Epidemiology Original research Antimicrobial resistance in Neisseria gonorrhoeae isolates from foreign-­born population in the European Gonococcal Antimicrobial Surveillance Programme Cristina Hernando Rovirola,1,2 Gianfranco Spiteri,3 Meritxell Sabidó,4,5 Alexandra Montoliu,2,6 Victoria Gonzalez,2,7 Jordi Casabona,2,5,6,8 Michelle Jayne Cole ‍ ‍ ,9 Teymur Noori,3 Magnus Unemo ‍ ‍ 10 ►► Additional material is Abstract Introduction published online only. To view, Objectives International spread has contributed Neisseria gonorrhoeae (gonococcus) has shown please visit the journal online (http://​dx.​doi.​org/​10.​1136/​ substantially to the high prevalence of antimicrobial an extraordinary ability to develop antimicrobial sextrans-​2018-​053912). resistant (AMR) Neisseria gonorrhoeae infections resistance (AMR) to any antimicrobial introduced worldwide. We compared the prevalence of AMR for gonorrhoea treatment. In the WHO European For numbered affiliations see gonococcal isolates among native persons to foreign-­ Region, a high prevalence of resistance to ciproflox- end of article. born (reporting country different from country of birth) acin, penicillins and tetracycline has been observed persons, and describe the epidemiological and clinical for many years. In the last decade, in vitro and clin- Correspondence to Dr Magnus Unemo, Department characteristics of foreign-­born patients and their ical resistance, resulting in treatment failures, to the of Laboratory Medicine, Örebro associations to AMR. extended-­spectrum cephalosporins (ESCs) cefixime University, Örebro SE-701 85, Methods We analysed isolates and patient data reported and ceftriaxone, as well as azithromycin have also Sweden; ​magnus.​unemo@​ to the European Gonococcal Antimicrobial Surveillance emerged.1–8 orebroll.​se Programme (Euro-­GASP) 2010–2014 (n=9529). To mitigate the emergence and/or dissemination Received 23 November 2018 Results Forty-­three per cent of isolates had known of AMR gonococcal strains, ceftriaxone (500 mg Revised 20 February 2019 country of birth and 17.2% of these were from persons single dose intramuscularly) plus azithromycin (2 Accepted 24 March 2019 born abroad. Almost 50% of foreign-­born were from the g single oral dose) is currently recommended for Published Online First WHO European Region (13.1% from non-­European Union empirical first-­line dual therapy of uncomplicated 4 February 2020 [EU] and the European Economic Area [EEA] countries). gonorrhoea in Europe. Similar dual therapy regi- Compared with isolates from natives, isolates from mens (ceftriaxone 250–500 mg plus azithromycin 1 foreign-­born had a similar level (p>0.05) of azithromycin g) are recommended in the USA, Canada, Australia, resistance (7.5% vs 7.2%), ciprofloxacin resistance (50.0% Brazil and globally by WHO, that is, when local, vs 46.3%) and of decreased susceptibility to ceftriaxone comprehensive, regular and quality-­assured AMR (1.9% vs 2.8%); a lower rate of cefixime resistance (5.7% surveillance is not supporting monotherapy. vs 3.6%, p=0.02), and a higher proportion of isolates However, in some countries ceftriaxone high-­dose producing penicillinase (8.4% vs 11.7%, p=0.02). Among monotherapy remains recommended, for example, isolates from persons born outside EU/EEA, the level of Japan (1 g) and China (0.5–1 g).1 8 9 The emergence decreased susceptibility to ceftriaxone was higher (1.8% vs of ceftriaxone resistance and relatively high rates 3.5%, p=0.02), particularly in those from the WHO Eastern of azithromycin resistance reported in Europe and Mediterranean Region and non-­EU/EEA WHO European globally1–3 5–10 threaten the effectiveness of these countries (1.9% vs 9.6% and 8.7%, respectively, p<0.01). regimens, which are currently the last evidence-­ In multivariable analysis, foreign-­born patients with AMR based options for first-­line empirical treatment. The isolates were more likely to be from non-­EU/EEA WHO first global failure to treat