Adherence to the 2012 European gonorrhoea guideline in the WHO European Region according to the 2018–19 International Union against Sexually Transmitted Infections European Collaborative Clinical Group gonorrhoea survey

Abstract

Gonorrhoea is a major public health problem globally. Increasing incidence in many particularly developed countries and the emergence of resistance to the extended-spectrum cephalosporin ceftriaxone, the last option for empiric first-line monotherapy, are of serious concern. This paper evaluates the results of the 2018–19 International Union against Sexually Transmitted Infections European Collaborative Clinical Group survey on the diagnosis and treatment of gonorrhoea in Europe. Although high quality clinical care was reported in many European settings, in several countries the testing, diagnostics, antimicrobial treatment, and follow-up of gonorrhoea patients were evidently suboptimal. Increased adherence to evidence-based European and/or nationally-adapted management guidelines is essential in controlling the increasing incidence of gonorrhoea in many European settings and the spread of ceftriaxone-resistant, multidrug-resistant, and extensively drug-resistant gonorrhoea.

Keywords

testing screening nucleic acid amplification test culture ceftriaxone azithromycin antimicrobial resistance Europe

Gonorrhoea, including its severe reproductive and sexual health complications, is a major public health concern globally. In 2016, the WHO estimated 86.9 million incident cases among adults worldwide.¹ In the European Union/European Economic Area (EU/EEA; 31 countries), the number of reported cases has increased by more than 200% since 2008.² Men who have sex with men (MSM) accounted for about 25–30% of the cases in the EU/EEA during recent years; however, over the last decade, significant increases also occurred among men not reporting sexual orientation, heterosexual men and women.² Nevertheless, reported rates of gonorrhoea widely vary, significantly affected by testing rates and use of sensitive diagnostics such as nucleic acid amplification tests (NAATs), with substantially higher rates in Northern Europe.² Clearly, the incidence in many WHO European Region (EUR) countries (n = 53) is underestimated because of suboptimal diagnostics, case reporting, and surveillance.^3–6

It is of grave concern that Neisseria gonorrhoeae has developed antimicrobial resistance (AMR) to all drugs introduced for treatment of gonorrhoea. The extended-spectrum cephalosporin ceftriaxone is the only remaining option for empiric first-line monotherapy in most countries; however, during the recent decade, resistance to ceftriaxone was described in many countries worldwide, including in Europe.^7–11 Consequently, dual antimicrobial therapy (mainly ceftriaxone 250–500 mg intramuscularly plus azithromycin 1–2 g orally) was introduced as the empiric first-line treatment of uncomplicated gonorrhoea in, for example, Europe, USA, Canada, and Australia, and globally by WHO.^6,12–17 In the 2012 European gonorrhoea management guideline,⁶ ceftriaxone 500 mg together with azithromycin 2 g is the recommended treatment in all cases of uncomplicated gonococcal infections of the urethra, cervix, rectum, and pharynx. This treatment effectively eradicates gonorrhoea, as well as possible concomitant Chlamydia trachomatis infection. However, an international spread of a ceftriaxone-resistant strain in 2015–19, including verified cases in Europe (Denmark, the UK, Ireland, and France);^18–27 increasing and/or high rates of azithromycin resistance in many settings globally;^8,10 the first global failure to treat gonorrhoea with ceftriaxone plus azithromycin dual therapy (in the UK)²⁸; and the first strain with ceftriaxone resistance combined with high-level azithromycin resistance (in the UK and Australia)^29,30 threaten the effectiveness of the recommended ceftriaxone plus azithromycin dual therapy.

