Background review for the ‘2020 European guideline for the diagnosis and treatment of gonorrhoea in adults’

Abstract

Gonorrhoea is a major public health concern globally. Increasing incidence and sporadic ceftriaxone-resistant cases, including treatment failures, are growing concerns. The 2020 European gonorrhoea guideline provides up-to-date evidence-based guidance regarding the diagnosis and treatment of gonorrhoea. The updates and recommendations emphasize significantly increasing gonorrhoea incidence; broad indications for increased testing with validated and quality-assured nucleic acid amplification tests (NAATs) and culture; dual antimicrobial therapy including high-dose ceftriaxone and azithromycin (ceftriaxone 1 g plus azithromycin 2 g) OR ceftriaxone 1 g monotherapy (ONLY in well-controlled settings, see guideline for details) for uncomplicated gonorrhoea when the antimicrobial susceptibility is unknown; recommendation of test of cure (TOC) in all gonorrhoea cases to ensure eradication of infection and identify resistance; and enhanced surveillance of treatment failures when recommended treatment regimens have been used. Improvements in access to appropriate testing, test performance, diagnostics, antimicrobial susceptibility surveillance and treatment, and follow-up of gonorrhoea patients are essential in controlling gonorrhoea and to mitigate the emergence and/or spread of ceftriaxone resistance and multidrug-resistant and extensively drug-resistant gonorrhoea. This review provides the detailed background, evidence base and discussions, for the 2020 European guideline for the diagnosis and treatment of gonorrhoea in adults (Unemo M, et al. Int J STD AIDS. 2020).

Keywords

gonorrhoea sexually transmitted infection Europe management diagnosis antimicrobial resistance treatment

The present review provides all background, evidence base and discussions for the 2020 European guideline for the diagnosis and treatment of gonorrhoea in adults (Unemo M, et al. Int J STD AIDS. 2020).

Aetiology, transmission, and epidemiology

Gonorrhoea (gonococcal infection), including its serious reproductive health complications and sequelae, is caused by the obligate human pathogenic, Gram-negative bacterium Neisseria gonorrhoeae;¹

Infection predominantly involves the epithelium of the urethra, endocervix, rectum, oropharynx, and conjunctivae. Infection usually remains localised to the initial sites of infection, however, if not detected and treated, it can ascend to the upper genital tract to cause pelvic inflammatory disease (PID) and epididymo-orchitis;^1–3

Transmission is by direct inoculation of infected secretions from one mucosa to another, i.e., genital-urogenital, urogenital-anorectal, oro-urogenital, or oro-anal contact, or by mother-to-child transmission at birth.^1–3 Recently, it has been suggested that the transmission from oropharynx and mouth, including through saliva by kissing, can be significant,^4–7 However, the contribution of kissing to transmission risk for gonorrhoea and the potential use of antiseptic mouthwash need to be further appropriately examined;^8,9

In 2016, the World Health Organization (WHO) estimated 87 million cases of gonorrhoea among adults (16–45 years of age) globally, representing the second most common estimated bacterial sexually transmitted infection (STI) after Chlamydia trachomatis infections (127 million cases).¹⁰ In the European Union (EU)/European Economic Area (EEA), gonorrhoea is also the second (after C. trachomatis infections) most frequently reported bacterial STI (100,673 cases in 2018 [26.4 cases per 100,000 population]), representing a significant increase of approximately 240% since 2008 (29,434 cases [7.85 cases per 100,000 population]).¹¹ However, the reported incidence of gonorrhoea in several countries is relatively low and clearly underestimated because of suboptimal testing, diagnostics, case reporting, and/or surveillance. In EU/EEA, there is significant geographic diversity in the distribution of gonorrhoea cases and in 2018 76% of gonorrhoea cases were reported in men,¹¹ reflecting the considerably higher proportion of diagnosed symptomatic urogenital infections in men and the high prevalence of gonorrhoea in men who have sex with men (MSM). MSM accounted for about 25–35% of all cases in the EU/EEA during recent years (59% of cases reporting sexual orientation in 2018); however, over the past decade substantial increases also occurred among heterosexual men and women. In 2018, the highest incidence of gonorrhoea in the EU/EEA was among 25-34 year olds, closely followed by 15-24 year olds and, in many countries, there is a disproportionate burden of disease in MSM and/or ethnic minority groups.^10–13

Clinical features^{1–3,14–20}

Symptoms and physical signs of gonorrhoea reflect localised inflammation of infected mucosal surfaces in the urogenital tract. Infections caused by C. trachomatis, Mycoplasma genitalium, Trichomonas vaginalis and Candida albicans, and conditions such as bacterial vaginosis, are common and can result in similar symptoms.

Symptoms

In men, the predominant presentation is of acute urethritis with symptoms of urethral discharge (>80%) and dysuria (>50%), usually starting within 2–8 days of exposure. Asymptomatic urethral infection in men is rare (<10% of urethral infections);

In women, urogenital tract symptoms related to endocervical and urethral infection include increased or altered vaginal discharge (≤50%), lower abdominal pain (≤25%), dysuria (10–15%), and occasionally intermenstrual bleeding or menorrhagia. Endocervical infection is frequently asymptomatic (≥50%);

Rectal and oropharyngeal infections in men and women are usually asymptomatic. However, rare symptoms may include anal discharge and perianal/anal pain, or discomfort and sore throat, respectively.

Physical signs

In men with urogenital gonorrhoea, the most common finding on examination is a mucopurulent urethral discharge, which may be accompanied by erythema of the urethral meatus;

In women with urogenital gonorrhoea, examination may be normal or a mucopurulent discharge may be evident from the cervix, sometimes accompanied with hyperaemia and contact bleeding of the endocervix.