gonorrhoea with dual European countries (adjusted OR [aOR]: 3.2, 95% CI 1.8 antimicrobial therapy was reported in 2016.11 In to 5.8), WHO Eastern Mediterranean countries (aOR: 1.8, early 2018, the first gonococcal strain with ceftri- 95% CI 1.1 to 3.3) and heterosexual males (aOR: 1.8, axone resistance combined with high-­level resist- 95% CI 1.2 to 2.7). ance to azithromycin was reported from England12 Conclusions Importation of AMR strains remains an followed by two similar cases in Australia.13 Due © Author(s) (or their to the development of difficult-­to-­treat or possibly employer(s)) 2020. Re-­use important threat in the EU/EEA. Research to improve permitted under CC BY-­NC. No understanding of sexual networks within foreign born untreatable gonorrhoea, AMR N. gonorrhoeae has commercial re-­use. See rights and sexual tourism populations could help to inform been designated as a priority global health issue by and permissions. Published effective tailor-­made interventions. The Euro-­GASP WHO.9 by BMJ. demonstrates the public health value of quality-­assured Robust gonococcal AMR surveillance is essen- To cite: Hernando Rovirola C, surveillance of gonococcal AMR and the need for tial to monitor the emergence and spread of AMR Spiteri G, Sabidó M, strengthened AMR surveillance, particularly in the non-­ gonococcal strains,2 3 6–8 which has been strongly et al. Sex Transm Infect EU/EEA WHO European Region. emphasised by the Global Action Plan14 and the 2020;96:204–210. European Response Plan,3 developed by WHO 204 Hernando Rovirola C, et al. Sex Transm Infect 2020;96:204–210. doi:10.1136/sextrans-2018-053912 Epidemiology and the European Centre for Disease Prevention and Control into resistance, intermediate susceptibility or susceptibility using (ECDC), respectively. Since 2009, ECDC has coordinated the breakpoints stated by the European Committee on Antimicrobial European Gonococcal Antimicrobial Surveillance Programme Susceptibility Testing.24 Strains with a ceftriaxone MIC of 0.12 (Euro-­GASP), which is a sentinel surveillance system that moni- mg/L have previously caused gonorrhoea treatment failures and tors antimicrobial susceptibility of gonococcal isolates across can be considered to have a decreased susceptibility.8 25 26 Only Member States of the European Union (EU) and the European whole MIC doubling dilutions were analysed. Economic Area (EEA). Linking the laboratory data to epidemi- ological data of the corresponding patients, Euro-­GASP allows surveillance to be focused in subpopulations and analysis of Epidemiological and clinical variables and statistical analysis patient risk groups.3 6 Epidemiological and clinical data analysed included: year of In Europe, international migration has been significant during diagnosis, age (<25, 25–44, ≥45 years), area of origin (Euro- recent decades.15 16 Particular groups of migrants, especially pean Region [EUR; 28 EU countries, 3 EEA countries and 23 those of lower socioeconomic status, refugees and sex workers, non-­EU/EEA countries]; Eastern Mediterranean Region [EMR]; can be more at risk and suffer disproportionally from STIs,17 Region of the Americas [AMRO]; African Region [AFR]; including gonorrhoea.18 19 Migrants and other mobile popula- South-­East Asia Region [SEAR] and WPR), sexual orientation tions can play a significant role in the international transmission (heterosexual females, heterosexual males and men who have of AMR including AMR gonococcal strains, and are considered sex with men [MSM]), site of infection (anorectal, urogenital key populations for gonorrhoea control by WHO.2 3 14 20 Histori- and pharyngeal), HIV status (positive, negative), previously diag- cally, most gonococcal AMR is considered to have initially devel- nosed with gonorrhoea (yes, no) and probable country of infec- oped in the WHO Western Pacific Region (WPR), particularly tion (reporting country, others). AMR isolates from foreign-­born in Japan, and subsequently spread globally.2 