Evidence-based international and/or national guidelines for management of gonorrhoea^6,13–17,31 and other STIs are essential, and European guidelines are available for most STIs (https://www.iusti.org/regions/Europe/euroguidelines.htm). Nevertheless, it is also crucial to survey the adherence to and promote the implementation of these guidelines. The European Collaborative Clinical Group (ECCG; www.iusti.org/regions/Europe/eccg.htm) is a network of nearly 130 STI specialists across 34 WHO EUR countries. The aim of the ECCG is to conduct questionnaire-based research in Europe that details the clinical management across the WHO EUR, evaluates the adherence to European guidelines, identifies areas for improvement, and informs development and revisions of future European STI guidelines. In the light of the increasing gonorrhoea case rates in Europe² and the European and global concern of ceftriaxone-resistant, azithromycin-resistant, multidrug-resistant (MDR), and extensively drug-resistant (XDR) N. gonorrhoeae,^7–12 the ECCG recently surveyed the clinical management of gonorrhoea (particular focus on testing, diagnostics, antimicrobial treatment, and follow-up of patients in different clinical scenarios) among STI specialists across Europe. From mid-November 2018 to mid-March 2019, 78 STI specialists (Table 1), representing 23 (67.6%) of the ECCG countries, anonymously provided evaluable surveys online.

Table 1.

Respondents (n = 78) of the 2018–19 ECCG survey regarding diagnosis and treatment of gonorrhoea in Europe.

Countries of respondents	Respondents, no (%)^a
European Union or European Economic Area (n=15)	58 (74.4)
United Kingdom (including Northern Ireland: 1; Scotland: 1)	12 (15.4)
Norway	7 (9.0)
Finland	5 (6.4)
Denmark	4 (5.1)
Greece	4 (5.1)
Portugal	4 (5.1)
Slovenia	3 (3.8)
Italy	3 (3.8)
Malta	3 (3.8)
Spain	3 (3.8)
Sweden	3 (3.8)
Austria	2 (2.6)
Ireland	2 (2.6)
Lithuania	2 (2.6)
Poland	1 (1.3)
Other WHO European countries (n=8)	18 (23.1)
Georgia	4 (5.1)
Switzerland	3 (3.8)
Turkey	3 (3.8)
Macedonia	2 (2.6)
Russia	2 (2.6)
Ukraine	2 (2.6)
Armenia	1 (1.3)
Azerbaijan	1 (1.3)

^aTwo (2.6%) respondents did not declare their country of work. Most respondents worked in urban (85.9%), government-funded (70.5%) clinics serving populations of more than 250,000 people (66.7%).

Details regarding all responses to the 2018–19 ECCG survey were published by Clarke et al.³² The responses to the main queries, except the ones regarding treatment, are summarized in Table 2 and discussed related to particularly the European gonorrhoea guideline⁶ below.

Table 2.

Clinical management of Neisseria gonorrhoeae infections in Europe; % of respondents (95% confidence interval).

Access to diagnostic method			Access to antimicrobial susceptibility testing	Routine testing in symptomatic low-risk heterosexuals	‘3-site testing’ in asymptomatic MSM	‘3-site testing’ in symptomatic MSM with positive microscopy^a	Test of cure	Contact tracing
Microscopy	Culture	NAAT	Access to antimicrobial susceptibility testing	Routine testing in symptomatic low-risk heterosexuals	‘3-site testing’ in asymptomatic MSM		Test of cure	Contact tracing
94.9% (87.4–98.6)^b	91.0% (82.4–96.3)^c	88.5% (79.3–94.6)^d,e	82.1% (71.8–89.9)^f	91.7% (82.8–96.9)^g	81.9% (71.1–90.0)^h	Culture: 50.7% (38.2–63.1)	77.6% (65.8–86.9)ⁱ	95.5% (87.4–99.1)^j
94.9% (87.4–98.6)^b	91.0% (82.4–96.3)^c	88.5% (79.3–94.6)^d,e	82.1% (71.8–89.9)^f	91.7% (82.8–96.9)^g	81.9% (71.1–90.0)^h	NAAT: 82.1% (70.8–90.4)	77.6% (65.8–86.9)ⁱ	95.5% (87.4–99.1)^j

MSM, men who have sex with men; NAAT, nucleic acid amplification test; ‘3-site testing’: urethra/urine, pharynx, and rectum.

^aMSM reporting recent receptive oral sex and having dysuria, urethral discharge, and Gram-negative diplococci in urethral smear.

^bAccess was lacking for some respondents in Finland (mixed access), Greece (mixed access), and Turkey (mixed access).

^cAccess was lacking for some respondents in Armenia (no access), Georgia (mixed access), Finland (mixed access), Malta (mixed access), Turkey (mixed access), and Macedonia (mixed access).