Complications and sequelae

PID in women, potentially resulting in ectopic pregnancy and infertility, and epididymo-orchitis in men are the most notable complications of infection ascending to the upper genital tract;

Gonococcal bacteraemia is rare and is usually manifested by skin lesions, fever, arthralgia, acute arthritis, and tenosynovitis (disseminated gonococcal infection [DGI]).^2,20–24

Indications for testing [2C]

Symptoms or signs of urethral discharge in men;

Cervical or vaginal discharge with risk factor for STIs (age <30 years, new sexual contact in the last year, or more than one partner in the last year);^11,25–27

Mucopurulent cervicitis;

Persons newly diagnosed with other STI;

Sexual contact of persons with an STI or PID;

Acute epididymo-orchitis in a male aged <40 years or with other risk factors for STIs (e.g., new sexual contact in the last year, or more than one partner in the last year);^11,25–27

Acute pelvic pain or signs of PID;

When performing a STI screen in young adults (<25 years of age) or MSM;

When performing a STI screen in individuals with new or multiple recent sexual contacts;

Purulent conjunctivitis in a neonate or adult;

Mother of a newborn with ophthalmia neonatorum;

Unplanned termination of pregnancy in areas or populations of high gonorrhoea prevalence;

Any intrauterine interventions or manipulations in areas or populations of high gonorrhoea prevalence.^28,29

Testing and diagnosis

Diagnosis of uncomplicated gonorrhoea is established by identification of N. gonorrhoeae in urogenital, rectal, oropharyngeal, or ocular secretions. No diagnostic test for gonorrhoea offers 100% sensitivity and specificity;^1,30

N. gonorrhoeae can be specifically detected by nucleic acid amplification tests (NAATs) or culture. The bacterium can also be visualized by microscopy of a stained anogenital tract smear to facilitate rapid diagnosis in symptomatic patients;

Microscopy (×1000) using Gram or methylene blue staining for identification of characteristic intracellular diplococci within polymorphonuclear leukocytes offers adequate sensitivity (90-95%) and specificity (>99%) as a rapid diagnostic test in symptomatic men with urethral discharge [1C].^{1–3,15,30,31} However, microscopy has a low sensitivity in asymptomatic men (50-75%) and from endocervical (16-50%) or rectal (≤40%) sites, and microscopy is not recommended as a test of exclusion in these patients [1C].^{1–3,15,17,30–34} Microscopy is also not recommended for detection of oropharyngeal gonorrhoea due to low specificity and sensitivity;

Culture, including appropriate species confirmation, is a highly specific test, and relatively sensitive for urogenital specimens. Culture is also the only diagnostic test that enables complete antimicrobial resistance (AMR) testing, and capacity to perform culture remains essential to detect and monitor evolving AMR. Ideally, all gonococcus-positive individuals diagnosed by NAAT should have cultures performed before initiation of gonorrhoea treatment to permit AMR testing and surveillance to be performed. Selective culture media containing antimicrobials such as vancomycin, colistin, nystatin, and trimethoprim are recommended [1C].^1,30,33 Non-selective culture media are of benefit when used in addition to the selective media for urogenital and conjunctival specimens, if affordable. Diagnostic culture is appropriate for endocervical, urethral, rectal, oropharyngeal and conjunctival specimens but not for urine or vaginal swabs.^1,3,30 The sensitivity of culture is high for urogenital specimens provided that specimen collection, transport, storage, and culture procedures are optimised. However, the sensitivity of culture for rectal and oropharyngeal specimens is significantly lower.^1,3,30,35 Appropriate quality assurance, including internal quality controls and external quality assessment, is recommended for the culture system since commercial culture media and culture procedures vary significantly in their sensitivity and specificity. Culture (ideally supplemented with a NAAT for optimal sensitivity), including AMR testing, should also be performed in patients with proven infection after treatment (i.e. positive test of cure [TOC]) or in the presence of symptoms following treatment with a recommended regimen;^1–3,30,36

NAATs are the recommended diagnostic tests for symptomatic and asymptomatic individuals,^1,3,37–41 however, culture of individuals with urogenital symptoms and in gonococcal NAAT-positive individuals prior to treatment to obtain isolates for AMR testing is also encouraged. NAATs are more sensitive than culture (particularly for oropharyngeal and rectal specimens); less demanding in specimen quality, transportation and storage; offer testing on a wider range of specimen types; and show high sensitivity (>95%) in both symptomatic and asymptomatic gonorrhoea.^{1,3,30,35–55} NAATs show equivalent sensitivity in urine and urethral swabs from men, and urine (up to 20 mL sampled >1 h after previous micturition) is preferable because it is less invasive.^1,3,39,45,55 In women, higher sensitivity for vulvo-vaginal swabs than for endocervical swabs has been reported and vaginal swabs may be self-collected.^1,3,39,55 Urine samples in women have lower sensitivity and are suboptimal.^{1,3,36–40,54–57} Accordingly, vulvo-vaginal swabs (health care worker- or self-collected) are recommended in women due to their superior sensitivity and ease of sampling [1A].^{1,3,36–41,47,54–57} The performance characteristics of different commercially available or in-house gonococcal NAATs can differ substantially in sensitivity and particularly specificity,^{1,3,30,58–60} and appropriate validation and quality assurance of all diagnostic NAATs are crucial.

NAATs are significantly more sensitive than culture^{1,3,30,35,38–41,49,52,53,61–67} for detection of rectal and oropharyngeal gonorrhoea due to frequently lower gonococcal load compared to urogenital infection.^61,62 Optimal sampling technique⁶⁸ and appropriate, validated and quality assured NAATs are recommended for testing and/or screening for infections at these sites.^{1,3,38–41,69,70} However, most commercially available gonococcal NAATs are not licensed for testing oropharyngeal and rectal specimens, and differ substantially in their specificity,^{1,3,30,38,40,58–60} particularly when examining oropharyngeal specimens due to the frequent presence of non-gonococcal Neisseria species. At present, only two commercially available gonococcal NAATs are approved by the US Food and Drug Administration (FDA) for testing rectal and oropharyngeal specimens.¹ If using other gonococcal NAATs, then strict local evaluation should be performed before introducing the NAAT for testing of oropharyngeal and rectal specimens. When used after appropriate evaluation, supplementary testing for confirmation is recommended as below [1C];^{1,3,30,38,39,69–72}

