available. Pregnancy does not diminish treatment efficacy.
- Ceftriaxone 500 mg intramuscularly as a single dose with azithromycin 1 g oral as a single dose (level of evidence IV; grade C recommendation) or
- Spectinomycin 2 g intramuscularly as a single dose (level of evidence Ib; grade A recommendation) with azithromycin 1 g oral as a single dose
Single-dose antimicrobial treatments have in general demonstrated lower efficacy (≤90%) in eradicating N. gonorrhoeae from the pharynx than in eradicating genital infection. Failure has even been reported with ceftriaxone.
- Ceftriaxone 500 mg intramuscularly as a single dose with azithromycin 1 g as a single dose (level of evidence IV; grade C recommendation) or
- Ciprofloxacin 500 mg orally as a single dose if N. gonorrhoeae known to be quinolone sensitive (level of evidence Ib; grade B recommendation) or
- Ofloxacin 400 mg orally as a single dose if N. gonorrhoeae known to be quinolone sensitive (level of evidence Ib; grade B recommendation). Single dose treatment with spectinomycin has poor efficacy in eradicating gonococcal infection of the pharynx.
Human Immunodeficiency Virus (HIV) Infection
Treatment for gonorrhoea in HIV-infected individuals is the same as in those who are HIV-negative.
Co-Infection with C. Trachomatis
Genital infection with C. trachomatis commonly accompanies genital gonococcal infection (35% of heterosexual men and 41% of women with gonorrhoea). Testing for C. trachomatis should routinely be performed on all adults with gonorrhoea or treatment given to eradicate possible co-infection (level of evidence IV; grade C recommendation).
Partner notification should be pursued in all patients identified with gonococcal infection, preferably by a trained health adviser in genitourinary (GU) medicine. Action and outcomes should be documented. Partner notification should follow national recommendations:
- Male patients with symptomatic urethral infection should notify all partners with whom they had sexual contact within the preceding two weeks or their last partner if longer ago.
- Patients with infection at other sites or asymptomatic infection should notify all partners within the preceding three months. Sexual partners should be offered testing and treated epidemiologically for gonorrhoea (level of evidence IV; grade C recommendation).
Follow-up and Test of Cure (TOC)
Assessment after treatment may be helpful (level of evidence IV; grade C recommendation):
- To confirm compliance with treatment
- To ensure resolution of symptoms
- To enquire about adverse reactions
- To take a sexual history to explore the possibility of reinfection
- To pursue partner notification and health promotion
A TOC is now recommended in all cases (level of evidence IV; grade C recommendation). This is (a) to identify emerging resistance, which on past experience is likely to occur in due course and (b) because the susceptibility results that indicate potential failure to ceftriaxone and cefixime are not yet defined.
Where resource or practical considerations require TOC to be selective rather than universal, then the following patients should be prioritized:
- Persisting symptoms or signs
- Pharyngeal infection (all treatments are less effective at eradicating pharyngeal infection)
- Treatment with anything other than the first-line recommendations
Method and Timing of TOC
The current evidence is very scanty and the following is based on expert opinion and pragmatic considerations:
- Persisting symptoms or signs – test with culture, performed at least 72 hours after completion of therapy
- If asymptomatic – test with NAATs where available, followed by culture if NAAT-positive. Test two weeks after completion of antibiotic therapy.
Note that infection identified after treatment may well be due to reinfection.
Cephalosporin Clinical Failure Following Treatment for Gonorrhoea
Cases of failure of cephalosporin therapy should be reported to the Health Protection Agency using on-line forms, at the HIV and STI web portal: https://www.hpawebservices.org.uk/HIV_STI_WebPortal/Login.aspx . Only authorized users are permitted to access this secure website – all GU clinics have been issued with usernames and passwords. Otherwise, they can be obtained from email@example.com.
Levels of Evidence
||Type of Evidence
||Evidence obtained from meta-analysis of randomised controlled trials
||Evidence obtained from at least one randomised controlled trial
||Evidence obtained from at least one well-designed controlled study without randomisation
||Evidence obtained from at least one type of well-designed quasi-experimental study
||Evidence obtained from well-designed, non-experimental descriptive studies, such as comparative studies, correlation studies and case control studies
||Evidence obtained from expert committee reports or opinions and/or clinical experience of respected authorities
Grades of Recommendation
|A (Evidence levels Ia, Ib)
||Requires at least one randomised controlled trial as part of the body of literature of overall good quality and consistency addressing the specific recommendation
|B (Evidence levels IIa, IIb, III)
||Requires availability of well-conducted clinical studies but no randomised clinical trials on the topic of recommendation
|C (Evidence level IV)
||Requires evidence from expert committee reports or opinions and/or clinical experience of respected authorities. Indicates absence of directly applicable studies of good quality