8 The reasons for patients were compared with those from native patients; and the initial emergence of gonococcal AMR in WPR are multifac- AMR isolates from patients born in EU/EEA were compared eted and include the high rates of gonorrhoea, the lack of effec- with AMR isolates from patients born outside EU/EEA. In our tive disease-­control measures, the extensive use and misuse of analysis, we excluded countries that had not reported consis- antimicrobials and the lack of optimal monitoring of AMR and tently throughout the study period (Estonia, Iceland, Poland and treatment failures.2 8 9 14 Romania). Statistical significance was determined by Pearson’s The objectives of this study were to investigate the preva- χ2 test or by Fisher’s exact test if cell numbers were <5, with lence of AMR gonococcal isolates among foreign-­born cases of two-­sided p values of <0.05 considered as significant. Data from gonorrhoea reported through Euro-­GASP from 2010 to 2014, 2010 to 2014 were combined. Among foreign-­born patients, the compare isolates from such cases with gonococcal isolates from association of gonococcal infection resistant to at least one anti- native born cases, and describe the epidemiological and clin- microbial with epidemiological and clinical characteristics were ical characteristics of foreign-­born patients with AMR gono- investigated using univariate and multivariable logistic regres- coccal isolates (resistance to at least one antimicrobial), with the sion analyses. Results were expressed with crude ORs (cORs) purpose of improving the understanding of the distribution of and adjusted ORs (aORs) and their 95% CI. Those variables AMR gonococcal strains among patient populations in the EU/ that were associated with the outcome in univariate models EEA and inform targeted interventions. at p<0.10 were included in the multivariable model. Using a backward stepwise approach, those that remained significant (p<0.05) were retained in the final model. Statistical analysis Materials and methods was performed in SPSS V.20. Data source We analysed Euro-­GASP isolates and corresponding patient data from 2010 to 2014. Euro-­GASP has been described in detail else- Ethical considerations where.3 6 21 Briefly, participating sites in each Euro-­GASP country All examined gonococcal isolates were cultured and stored as collected around 100 gonococcal isolates (200 isolates in the part of routine diagnostics (standard care). Patient data were UK, Spain and the Netherlands, which report higher numbers reported as part of a surveillance programme (EU Decisions of gonorrhoea cases) from consecutive gonorrhoea patients 2119/98/EC and 1082/2013/EU) with no patient-­ identifiable (one isolate per patient and infection episode). The collection information. Accordingly, separate ethical approval for the study periods were April–May and October–November during 2010– was not required. 2013, and September–November in 2014. We defined persons as foreign-­born when the reporting country differed from the Results country of birth20 and native as those with reporting country Study population identical to country of birth.22 Geographic region of origin was Out of the 9529 isolates, the patient’s country of birth was assigned based on WHO definitions.7 known for 4098 (43%) isolates and was reported by 14 (60.8%) of the Euro-­GASP countries (online supplementary table 1). Of Antimicrobial susceptibility testing these isolates (n=4098), 704 (17.2%) were from foreign-­born AMR testing was conducted using Etest for ceftriaxone and patients. The Netherlands (34.9%), Ireland (13.1%) and the cefixime, agar dilution breakpoint method or Etest for azith- UK (12.9%) reported 60.9% of the isolates from foreign-­born romycin and ciprofloxacin and nitrocefin test for detection of patients (online supplementary table 1). Among the foreign-­ penicillinase production.3 6 21 The WHO gonococcal reference born patients, 345 (49%) were from another country in