When using NAATs to detect N. gonorrhoeae, the positive predictive value (PPV) of the testing should exceed 90%. The PPV is highly influenced by the prevalence of gonorrhoea in the tested population and of the specificity of the NAAT.^1,3,30,58,60 If the diagnostic NAAT used does not display a PPV exceeding 90%, positive specimens should be subjected to confirmatory testing, i.e. repeated testing with a NAAT targeting another genetic sequence, particularly if oropharyngeal specimens are tested [1C];^{1,3,30,38,39,59,60,69–73}

Point-of-care tests (POCTs): rapid, validated and quality-assured POCTs for diagnosis of gonorrhoea with sufficient sensitivity compared to NAATs are still lacking; however, several NAAT-based POCTs with high sensitivity and specificity are in late development (https://www.who.int/reproductivehealth/topics/rtis/Diagnostic-Landscape-for-STIs-2019.pdf).^1,74–76 Ideally, such tests should combine detection of N. gonorrhoeae and antimicrobial resistance prediction.^77–79

Testing of rectal and oropharyngeal specimens should be routine in MSM, considered in women who are sexual contacts of gonorrhoea patients [1C], and be guided based on sexual history, risk and symptoms or signs in all other patients.^3,39,80–89

Testing of pooled specimens (oropharyngeal, rectal, and urine/urogenital) could provide cost savings, but is not recommended, due to potentially decreased sensitivity,^3,39,90–93 increased complexity, including risk of cross-contamination of sample, and lack of approval by FDA or other regulatory agencies. However, the evidence is limited and additional appropriate studies using different NAATs and evaluating cost and benefits (e.g. if the lower sensitivity is compensated by detecting more cases compared to only testing urogenital specimens) are encouraged, especially in less-resourced settings where testing three sites may not be affordable.

Management of patients

Information, explanation and advice for the patient

Patients with verified gonorrhoea should be advised to abstain from sexual contact (or if this is not possible to consistently use barrier contraception) for 14 days (seven days if ceftriaxone monotherapy)^3,39,40 after they and their sexual partners have completed a ceftriaxone plus azithromycin dual treatment and their symptoms have resolved [2D]. This is to avoid possible re-exposure in the presence of residual azithromycin;

Patients (and their sexual partners) should be given information about their infection, including details about transmission, prevention, complications and treatment. It is recommended that both verbal and written information be provided [1D];

A patient information leaflet is available in different languages from the European branch of the International Union Against Sexually Transmitted Infections (IUSTI) (https://iusti.org/patient-information/).

Patients with verified gonorrhoea (and their sexual contacts) are recommended to be offered testing for other STIs, e.g. C. trachomatis, Mycoplasma genitalium (only if symptomatic patient and always including macrolide resistance testing), syphilis, hepatitis B, hepatitis C, and HIV [1C].