^dAccess was lacking for some respondents in Poland (no access), Armenia (no access), Ukraine (mixed access), Italy (mixed access), Turkey (mixed access), and Greece (mixed access).

^eType of NAAT used: polymerase chain reaction (PCR) assay by Roche Diagnostics (23.2%); transcription mediated amplification assay by Hologic (18.8%); real-time PCR assay by Abbott Laboratories (17.4%); in-house PCR assays (8.7%; used by clinicians in four countries); strand displacement amplification assay by Becton Dickinson (4.3%); other (27.5%), which included PCR assays by InterLabService (AmpliSens), Cepheid (GeneXpert), DNA technology, Fast-Track Diagnostics, Hain Lifescience GmbH, Sacace Biotechnologies S.r.l., Seegene Inc., Vector-Best. Worryingly, only 23% reported that they use a second NAAT target sequence for confirmation of gonococcal reactive NAAT samples.

^fAccess was lacking for some respondents in Azerbaijan (no access), Poland (no access), Turkey (no access), Armenia (no access), Georgia (mixed access), Italy (mixed access), Macedonia (mixed access), Greece (mixed access), and Ukraine (mixed access).

^gAccess was lacking for some respondents in Georgia (mixed access), Norway (mixed access), Turkey (mixed access), Macedonia (mixed access), and Spain (mixed access).

^hAnatomical sites tested in the remaining cases: no testing (4.2%), urethra/urine only (9.7%), urethra/urine and pharynx (2.8%), urethra/urine and rectum (1.4%).

ⁱMethods used for test of cure: NAAT (71.6%), culture (20.9%), microscopy (14.9%). Thus, NAAT only (49.3%), culture and NAAT (9%); culture with microscopy and NAAT (7.5%), microscopy and NAAT (6%), culture only (4.5%), and microscopy only (1.5%).

^jLook back period: 1 month (21%), 6 weeks (3%), 2 months (12%), 3 months (38.8%), 6 months (17.9%), 12 months (3%).

Diagnostics and access to testing for gonorrhoea

Briefly, all respondents had access to laboratory facilities to confirm all suspected cases of gonorrhoea; however, only 91 and 82% had access to gonococcal culture and AMR testing, respectively (Table 2).³² Accordingly, the access to culture and AMR testing has decreased since the previous ECCG gonorrhoea survey published in 2012 (95 and 86%, respectively),^4,5 and in 2018–19 ECCG respondents from nine countries (39% of responding countries) reported no access (n = 4) or only mixed access (n = 5) to AMR testing (Table 2). It is essential to significantly increase the access to culture and phenotypic AMR testing in the era of MDR and XDR gonococcal strains spreading, which has been strongly recommended at both European and WHO global levels.^6,33,34 This is especially important for individual case management and/or local surveillance of AMR when several of the countries in the 2018–19 ECCG survey do not have or are not involved in any quality-assured gonococcal AMR surveillance,^35,36 which aims to identify emerging AMR, monitor AMR trends, and ensure effective patient management by timely refinements of management guidelines. It is imperative with quality-assured gonococcal AMR surveillance in the entire WHO EUR and not only in the EU/EEA through Euro-GASP.^6,34–36

Access to NAATs among the ECCG respondents had increased from 81% in 2012^4,5 to 88% in 2018–19.³² However, many different NAATs were used, including several less-validated ones and 8.7% were in-house NAATs (used in 17% of responding ECCG countries) (Table 2). Worryingly, gonococcal reactive NAAT samples were only confirmed by 61% of respondents, and only 23% reported that they use a second NAAT target sequence for confirmation.³² This type of confirmation is recommended in the European gonorrhoea guideline,⁶ due to the suboptimal specificity of many gonococcal NAATs,^6,37 when the used NAAT does not display a positive predictive value exceeding 90% and especially when testing pharyngeal samples. Thirteen per cent used culture for confirmation of positive NAAT samples,³² which will – due to the inferior sensitivity of culture – result in many false-negative NAAT samples. It is crucial to increase the access to and use of validated and quality-assured NAATs, including confirmation of reactive samples, due to their superior sensitivity particularly for pharyngeal and rectal samples.