WHO strains WHO G, K, M, O and P23 should be used for quality EUR (253 [35.9%] from EU/EEA and 92 [13.1%] from non-­EU/ control and all laboratories performing AMR testing are EEA countries), 174 (24.7%) from WHO AMRO, 83 (11.8%) required to participate with acceptable results in the Euro-­GASP from WHO EMR, 55 (7.8%) from WHO AFR, 25 (3.6%) from external quality assessment. The minimum inhibitory concen- WHO WPR and 22 (3.1%) from WHO SEAR. The proportion trations (MICs; mg/L) of each antimicrobial were interpreted of isolates reported from foreign-­born persons did not vary Hernando Rovirola C, et al. Sex Transm Infect 2020;96:204–210. doi:10.1136/sextrans-2018-053912 205 Epidemiology significantly during the study period (ranging from 13.1% to §The clinical breakpoints (susceptible, resistant) were as follows: ceftriaxone and cefixime (MIC ≤0.12 mg/L, MIC >0.12 mg/L), azithromycin (MIC ≤0.25 mg/L, MIC >0.5 mg/L) and ciprofloxacin (MIC ≤0.03 mg/L, MIC >0.06 mg/L). Furthermore, 18.5%; p=0.19). P value† AFR, African Region; AMRO, Region of the Americas; EMR, Eastern Mediterranean Region; Euro-­GASP, European Gonococcal Antimicrobial Surveillance Programme; MIC, minimum inhibitory concentration; SEAR, South-­East Asia Region; WPR, 0.07 0.02 0.10 0.02 0.45 0.8 1.0 Antimicrobial resistance and decreased susceptibility to ceftriaxone from persons born outside the reporting country The proportion of isolates with AMR to at least one antimi- Natives, no. (%) crobial was similar for foreign-­ born persons compared with 1693 (50.0) 1817 (53.5) isolates from native persons (natives: 53.5%; foreign born: 63 (1.9) 251 (7.5) 192 (5.7) 240 (8.4) 4 (0.1) 52.0%, p=0.45). Compared with isolates from native persons, strains with a ceftriaxone MIC of 0.12 mg/L have previously caused gonorrhoea treatment failures and can be considered to have a decreased susceptibility.8 25 26 Only whole MIC doubling dilutions were analysed. isolates from foreign-­born had lower level of cefixime resistance (5.7% vs 3.6%, p=0.02), and similar rates of azithromycin resis- tance (7.5% vs 7.2%, p=0.8), ciprofloxacin resistance (50.0% Total foreign-­ born, no. (%) vs 46.3%, p=0.07) and decreased susceptibility to ceftriaxone 57 (11.7) 326 (46.3) 366 (52.0) (1.9 vs 2.8, p=0.10). Only the proportion of isolates producing 50 (7.2) 25 (3.6) 20 (2.8) 0 (0.0) penicillinase was higher among foreign-­born persons (8.4% vs 11.7%, p=0.02). All isolates from foreign-­born persons were also susceptible to ceftriaxone; however, four (0.1%) isolates from natives (two MSM and two heterosexual males) were resis- WHO WPR, 14 (56.0) 15 (60.0) 4 (28.6) tant to ceftriaxone, all with a ceftriaxone MIC of 0.25 mg/L no. (%) 1 (4.0) 0 (0.0) 0 (0.0) 0 (0.0) (table 1). The proportion of isolates with AMR to at least one antimi- crobial was significantly higher among those born in non-­EU/ *Divided into WHO regions: EUR, European Region (28 European Union [EU] countries, 3 European Economic Area [EEA] countries and 23 non-­EU/EEA countries). WHO SEAR, The MIC ranges in the isolates resistant to ciprofloxacin, azithromycin, cefixime and ceftriaxone were 0.125–>32, 1–>256, 0.25–0.5 and 0.25 mg/L, respectively. EEA WHO EUR countries and in WHO EMR countries than 14 (63.6) 14 (63.6) no. (%) 1 (4.8) 1 (4.5) 0 (0.0) 0 (0.0) 1 (7.1) in native patients (53.5% vs 78.3% and 68.7%, respectively, Antimicrobial resistance and decreased susceptibility to ceftriaxone by region of birth, Euro-­GASP isolates 2010–2014 p<0.01). Those born in non-­EU/EEA WHO EUR countries had †P value (Pearson’s χ2 test or by Fisher’s exact test if cell numbers were <5) between total number of isolates from foreign-­born and native patients. the highest rates of resistance to ciprofloxacin (71.7%), azithro- mycin (11.2%) and cefixime (9.1%), and the second highest rate WHO AFR, 20 (36.4) 22 (40.0) 4 (10.3) of decreased susceptibility to ceftriaxone (8.7%). Isolates from no. (%) 0 (0.0) 1 (1.8) 0 (0.0) 0 (0.0) patients born in