Therapy

N. gonorrhoeae has shown an extraordinary capacity to develop resistance to all classes of antimicrobials available for treatment of gonorrhoea.^94,95 When in vitro and sporadic clinical resistance to ceftriaxone emerged in the last decade,^94–97 dual antimicrobial therapy (mainly ceftriaxone plus azithromycin) was introduced as the first-line empirical treatment for uncomplicated gonorrhoea in Europe³ and in many additional settings such as the USA,⁴⁰ Canada,⁹⁸ Australia,⁹⁹ and globally by the WHO.¹⁰⁰ The dual antimicrobial therapy aimed to provide cure for all gonorrhoea cases and, accordingly, to delay the emergence and/or spread of multi-drug resistance in general and ceftriaxone resistance in particular. Ceftriaxone and azithromycin have not shown any synergy conclusively in vitro, however, they are not antagonistic,^101–105 have very high cure rates, effectively target both intracellular and extracellular bacteria,¹⁰⁶ have likely been involved in decreasing the level of resistance to extended-spectrum cephalosporins (ESCs; mainly ceftriaxone and cefixime) internationally,^107–111 and inhibited spread of ESC-resistant as well as azithromycin-resistant gonococcal strains (because concurrent resistance to ceftriaxone and azithromycin has been exceedingly rare globally) (https://www.ecdc.europa.eu/en/publications-data).^{107,109–111} The ceftriaxone plus azithromycin dual therapy also effectively eradicates concomitant C. trachomatis infection^3,40,112 and a proportion of M. genitalium infections, which are common in many settings. Ceftriaxone 500 mg plus azithromycin 2 g was introduced as the first-line therapy for gonorrhoea in Europe in 2011–2012,³ and the vast majority of clinicians appear to adhere to the recommendations of dual therapy, i.e. to give ceftriaxone 500 mg plus azithromycin 1-2 g.¹¹³ Since its introduction, the resistance to cefixime in the EU/EEA has decreased from 7.6% in 2010 to 1.4% in 2018 and only three ceftriaxone-resistant isolates were identified in the European Gonococcal Antimicrobial Surveillance Programme (Euro-GASP) 2015–2018 (all in 2018). Nevertheless, resistance to azithromycin increased from 5.3% in 2011 to 7.9% in 2014, remained stable at 7-7.5% 2015–2017, and then increased to 13.3% in 2018, which is nearly identical to the azithromycin resistance recorded in the EU/EEA in 2009 (13.2%) (https://www.ecdc.europa.eu/en/publications-data).^{107,109–111} Sporadic cases of N. gonorrhoeae strains with high-level resistance to azithromycin (MIC > 256 mg/L) have been identified in many countries, however, a sustained spread of such strains has only been verified in England.^94,114 However, no azithromycin clinical resistance breakpoints have existed since 2019, due to its limited recent use as monotherapy and suboptimal correlation between in vitro data and clinical outcome.^115–117 According to the epidemiological cutoff (ECOFF) stated by the European Committee on Antimicrobial Susceptibility testing (EUCAST; www.eucast.org), 7.6% of isolates in 2018 had azithromycin resistance determinants (“in vitro non-susceptible”). Importantly, resistance to ceftriaxone combined with in vitro non-susceptibility to azithromycin has remained exceedingly rare compromising only 4 (0.02%) isolates in the Euro-GASP in 2011–2018 (2011 [n = 1], 2014 [n = 2], 2018 [n = 1]) (https://www.ecdc.europa.eu/en/publications-data).^{107,109–111} Notably, selection of gonococcal non-susceptibility to azithromycin through the use of ceftriaxone plus azithromycin therapy for gonorrhoea is limited, i.e. when ceftriaxone resistance is very rare (https://www.ecdc.europa.eu/en/publications-data) and ceftriaxone quickly eradicates any emerging azithromycin-non-susceptible gonococcal cells.^106,118 Instead, the non-susceptibility in N. gonorrhoeae (and M. genitalium) to azithromycin is likely mostly a consequence of the widespread use of azithromycin therapy to treat C. trachomatis and M. genitalium infections, non-gonococcal urethritis, respiratory tract infections, and general use of macrolides for other infections.^106,118,119 Nevertheless, azithromycin may be detected in some body sites for up to 2-4 weeks after treatment.^{106,120–122} If a very high-risk individual is re-infected with gonorrhoea (after effective cure of initial gonorrhoea with dual antimicrobial therapy) during this time period, azithromycin resistance could potentially be selected, however, further understanding regarding the frequency and mechanisms for selecting gonococcal azithromycin resistance by this type of low-concentration subinhibitory azithromycin “tail” is required. Furthermore, the significance of prior exposure to azithromycin for selection of gonococcal resistance also remains unclear.^123–127 Worryingly, decreased susceptibility or resistance to ceftriaxone has been identified worldwide¹²⁸ and since 2015 a gonococcal strain with ceftriaxone resistance (but susceptibility or susceptibility, increased exposure, to azithromycin) has been sporadically identified worldwide, including in many EU/EEA countries.^129–138 In early 2018, isolates of the first strain with combined ceftriaxone resistance and high-level azithromycin resistance were cultured in both the UK and Australia,^139,140 but fortunately no further spread of this strain has been reported. Importation of AMR gonococcal strains remains an important threat in Europe.¹⁴¹ Several treatment failures have been verified even with the use of higher doses of ceftriaxone (500–1000 mg) monotherapy.¹²⁸ It has been suggested that maintaining free ceftriaxone levels above the MIC (fT_>MIC) for 20–24 hours is required for effective cure.¹⁴² Consequently, even with ceftriaxone 1 g treatment, sufficient fT_>MIC (≥20 hours) will not be reached in many patients infected with the internationally spreading ceftriaxone-resistant strain showing ceftriaxone MIC = 0.5-1 mg/L.¹⁴² The same is true for up to 5% of individuals infected with gonococcal strains which have ceftriaxone MICs of 0.125 mg/L,¹⁴² which represented 0.8% of the gonococcal isolates in Euro-GASP in 2018 (https://www.ecdc.europa.eu/en/publications-data). This is in line with the relatively low ceftriaxone MICs of strains associated with several verified treatment failures.¹²⁸ Most verified gonorrhoea treatment failures with ceftriaxone (±azithromycin or doxycycline), were subsequently cured by increasing the ceftriaxone dose and/or adding azithromycin to the treatment regimen.¹²⁸ At present, no gonorrhoea treatment failure has been verified following the use of the ceftriaxone 500 mg plus azithromycin 2 g regimen recommended in the 2012 European gonorrhoea guideline.³ Azithromycin 2 g more effectively cures azithromycin-susceptible gonococcal infections, compared to azithromycin 1 g.^{115,128,143–145} However, azithromycin 2 g single oral dose also results in more gastrointestinal side effects, particularly if taken on empty stomach.^144,146,147 Most important, severe vomiting needs to be avoided before the azithromycin dose has been absorbed, i.e. in about one hour, which reduces the efficacy.^106,143,144 A high “front-end” azithromycin dose results in superior clearance of bacteria and is more beneficial in acute infections.^106,148 Dividing the dose of azithromycin to give it over a longer period of time reduces the high and sustained tissue concentration, but also reduces the risk of gastrointestinal side effects.^{106,148–154} Notably, some gonorrhoea treatment studies and syphilis treatment studies using azithromycin 2 g single oral dose report substantially lower rates of mild and severe gastrointestinal side effects.^143,155,156 The availability of novel antimicrobials for effective treatment of gonorrhoea is imperative,^157,158 and ultimately, a gonococcal vaccine is the only sustainable solution for effective control of gonorrhoea.¹⁵⁹

In general, recent published randomised controlled clinical trials (RCTs) on the treatment of gonorrhoea are very few and do not address the rapidly evolving situation of AMR in N. gonorrhoeae. Treatment regimens recommended in the present guideline are based on early clinical efficacy trials, pharmacokinetic/pharmacodynamic (PK/PD) considerations,¹⁴² in vitro AMR surveillance data in Europe and internationally,^{107,109–111,128} case reports of verified treatment failures,^96,97,128 and expert opinion. However, significant variations between different European countries in STI health care, patient and partner management, including follow up, and gonococcal AMR and AMR surveillance exist. Accordingly, national adoption of the European gonorrhoea guideline based on comprehensive, recent, quality-assured AMR data and an effective patient management strategy, e.g. including mandatory TOC, locally can be reasonable.^3,158,160

Indications for therapy [1C]

Identification of characteristic intracellular diplococci within polymorphonuclear leukocytes in a sample from a urogenital site by Gram-stained or methylene blue-stained microscopy;

Positive culture or confirmed NAAT from any site for N. gonorrhoeae (or unconfirmed NAAT from urogenital specimens in settings where PPV>90%);

On epidemiological grounds, if a recent sexual contact has confirmed gonorrhoea,¹⁶¹ mother of neonate with verified gonorrhoea, and can be considered following sexual assault. When giving treatment based on epidemiological grounds, specimen(s) for laboratory testing should be collected;

On demonstration of a purulent urethral discharge in men or mucopurulent cervicitis in women when rapid diagnostic tests such as microscopy are not available and after specimen collection for laboratory testing. In this circumstance, empirical treatment covering also C. trachomatis infection should be considered.