The European gonorrhoea guideline recommends increased testing of urogenital samples but also substantially increased testing of pharyngeal and rectal samples, when indicated.⁶ In the ECCG 2018–19 survey,³² routine testing in symptomatic low-risk heterosexuals, ‘3-site testing’ in asymptomatic MSM, and ‘3-site testing’ in symptomatic MSM with positive microscopy were available for 92, 82, and 82% (using NAAT), respectively (Table 2). This is a substantial improvement since 2012 when the corresponding numbers for the ECCG respondents were 81, 65, and 49%, respectively.^4,5 However, in line with the European gonorrhoea guideline,⁶ increased gonorrhoea testing in general, and especially 3-site testing in MSM and heterosexual patients with a recent history of oral and anal sex, need to be of highest priority to combat the increasing gonorrhoea incidences across Europe. Rectal and pharyngeal gonorrhoea can be exceedingly common in particular and not exclusively limited to MSM,^2,6,31 and the very limited ‘3-site testing’ in many European settings results in a substantial number of missed gonorrhoea cases. Pharyngeal gonorrhoea is also substantially harder to eradicate compared to urogenital gonorrhoea.^6,33,38

Antimicrobial treatment of gonorrhoea

The majority of respondents in the 2018–19 ECCG survey³² administered recommended treatment regimens in concordance with the European gonorrhoea guideline,⁶ UK BASHH gonorrhoea guidelines (previous¹⁶ or recently updated version,³¹ which was published in early 2019 during the 2018–19 ECCG survey), or other slightly adapted national guidelines.

As an example, the treatment given for symptomatic men with Gram-negative diplococci on microscopy of a urethral smear (when C. trachomatis infection has not been excluded)³² is described in Figure 1.

Briefly, 68.7% of respondents gave ceftriaxone 500 mg (28.4, 3.0, and 31.3% in combination with azithromycin 1, 1.5, and 2 g, respectively),³² which is mainly in line with the European gonorrhoea guidelines (recommending azithromycin 2 g)⁶ and/or the previous UK BASHH gonorrhoea guideline (azithromycin 1 g).¹⁶ Furthermore, 20.9% administered ceftriaxone 1 g (10.4% as monotherapy, 4.5% with azithromycin 1–2 g, and 6% with a doxycycline course) (Figure 1), which is mainly in concordance with the recently updated UK BASHH gonorrhoea guideline (recommending ceftriaxone 1 g monotherapy if C. trachomatis infection has been excluded).³¹ In total, 15.4% of respondents were from the UK (Table 1) and 19% reported that they used the UK BASHH gonorrhoea guidelines,^16,31 which likely affected these results. Notably, the European gonorrhoea guideline⁶ provides recommendations regarding the diagnosis and treatment of gonorrhoea in all the 53 WHO EUR countries, including many diverse sexual health care systems of varying quality. Consequently, minor evidence-based national adaptations of these guidelines are acceptable. For example, in a country with a well-developed sexual health care system, no gonococcal ceftriaxone resistance according to recent, comprehensive, and quality-assured AMR surveillance; mandatory test of cure (TOC); and most patients returning for TOC, treatment with ceftriaxone 1 g without azithromycin 2 g can be acceptable when concomitant C. trachomatis infection has been appropriately excluded. In the 2018–19 ECCG survey, 28.3% did not give any dual therapy including ceftriaxone plus azithromycin that additionally eradicates possible C. trachomatis co-infection, but 6% of the respondents instead added a course of doxycycline (all combined with ceftriaxone 1 g) for this purpose (Figure 1).³² For comparison, in the 2012 ECCG survey^4,5 ceftriaxone 500 mg was administered by 70.2% and ceftriaxone 1 g by 6.8% of respondents, and only 8.1% combined ceftriaxone with azithromycin 2 g, as currently recommended in the European gonorrhoea guideline.⁶ Worryingly, in 2018–19, 4.5% of respondents used ceftriaxone 250 mg combined with azithromycin 1 g, 3.0% used cefixime 400 mg with azithromycin 1 g, and 3.0% used ciprofloxacin 500 mg with azithromycin 1 g (Figure 1).³² According to the European gonorrhoea guideline,⁶ ceftriaxone 250 mg should not be administered, cefixime should only be used in exceptional cases when ceftriaxone is not available or injection refused, and ciprofloxacin should never be used before AMR testing results are available.