WHO EMR had the highest level of decreased susceptibility to ceftriaxone (9.6%), and additionally the second highest rate of resistance to ciprofloxacin (66.3%) and cefixime WHO AMRO, (8.9%). The rates of decreased susceptibility to ceftriaxone in 54 (31.0) 68 (39.1) 15 (8.6) no. (%) 2 (1.1) 0 (0.0) 0 (0.0) 7 (7.4) those coming from WHO EMR countries and non-­ EU/EEA WHO EUR were significantly higher than in native patients (1.9% vs 9.6% and 8.7%, respectively, p<0.01) (table 1). Data including isolates with unknown country of birth are summa- WHO EMR, 55 (66.3) 11 (16.7) 57 (68.7) rised in online supplementary table 2. no. (%) 6 (7.6) 7 (8.9) 0 (0.0) 8 (9.6) Country of birth of foreign-­born* Antimicrobial resistance in isolates from persons born outside Non-­EU/EEA, the EU/EEA 66 (71.7) 10 (11.2) 72 (78.3) 9 (11.4) Isolates from patients born outside the EU/EEA when compared no. (%) 8 (9.1) 0 (0.0) 8 (8.7) with patients born in the EU/EEA had similar levels of resis- ‡Number of isolates with known country of birth tested for each antimicrobial. tance to ciprofloxacin (n=1796, 49.4% vs n=223, 49.4%; p=1.0), azithromycin (n=268, 7.4% vs n=33, 7.5%; p=1.0), 21 (11.6) WHO EUR 103 (40.7) 118 (46.6) cefixime (n=198, 5.5% vs n=19, 4.3%; p=0.3) and penicilli- 17 (6.7) 6 (2.4) 0 (0.0) 4 (1.6) EU/EEA, no. (%) nase production (n=261, 8.6% vs n=36, 11.8%; p=0.07). All four ceftriaxone-­resistant isolates were from patients born in the EU/EEA; however, the proportion of decreased susceptibility to ceftriaxone was higher among isolates from patients born Decreased susceptibility to ceftriaxone (n=4098)§ outside the EU/EEA (n=67, 1.8% vs n=16, 3.5%; p=0.02). Epidemiological and clinical characteristics of antimicrobial resistant isolates from foreign-born patients compared with Ciprofloxacin resistant (n=4088)‡§ Penicillinase production (n=3352) Azithromycin resistant (n=4048)§ isolates from native patients Ceftriaxone resistant (n=4098)§ Cefixime resistant (n=4050)§ Foreign-­born patients with AMR isolates had a mean age of Resistant isolates (n=4098) 31.1 years (SD 9.1) and natives of 33.0 years (11.3). Compared Western Pacific Region. with isolates from native persons, foreign-­born persons were younger (82.9% vs 89.6% were <45 years, p<0.01), had higher proportions of anorectal (11.0% vs 18.4%, p<0.01) and lower Table 1 frequency of urogenital (83.9% vs 74.7%, p<0.01) infections, as well as higher proportion of infections acquired abroad compared with the reporting country (5.7% vs 11.0%, p<0.01) 206 Hernando Rovirola C, et al. Sex Transm Infect 2020;96:204–210. doi:10.1136/sextrans-2018-053912 Epidemiology Over the last decade, international transmission of AMR gono- Table 2 Epidemiological and clinical characteristics of patients with coccal strains has been recorded in detail, for example, the antimicrobial resistant isolates by country of birth (n=2183), Euro-­ multidrug-­ resistant NG-­ MAST genogroup 1407 clone associ- GASP 2010–2014 ated with cefixime and ciprofloxacin resistance, increased MICs Country of birth of ceftriaxone and azithromycin and causing the majority of Foreign-­ verified cephalosporin treatment failures has been spreading in Epidemiological and clinical Native no. born no. Europe, the USA and Canada.2 8 27–29 Furthermore, resistance or characteristics (%) (%) P value P value* decreased susceptibility to ceftriaxone and/or resistance to azith- Year of diagnosis 2010 225 (12.4) 31 (8.5) 0.02 0.04 romycin has been described in many regions globally.7 Recently, (n=2183) 2011 383 (21.1) 66 (18.0) 0.2 the first three cases of ceftriaxone resistance combined with high-­ 2012 393 (21.6) 99 (27.0) 0.02 level resistance to azithromycin12 13 have been identified, two of 2013 443 (24.4) 84 (23.0) 0.59 them in men who had travelled to southeast Asia and had sexual 2014 373 (20.5) 86 (23.5) 0.2 intercourse with locally resident women. During recent years, Age (years) <25 459 (25.5) 96 (26.3) <0.01 0.79 in the EU/EEA, the