Recommended treatment for uncomplicated N. gonorrhoeae infections of the urethra, cervix and rectum in adults and adolescents when the antimicrobial susceptibility of the infection is unknown^{3,39,40,98,106,118,162–170}

Ceftriaxone 1 g intramuscularly (IM) as a single dose together with azithromycin 2 g as a single oral dose [1C]

If gastrointestinal side effects are anticipated: ceftriaxone 1 g IM single dose plus azithromycin 1 g oral dose followed by azithromycin 1 g oral dose 6–12 h later may be used to limit gastrointestinal side effects^106,154

NOTE: Azithromycin tablets should not be taken on empty stomach due to possible gastrointestinal side effects. If required, snack or crackers can be given to patients before taking the azithromycin tablets.^143,144,162 For patients perceived to be at risk of vomiting, an anti-emetic can be provided.⁹⁹

Ceftriaxone 1 g IM as a single dose [2C]

NOTE: Only recommended in settings where:

comprehensive, recent and quality-assured local in vitro ceftriaxone susceptibility testing has shown lack of ceftriaxone resistance;

TOC is mandatory;

the patient is considered very likely to return for TOC;

doxycycline 100 mg oral dose twice daily for 7 days is administered at the same time to cover any concomitant C. trachomatis infection, if C. trachomatis infection has not been excluded by NAAT.

In other settings, ceftriaxone 1 g IM monotherapy is only an alternative option if azithromycin is not available or patient is unable to take oral medication.

Treatment when patient has history of severe hypersensitivity (e.g. anaphylaxis) to any β-lactam antimicrobial (penicillins, cephalosporins, monobactams or carbapenems)^3,39,40

Third-generation cephalosporins, such as ceftriaxone, show negligible cross-allergy with penicillins and allergy to these cephalosporins is rare.^171–175 If allergy is not excluded and ceftriaxone needs to be given, the patient should be under medical supervision for at least 30 minutes post-treatment.

Spectinomycin resistance is currently exceedingly rare but it has poor efficacy for oropharyngeal infection,^3,40,94,163 and should not be used as monotherapy if oropharyngeal infection has not been excluded by appropriate NAAT testing.

Recommended treatment

Spectinomycin 2 g IM as a single dose [1B] together with azithromycin 2 g as a single oral dose [1C]

If gastrointestinal side effects are anticipated: spectinomycin 2 g IM single dose plus azithromycin 1 g oral dose followed by azithromycin 1 g oral dose 6–12 h later may be used^106,154

NOTE: See use of azithromycin 2 g for treatments of uncomplicated N. gonorrhoeae infections of the urethra, cervix and rectum.

Alternative treatment

Resistance to ciprofloxacin is very common across EU/EEA (https://www.ecdc.europa.eu/en/publications-data) and internationally.^{107,109–111,128} For susceptible gonococcal infections, early clinical trials demonstrated that ciprofloxacin (500 mg) had high efficacy.^163,164,176 Accordingly, for gonorrhoea patients with severe hypersensitivity to β-lactam antimicrobials, this is an alternative treatment when the infection has been confirmed before treatment to be susceptible to ciprofloxacin, that is, using phenotypic AMR testing or validated and quality-assured molecular gyrA-based resistance testing for fluoroquinolones (molecular testing should only be used for anogenital samples due to potential cross-reactions with commensal Neisseria species in pharyngeal samples):^{69,77–79,177–}¹⁸⁰

Ciprofloxacin 500 mg as a single oral dose [1B]

Gentamicin 240 mg IM as a single dose together with azithromycin 2 g as a single oral dose [1B]

If gastrointestinal side effects are anticipated: gentamicin 240 mg IM single dose plus azithromycin 1 g oral dose followed by azithromycin 1 g oral dose 6-12 h later may be used^106,154

NOTE: The European Medicines Agency (EMA) has alerted a risk of serious side effects associated with the use of quinolone/fluoroquinolone antibiotics.¹⁸¹ Ciprofloxacin should be avoided in people who have previously had serious side effects with any quinolone, and it should be used with caution in those >60 years, taking a corticosteroid, having kidney disease and who have had an organ transplantation. However, single ciprofloxacin 500 mg oral dose likely limits the risk of side effects. See note regarding use of azithromycin 2 g for treatments of uncomplicated N. gonorrhoeae infections of the urethra, cervix and rectum.

Treatment when administration of an intramuscular injection is contraindicated or refused

Multiple reports of treatment failures with cefixime and PK/PD investigations have raised serious concerns over the adequacy of 400 mg of cefixime for treatment, particularly for monotherapy and treatment of oropharyngeal gonorrhoea.^{96,97,128,142,182–185} The cefixime resistance level in Europe has decreased to 1.4% in 2018, however, it ranges from 0% to 20% in different EU/EEA countries (https://www.ecdc.europa.eu/en/publications-data).

Recommended treatment

Cefixime 400 mg as a single oral dose together with azithromycin 2 g as a single oral dose [1B]

If gastrointestinal side effects are anticipated: cefixime 400 mg single oral dose plus azithromycin 1 g oral dose followed by azithromycin 1 g oral dose 6–12 h later may be used^106,154

NOTE: See use of azithromycin 2 g for treatments of uncomplicated N. gonorrhoeae infections of the urethra, cervix and rectum.

Alternative treatment

When the infection has been confirmed before treatment to be susceptible to ciprofloxacin, that is, using phenotypic AMR testing or validated and quality-assured molecular gyrA-based resistance testing for fluoroquinolones (molecular testing should only be used for anogenital samples due to potential cross-reactions with commensal Neisseria species in pharyngeal samples):^{69,77–79,177–180}

Ciprofloxacin 500 mg as a single oral dose [1B]

NOTE: Co-infection with C. trachomatis is common in young (<30 years) heterosexual patients and MSM with gonorrhoea.^{3,11,12,39,40} If treatment for gonorrhoea does not include azithromycin, doxycycline 100 mg oral dose twice daily for 7 days should be considered for possible C. trachomatis co-infection unless co-infection has been excluded with NAAT testing.^3,39,40

Treatment for gonococcal infection of the pharynx or when such infection has not been excluded