The treatments, including co-therapy for C. trachomatis infection, of asymptomatic contacts (before tests results are available) of men with diagnosed gonococcal infection and symptomatic MSM with Gram-negative diplococci in microscopy of urethral smears were similar to the first-line treatments mentioned above. Notably, according to the European gonorrhoea guideline,⁶ if a recent partner has confirmed gonococcal infection, the individual should receive epidemiological treatment. However, only 34.4% of respondents completely followed this recommendation, and, worryingly, 5% of respondents administered azithromycin 1 g (2%) or cefixime 400 mg plus azithromycin 1 g (3.9%) for asymptomatic sexual partners.³² Similar deviations of the current European gonorrhoea guideline⁶ were also reported by 13.4 and 4.5% of respondents when treating patients with history of rash to penicillin, i.e. using azithromycin 1 g and ciprofloxacin 500 mg, respectively.³²

It is essential to further improve the treatments used for many gonorrhoea patients and their contacts in several European settings, and a stricter implementation of the European gonorrhoea guideline⁶ or similar slightly-adapted national evidence-based guidelines is imperative.

Follow-up of gonorrhoea patients

The majority (78%) of respondents performed TOC to ensure microbiological cure following treatment of gonorrhoea (Table 2),³² which is a minor increase compared to the 2012 ECCG survey (74%).^4,5 In the European gonorrhoea guideline,⁶ TOC is recommended for all gonorrhoea cases. Accordingly, the performance of TOC needs to improve in many European settings and clearly microscopy only should not be used for TOC,⁶ which was reported by 2% of respondents.³²

The vast majority of respondents (96%) undertook contact tracing for patients with confirmed gonorrhoea (Table 2)³²; however, this is still a minor decrease compared to the 2012 ECCG study (99%).^4,5 The look back periods varied: one month (21%), six weeks (3%), two months (12%), three months (39%), six months (18%), and one year (3%) (Table 2).³² According to the European gonorrhoea guideline⁶ and the European guidelines for the management of partners of persons with sexually transmitted infections,³⁹ all sexual contacts of gonorrhoea patients within at least the preceding two months and three months, respectively, of onset of symptoms or diagnosis are recommended to be traced. Accordingly, a significant proportion of ECCG respondents should use a longer look-back period for sexual contacts of gonorrhoea patients.

Conclusions

As emphasized in the 2018–19 ECCG survey,³² high quality clinical care for gonorrhoea is provided in many European settings; however, the clinical management of gonococcal infections across Europe also continues to vary considerably. Accordingly, in several European countries the testing, diagnostics, antimicrobial treatment, and follow-up of gonorrhoea patients remain suboptimal and have to improve. Increased adherence to the evidence-based European gonorrhoea guideline,⁶ which is updated in 2019, or slightly-adapted national guidelines, is essential in controlling the increasing incidence of gonorrhoea in many European settings² and the spread of ceftriaxone-resistant, MDR, and XDR gonorrhoea.^7–12 In particular, the access to validated and quality-assured culture, AMR testing, NAATs (including confirmation of gonococcal reactive samples), ‘3-site testing’ (when indicated), TOC, and recommended antimicrobial treatment (choice of antimicrobial and dosage in different clinical scenarios)⁶ is essential to significantly enhance, with a special emphasis on pharyngeal gonorrhoea that is frequently more difficult to eradicate compared to urogenital infections.^6,33,38 In future European surveys regarding the management of gonorrhoea, it would be valuable to also review testing and treatment used in additional clinical scenarios; more details on the methods used for diagnosis and AMR testing, including number of samples being tested with each method; prevalence and treatment of complicated gonorrhoea, including disseminated gonococcal infection, pelvic inflammatory disease, and epididymitis; alternative treatment regimens used; and identification, verification, and reporting of treatment failures. Gonorrhoea, as well as other STIs, is a truly global infection, crossing national boundaries readily. The importance of a co-ordinated European approach with best practice undertaken across the region cannot be over-emphasized,

Footnotes

Acknowledgements

We are very grateful to all the members of the ECCG. The full membership list of the ECCG is available at .

Declaration of conflicting interests

The authors 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

E Clarke

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