level of cefixime resistance has decreased (n=2165) 25–44 1033 (57.4) 231 (63.3) 0.04 and appeared to stabilise at around 2%, ceftriaxone resistance ≥45 308 (17.1) 38 (10.4) <0.01 has been exceedingly rare and azithromycin resistance has been stably relatively high (approximately 7%–8%).6 Sexual Heterosexual 169 (12.1) 29 (8.5) 0.14 – orientation females The role of importation of AMR strains in the transmission (n=1737) Heterosexual 637 (45.7) 158 (46.2) – and prevalence of AMR in a country or region is difficult to males elucidate and is largely unexplored. Global population mobility Men who have 589 (42.2) 155 (45.3) – and international travel including sex tourism are providing sex with men additional challenges in the prevention and control of N. gonor- Isolation site Anorectal 195 (11.0) 66 (18.4) <0.01 <0.01 rhoeae AMR internationally.30 Recent data from Euro-­GASP also (n=2127) Urogenital 1484 (83.9) 268 (74.7) <0.01 showed that the majority (94%) of AMR gonococcal isolates are Pharyngeal 89 (5.0) 25 (7.0) 0.15 most likely acquired in the reporting country.21 In the present HIV status Positive 144 (12.7) 42 (15.8) 0.19 – study, the higher rate of decreased susceptibility to ceftriaxone in (n=1396) Negative 987 (87.3) 223 (84.2) – isolates from persons born outside the EU/EEA (1.8% vs 3.5%, p=0.02) and particularly in those from WHO EMR countries and Previous Yes 181 (14.7) 31 (12.8) 0.48 – gonorrhoea non-­EU/EEA WHO EUR (1.9% vs 9.6% and 8.7%, respectively, No 1054 (85.3) 212 (87.2) – (n=1478) p<0.01), and the higher proportion of foreign-­born patients Probable country Reporting 1081 (94.3) 162 (89.0) <0.01 – likely infected abroad versus in the reporting country (5.7% vs of infection country 11.0%, p<0.01) indicate that importation of AMR gonococcal (n=1328) Other country 65 (5.7) 20 (11.0) – strains, and especially with decreased susceptibility to ceftri- *Calculated only for those variables with more than two categories and p value axone, to the EU/EEA by foreign-­born persons remains a threat. <0.05. Despite this, native cases, although more likely to acquire gonor- Euro-­GASP, European Gonococcal Antimicrobial Surveillance Programme. rhoea in the reporting country, are larger in number and there- fore may represent a greater risk for importation of gonorrhoea. Further detailed molecular investigations of the international (table 2). Data including isolates with unknown country of birth transmission of gonococcal strains with decreased susceptibility are summarised in online supplementary table 3. or resistance to ESCs and azithromycin are essential.27 Although absolute numbers were small, isolates from foreign-­ Risk factors for antimicrobial resistant isolates among born persons from non-­EU/EEA WHO EUR countries had the foreign-born patients highest rates of resistance to ciprofloxacin (71.7%), azithromycin Among foreign-­born persons, those with N. gonorrhoeae isolates (11.2%) and cefixime (9.1%), and together with those from resistant to at least one antimicrobial were found to be more WHO EMR, of decreased susceptibility to ceftriaxone (8.7% likely from non-­EU/EEA WHO EUR countries (cOR: 4.1, 95% and 9.6%, respectively). The major challenge in the non-­EU/EEA CI 2.3 to 7.1) and from WHO EMR (cOR: 2.5, 95% CI 1.4 to part of the WHO EUR Region (former Soviet Union countries 4.2), heterosexual males (cOR: 2.3, 95% CI 1.6 to 3.2), HIV in Eastern Europe and Central Asia) is the very limited quality-­ negative (cOR: 1.7, 95% CI 1.1 to 2.7), without a previous assured surveillance of gonococcal AMR.4 5 7 [w1,w2] In this gonorrhoea episode (cOR: 1.7, 95% CI 1.0 to 2.9) and with region, the burden of gonorrhoea is estimated to be relatively urogenital site of infection (cOR: 1.9, 95% CI 1.3 to 2.8). In the high, and, together with suboptimal laboratory diagnostics, lack multivariable analysis, the associations remained significant for of gonococcal culture, scarce surveillance of both gonorrhoea being from