Many antimicrobials have a substantially lower efficacy (≤90%) in curing oropharyngeal gonorrhoea compared to urogenital and anorectal infection.^{3,39,40,96,97,115,128,139,142,163,164,181–192} This is likely due to suboptimal PK/PD properties, and improved PK/PD data for gonorrhoea are imperative, in particular for oropharyngeal infection.^106,185,195 All verified failures to cure gonorrhoea with ceftriaxone (±azithromycin or doxycycline), except one recent case in the UK,¹³⁶ have been at the oropharyngeal site.¹²⁸ Most of these infections were cured by increasing the ceftriaxone dose and/or adding azithromycin to the treatment regimen.¹²⁸ Oropharyngeal gonorrhoea is usually asymptomatic, tissue penetration of several antimicrobials is limited, and it has been suggested that N. gonorrhoeae acquires molecular AMR determinants from cohabiting non-gonococcal Neisseria species at this site.^{8,96,97,129,185,194,195} Furthermore, it has been suggested that the direct transmission of N. gonorrhoeae from oropharynx to other sites can be substantial.^4–7 Ceftriaxone 1 g effectively cures ceftriaxone-susceptible oropharyngeal gonorrhoea.¹⁶⁶ Azithromycin reaches high levels in saliva/gingiva^106,196 and tonsillar tissue,^106,197 indicating high oral tissue penetration. This suggests that azithromycin at an appropriate dose is highly effective for the treatment of oropharyngeal gonorrhoea. Azithromycin 2 g, but not azithromycin 1 g,^115,116,145 effectively cures azithromycin-susceptible gonococcal infections, including in the oropharynx.^{3,39,115,116,143,144} Cephalosporins combined with another antimicrobial active against N. gonorrhoeae, including azithromycin, can more effectively cure oropharyngeal gonorrhoea.^{3,108,118,128,143,198,199} Spectinomycin has very low efficacy in treatment of oropharyngeal gonorrhoea.^{3,40,94,163,164}

Recommended treatment

Ceftriaxone 1 g IM as a single dose together with azithromycin 2 g as a single oral dose [1D]

If gastrointestinal side effects are anticipated: ceftriaxone 1 g IM single dose plus azithromycin 1 g oral dose followed by azithromycin 1 g oral dose 6–12 h later may be used^106,154

NOTE: See use of azithromycin 2 g for treatments of uncomplicated N. gonorrhoeae infections of the urethra, cervix and rectum.

Alternative regimens

Ceftriaxone 1 g IM as a single dose [2D]

NOTE: This regimen is only an option if azithromycin is not available or the patient is unable to take oral medication.

Ciprofloxacin 500 mg as a single oral dose [1B]

NOTE: This regimen is only an alternative for treatment when the infection has been confirmed before treatment to be susceptible, that is, using phenotypic AMR testing or validated and quality-assured molecular gyrA-based resistance testing for fluoroquinolones (molecular testing should only be used for anogenital samples due to potential cross-reactions with commensal Neisseria species in pharyngeal samples)^{69,77–79,177–180}

Recommended treatment for genital, anorectal and oropharyngeal gonococcal infection when ceftriaxone resistance is identified^{3,100,143,144}

The management of patients with ceftriaxone-resistant gonorrhoea or verified treatment failures following other recommended antimicrobial regimens requires advice from specialist STI clinicians and microbiologists, and should include sexual contact notification and follow-up with TOC. Where relevant, these cases should be notified to local, regional and/or national authorities as mandated by statute. Three-site testing for N. gonorrhoeae, including culture and AMR testing, is recommended for all patients with ceftriaxone-resistant gonorrhoea. AMR testing, when available, should inform on further treatment.

Ceftriaxone 1 g IM as a single dose together with azithromycin 2 g as a single oral dose [1D], i.e. when ceftriaxone monotherapy, a lower ceftriaxone dose, or another treatment regimen was given initially given.

Spectinomycin 2 g IM as a single dose [1B] together with azithromycin 2 g as a single oral dose [1C]

Gentamicin 240 mg IM as a single dose together with azithromycin 2 g as a single oral dose [1B]

The high efficacy (100% [95%CI 95–100%]) of the gentamicin 240 mg plus azithromycin 2 g treatment regimen for treatment of anogenital and oropharyngeal gonorrhoea was confirmed in two recent RCTs.^143,144 The in vitro susceptibility to gentamicin of N. gonorrhoeae strains circulating in Europe and globally is also high.^200–203 Notable, according to another recent RCT gentamicin 240 mg IM combined with only 1 g of azithromycin orally is relatively effective against urogenital gonorrhoea (clearance: 94%), but suboptimal to eradicate rectal (90%) and particularly oropharyngeal gonorrhoea (82%), which additionally indicates that both gentamicin 240 mg and azithromycin 1 g are insufficient to treat gonorrhoea when used as monotherapy.^115,116,145 Furthermore, gentamicin IM monotherapy also in higher dose (360 mg) fails to eradicate N. gonorrhoeae in many pharyngeal infections.¹⁹²

NOTE: See use of azithromycin 2 g for treatments of uncomplicated N. gonorrhoeae infections of the urethra, cervix and rectum.

Ertapenem 1 g IM once daily for three days [2D]

This treatment regimen has only been used in a very small number of patients with oropharyngeal gonorrhoea resistant to ceftriaxone or ceftriaxone plus azithromycin.^128,136,139 The in vitro susceptibility to ertapenem is high and, despite having increased MICs due to ceftriaxone-resistance determinants, it has some in vitro advantages over ceftriaxone for ceftriaxone-resistant strains. However, ertapenem also has suboptimal PK/PD properties.^{190,204–207}

Treatment for gonococcal infections in pregnancy or when breastfeeding^208–210

Recommended treatment

Ceftriaxone 1 g IM as a single dose together with azithromycin 2 g as a single oral dose [1D]

If gastrointestinal side effects are anticipated: ceftriaxone 1 g IM single dose plus azithromycin 1 g oral dose followed by azithromycin 1 g oral dose 6-12 h later may be used^106,154

Alternative regimens

Spectinomycin 2 g IM as a single dose together with azithromycin 2 g as a single oral dose [1D]

If gastrointestinal side effects are anticipated: spectinomycin 2 g IM single dose plus azithromycin 1 g oral dose followed by azithromycin 1 g oral dose 6–12 h later may be used^106,154

Ceftriaxone 1 g IM as a single dose [2D]

NOTE: Pregnancy does not significantly affect the efficacy of treatment. Pregnant and breastfeeding women should not be treated with fluoroquinolones or tetracyclines. The safety of azithromycin 2 g in pregnancy cannot be guaranteed but clinical experience indicates that it can be used safely. However, it should only be used under medical supervision if the expected benefit to the mother is thought to be greater than the possible risk to the foetus.²¹¹ See note regarding use of azithromycin 2 g for treatments of uncomplicated N. gonorrhoeae infections of the urethra, cervix and rectum.

Treatment for upper genital tract gonococcal infection

Epididymo-orchitis

See the latest version of the ‘European guideline on the management of epididymo-orchitis’ (https://iusti.org/treatment-guidelines/).

Pelvic inflammatory disease

See the latest version of the ‘European guideline for the management of pelvic inflammatory disease’(https://iusti.org/treatment-guidelines/).

Recommended treatment for disseminated gonococcal infection [2D]

There have been no clinical trials on the treatment of DGI since the progressive development of AMR by N. gonorrhoeae. Verified DGI cases are generally rare,^20,22,23 but can be substantially more common in high-prevalent gonorrhoea areas and can be expected to increase when the gonorrhoea incidence increases.²⁴ Recommended treatment is based on current AMR data, observational data from case series and the principals of treating septicaemia. Hospitalization is recommended for initial therapy,^{3,20,21,39,40,212,213} and gonococcal culture and AMR testing should be performed.

Initial therapy:

Ceftriaxone 1 g IM or IV every 24 hours OR

Cefotaxime 1 g IV every 8 hours OR

Spectinomycin 2 g IM every 12 hours.

Therapy should continue for 7 days, but may be switched 24–48 hours after substantial clinical improvement to one of the following oral regimens guided by AMR testing:

Cefixime 400 mg oral dose twice daily OR

Ciprofloxacin 500 mg oral dose twice daily.

NOTE: Ciprofloxacin should only be used when the infection has been confirmed before treatment to be susceptible, that is, using phenotypic AMR testing or validated and quality-assured molecular gyrA-based resistance testing for fluoroquinolones (molecular testing should only be used for anogenital samples due to potential cross-reactions with commensal Neisseria species in pharyngeal samples)^{69,77–79,177–}¹⁸⁰

Recommended treatment for gonococcal conjunctivitis^3,39,40

There is a lack of recent clinical data for treatment of gonococcal conjunctivitis. Only a single outdated study of the treatment of gonococcal conjunctivitis with ceftriaxone 1 g, including 13 adults, has been performed.²¹⁴ All 13 patients were successfully treated. The eye should be irrigated frequently with sterile saline solution.

Ceftriaxone 1 g IM as a single dose together with azithromycin 2 g as a single oral dose [2D]

If gastrointestinal side effects are anticipated: ceftriaxone 1 g IM single dose plus azithromycin 1 g oral dose followed by azithromycin 1 g oral dose 6-12 h later may be used to limit gastrointestinal side effects^106,154

NOTE: See use of azithromycin 2 g for treatments of uncomplicated N. gonorrhoeae infections of the urethra, cervix and rectum.

Recommended treatment for ophthalmia neonatorum (gonococcal neonatal conjunctivitis)^3,39,40

The eye should be irrigated frequently with sterile saline solution.

Ceftriaxone 25–50 mg/kg IV or IM as a single dose, not to exceed 125 mg

Recommended treatment for people living with HIV^3,39,40

People living with HIV with gonorrhoea should be treated in an identical way to HIV-negative individuals.

Recommended treatment for uncomplicated Neisseria meningitidis infection of the urethra^215–217

Individuals with uncomplicated urethritis caused by N. meningitidis should be treated in an identical way to patients with gonococcal urethritis.

Sexual contact notification and management of sex contact(s)

Sexual contact notification should be performed and documented by appropriately trained professionals at the time of diagnosis to prevent reinfection and reduce onward transmission [1B];

Sexual contacts should be contacted and offered (and encouraged to have) testing for gonorrhoea (and other STIs) together with antimicrobial treatment if appropriate (i.e. if positive N. gonorrhoeae test or clinician considers contacts will not return for treatment after testing results are available), and receive counseling for gonorrhoea and other STIs [1D];

For cases of gonorrhoea, all sexual contact(s) within the preceding 3 months of onset of symptoms or diagnosis should be tested and treated if positive [2D].^3,39,40,161 For further information, see the latest version of the ‘European guidelines for the management of partners of persons with sexually transmitted infections’ (https://iusti.org/treatment-guidelines/).

Follow-up and test of cure

Assessment after treatment is recommended to confirm eradication of infection, compliance with therapy, enquire about adverse effects, resolution of symptoms and signs, take a sexual history to explore the possibility of re-infection, and pursue partner notification and health promotion [1D];

A TOC is recommended in all cases to identify persisting infection (possible treatment failure) and emerging AMR.^3,36 TOC is particularly important to perform if any alternative treatment regimen has been used and to ensure effective eradication of oropharyngeal infection, which is substantially harder to treat than urogenital and anorectal infections.^{3,39,40,96,97,115,128,139,142,163,164,182–193} When symptoms and/or signs persist after treatment, culture is recommended to identify persisting infection and for AMR testing, and should be performed 3–7 days after completion of therapy, possibly supplemented a week later with a NAAT for increased sensitivity if culture is negative. TOC in asymptomatic patients can be performed with a NAAT 2 weeks after completion of treatment and ideally, all positive patients should be cultured and AMR testing performed before further treatment is given. It is important to emphasize that the time to a negative TOC with a NAAT after successful eradication of anogenital gonorrhoea varies (and also varies depending on whether RNA- or DNA-based NAATs are used).^35,218,219 There is limited evidence available, and no relevant evidence for oropharyngeal gonorrhoea, for which a longer time to achieve a negative TOC using NAAT cannot be excluded. A positive TOC can be due to treatment failure, but also reinfection or, when NAATs are used, residual nucleic acid from non-viable gonococci, and needs to be followed up and interpreted in the clinical context [2C].^35,218,219