non-­EU/EEA WHO EUR country (aOR: 3.2, 95% cases and gonococcal AMR and misuse of antimicrobials of CI 1.8 to 5.8), from EMR (aOR: 1.8, 95% CI 1.1 to 3.3) and uncertain quality and origin without prescription from a physi- heterosexual male (aOR: 1.8, 95% CI 1.2 to 2.7) (table 3). There cian predispose for emergence and rapid spread of gonococcal was no association with age and year of diagnosis. AMR.7 [w1–w3] The rapid spread of AMR might be further accelerated by the introduction AMR gonococcal strains in more Discussion antimicrobial susceptible populations. For example, it has been In our study, the proportion of overall AMR isolates among shown that some ciprofloxacin resistance mutations enhance the native and foreign-­born patients (53.5%, n=1817, vs 52.0%, fitness of the gonococcal strains,[w4] which can result in an out-­ n=366; p=0.45) was similar. However, gonococcal AMR levels competition of the ciprofloxacin-­susceptible strains due to both for cefixime (more common among native patients) and penicil- the ciprofloxacin resistance and the enhanced fitness. Despite linase production (more common among foreign-­born patients) that quality-­assured data are available from Russia and Belarus,4 5 differed significantly depending on the region of birth of patients. a quality-­assured GASP in the Eastern and Central Asian part of Hernando Rovirola C, et al. Sex Transm Infect 2020;96:204–210. doi:10.1136/sextrans-2018-053912 207 Epidemiology Table 3 Univariate and multivariate analysis of foreign-­born patients with antimicrobial resistant isolates (n=366), Euro-­GASP 2010–2014 Resistant isolates from foreign-­born patients Crude OR Adjusted OR Epidemiological and clinical characteristics No. (%) (95% CI) P value (95% CI) P value Year of diagnosis 0.21 – – (n=704) 2010 31/50 (62.0) 1 2011 66/143 (46.2) 0.5 (0.2 to 1.0) 0.05 2012 99/183 (54.1) 0.7 (0.3 to 1.3) 0.32 2013 84/173 (48.6) 0.5 (0.3 to 1.1) 0.09 2014 86/155 (55.5) 0.7 (0.3 to 1.4) 0.41 Age (years) 0.25 – – (n=701) <25 96/177 (54.2) 0.7 (0.4 to 1.4) 0.4 25–44 231/461 (50.1) 0.6 (0.3 to 1.1) 0.13 ≥45 38/63 (60.3) 1 Area of origin <0.01 <0.01 (n=704) EU/EEA 118/253 (46.6) 1 1 Non-­EU/EEA WHO EUR 72/92 (78.3) 4.1 (2.3 to 7.1) <0.01 3.2 (1.8 to 5.8) <0.01 WHO EMR 57/83 (68.7) 2.5 (1.4 to 4.2) <0.01 1.8 (1.1 to 3.3) 0.02 WHO AMRO 68/174 (39.1) 0.7 (0.4 to 1.0) 0.12 0.7 (0.5 to 1.1) 0.21 WHO AFR 22/55 (40.0) 0.7 (0.4 to 1.3) 0.37 0.6 (0.3 to 1.2) 0.17 WHO SEAR 14/22 (63.6) 2.0 (0.8 to 4.9) 0.13 1.9 (0.7 to 5.0) 0.13 WHO WPR 15/25 (60.0) 1.7 (0.7 to 3.9) 0.2 1.6 (0.7 to 3.9) 0.23 Sexual orientation <0.01 <0.01 (n=677) Heterosexual females 29/67 (43.3) 1.0 (0.6 to 1.7) 0.94 1.0 (0.6 to 1.8) 0.81 Heterosexual males 158/248 (63.7) 2.3 (1.6 to 3.2) <0.01 1.8 (1.2 to 2.7) <0.01 Men who have sex with men 155/362 (42.8) 1 1 Isolation site <0.01 – – (n=694) Ano-­rectal 66/164 (40.2) 1 Urogenital 268/469 (57.1) 1.9 (1.3 to 2.8) <0.01 Pharyngeal 25/61 (41.0) 1.0 (0.5 to 1.8) 0.92 HIV status Positive 42/115 (36.5) 1 <0.01 – – (n=555) Negative 223/440 (50.7) 1.7 (1.1 to 2.7) Previous gonorrhoea Yes 31/68 (45.6) 1 0.03 – – (n=425) No 212/357 (59.4) 1.7 (1.0 to 2.9) Probable country of Reporting country 162/286 (56.6) 1 0.66 – – infection Other country 20/33 (60.6) 1.1 (0.5 to 2.4) (n=319) EEA, European Economic Area; EU, European Union; Euro-­GASP, European Gonococcal Antimicrobial Surveillance Programme; WHO AFR, WHO African Region; WHO AMRO, WHO Region of the Americas; WHO EMR, WHO Eastern Mediterranean Region; WHO SEAR, WHO South-­East Asia Region; WHO WPR, WHO Western Pacific Region. WHO EUR is still needed. As previously stressed,7 such a GASP phenomenon that transmission of AMR gonococcal strains may is crucial to also develop in the WHO EMR. spread from heterosexual to MSM networks or vice versa very In the multivariable analysis, among foreign-­ born persons, quickly. Further studies on the molecular epidemiology of AMR those from non-­EU/EEA WHO EUR (aOR: 3.2, 95% CI 1.8 