Identification, confirmation and reporting of treatment failures

The surveillance (including identification, confirmation and reporting) of possible and confirmed failures with recommended treatment regimens should be enhanced, which is detailed in the ECDC Response Plan.¹⁶⁰ Ideally, as much clinical and laboratory data as feasible should be collected and reported on treatment failures, including a detailed clinical history (including all antimicrobial treatments given), the exclusion of reinfection, whole genome sequencing of pre-treatment and post-treatment gonococcal isolates or other highly discriminative molecular epidemiological typing of NAAT specimens (identifying indistinguishable isolates/genetic variants), and presence of phenotypic and/or molecular assessment of resistance (AMR determinants) to the prescribed treatment using the gonococcal isolates or NAAT specimens.^160,220

Notification

N. gonorrhoeae infections should be notified to local, regional and national authorities as mandated by statute. The ECDC is responsible for the EU/EEA-wide surveillance of communicable diseases including gonorrhoea.

Search strategy

This evidence-based guideline represents an updated version of the ‘2012 European guideline on the diagnosis and treatment of gonorrhoea in adults’.³ The present guideline was produced according to the protocol for production and revision of European STI guidelines, which has been written and approved by the IUSTI European STI Guidelines Editorial Board (https://iusti.org/wpcontent/uploads/2019/12/Euro_Guidelines_Protocol_2010.pdf). A Medline search was conducted up to June 2020 using PubMed for articles published since the development of the 2012 European gonorrhoea guideline.³ Search headings were kept broad (i) gonorrhoea, iii) gonorrhea or ii) Neisseria gonorrhoeae to include epidemiology, diagnosis, antimicrobial resistance, therapy, clinical trials and prevention and control. Only publications and abstracts in the English language were considered. The Cochrane Library was searched for all entries related to gonorrhoea/gonorrhea or Neisseria gonorrhoeae. Relevant STI guidelines produced by the WHO (www.who.int), US Centers for Disease Control and Prevention (www.cdc.gov/std/) and the British Association for Sexual Health and HIV (www.bashh.org) were also reviewed.

Levels of evidence and grading of recommendations

Levels of evidence and grading of recommendations that were used in the present guideline can be found in the protocol for production and revision of European STI guidelines at: https://iusti.org/wpcontent/uploads/2019/12/Euro_Guidelines_Protocol_2010.pdf

Footnotes

Acknowledgements

The authors are grateful to Chris Bignell for being the first author of the outdated 2012 European gonorrhoea guidelines,³ and to Fabian Kong for valuable discussions regarding PK/PD.

Declaration of conflicting interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JR reports personal fees from GSK Pharma, Mycovia, and Nabriva Therapeutics as well as ownership of shares in GSK Pharma and AstraZeneca Pharma. The other author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

M Unemo

JS Jensen

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Background review for the ‘2020 European guideline for the diagnosis and treatment of gonorrhoea in adults’

Abstract

Keywords

Aetiology, transmission, and epidemiology

Clinical features1–3,14–20

Symptoms

Physical signs

Complications and sequelae

Indications for testing [2C]

Testing and diagnosis

Management of patients

Information, explanation and advice for the patient

Therapy

Indications for therapy [1C]

Recommended treatment for uncomplicated N. gonorrhoeae infections of the urethra, cervix and rectum in adults and adolescents when the antimicrobial susceptibility of the infection is unknown3,39,40,98,106,118,162–170

Treatment when patient has history of severe hypersensitivity (e.g. anaphylaxis) to any β-lactam antimicrobial (penicillins, cephalosporins, monobactams or carbapenems)3,39,40

Recommended treatment

Alternative treatment

Treatment when administration of an intramuscular injection is contraindicated or refused

Recommended treatment

Alternative treatment

Treatment for gonococcal infection of the pharynx or when such infection has not been excluded

Recommended treatment

Alternative regimens

Recommended treatment for genital, anorectal and oropharyngeal gonococcal infection when ceftriaxone resistance is identified3,100,143,144

Treatment for gonococcal infections in pregnancy or when breastfeeding208–210

Recommended treatment

Alternative regimens

Treatment for upper genital tract gonococcal infection

Epididymo-orchitis

Pelvic inflammatory disease

Recommended treatment for disseminated gonococcal infection [2D]

Recommended treatment for gonococcal conjunctivitis3,39,40

Recommended treatment for ophthalmia neonatorum (gonococcal neonatal conjunctivitis)3,39,40

Recommended treatment for people living with HIV3,39,40

Recommended treatment for uncomplicated Neisseria meningitidis infection of the urethra215–217

Sexual contact notification and management of sex contact(s)

Follow-up and test of cure

Identification, confirmation and reporting of treatment failures

Notification

Search strategy

Levels of evidence and grading of recommendations

Footnotes

Acknowledgements

Declaration of conflicting interests

Funding

ORCID iDs

References

Clinical features^{1–3,14–20}

Recommended treatment for uncomplicated N. gonorrhoeae infections of the urethra, cervix and rectum in adults and adolescents when the antimicrobial susceptibility of the infection is unknown^{3,39,40,98,106,118,162–170}

Treatment when patient has history of severe hypersensitivity (e.g. anaphylaxis) to any β-lactam antimicrobial (penicillins, cephalosporins, monobactams or carbapenems)^3,39,40

Recommended treatment for genital, anorectal and oropharyngeal gonococcal infection when ceftriaxone resistance is identified^{3,100,143,144}

Treatment for gonococcal infections in pregnancy or when breastfeeding^208–210

Recommended treatment for gonococcal conjunctivitis^3,39,40

Recommended treatment for ophthalmia neonatorum (gonococcal neonatal conjunctivitis)^3,39,40

Recommended treatment for people living with HIV^3,39,40

Recommended treatment for uncomplicated Neisseria meningitidis infection of the urethra^215–217