gonococcal strains27 can contribute to a better understanding to 5.8), from WHO EMR (aOR: 1.8, 95% CI 1.1 to 3.3) and of epidemiology and population dynamics in the national and heterosexual males (aOR: 1.8, 95% CI 1.2 to 2.7) were associ- international spread of AMR gonococcal strains. ated with AMR gonococcal isolates. Most likely, area of origin, The present study includes other limitations such as the country of infection, sexual orientation and additional epidemio- absence of participation of some countries along with differ- logical characteristics can play a major role in the spread of AMR ences in representativeness that limit the generalisability of the gonococcal strains in many countries. These results are in line findings. In addition, the limited number of isolates resistant to with recent data from Euro-­GASP, where geometric means were ceftriaxone, cefixime and azithromycin did not allow for analysis higher for both cefixime and ceftriaxone MICs for heterosexual by antimicrobial. When considering the AMR all together, the males compared with MSM (p<0.001) and females (cefixime: high levels of resistance to ciprofloxacin account for most of the p=0.014, ceftriaxone: p=0.025).[w5] In England and Wales, a AMR described. Missing patient data, particularly for country of higher rate of decreased susceptibility to ceftriaxone has been birth (57%), and the different proportions of reported patient reported within MSM compared with heterosexual males.[w6] characteristics between different countries may bias the results. Among heterosexual males, those with older age (especially ≥35 The results might also not be representative of all foreign-­ years), rapid partner turnover and sex abroad also had a higher born cases of gonorrhoea as some categories of foreign-­born proportion of decreased susceptibility to ceftriaxone.[w6] The persons such as refugees, undocumented migrants, trafficked emergence and spread of gonococcal AMR is such a dynamic people, migrant MSM and subgroups of migrant women can 208 Hernando Rovirola C, et al. Sex Transm Infect 2020;96:204–210. doi:10.1136/sextrans-2018-053912 Epidemiology 3 face particular challenges in accessing healthcare services. Male European Centre for Disease Prevention and Control, Stockholm, Sweden 4 heterosexuals are over-­represented in Euro-­GASP, likely because TransLab, Medical Science Department, Universitat de Girona, Girona, Spain 5 CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain the majority of males with urogenital gonorrhoea are sympto- 6 Health Sciences Research Institute of the Germans Trias i Pujol Foundation (IGTP), matic and attend for testing, the high sensitivity of culture for Badalona, Spain these males, and possibly due to undeclared or misclassified 7 Laboratory of Microbiology, Germans Trias i Pujol Hospital (HGTiP), Badalona, Spain 8 MSM. In some Euro-­GASP countries, under-­reporting of patient Department of Pediatrics, Obstetrics and Gynecology, and Preventive Medicine, data is also due to ethical or juridical restrictions around linking Universitat Autònoma de Barcelona, Badalona, Spain 9 National Infection Service, Public Health England, London, UK patient and isolate data. The under-­representation of patients 10 WHO Collaborating Centre for Gonorrhoea and other STIs, Örebro University, younger than 25 years in Euro-­GASP may be due to Chlamydia Örebro, Sweden trachomatis screening programmes targeting this group and their use of dual C. trachomatis and N. gonorrhoeae molecular tests Handling editor Catherine A Ison instead of culture for diagnosis. Acknowledgements The authors would like to thank the European STI Increasing the number of participating countries and exam- surveillance network for its contribution to the development and implementation of ined isolates, facilitating and promoting culture of N. gonor- Euro-­GASP and the submission of gonococcal isolates and linked epidemiological rhoeae, achieving more complete reporting of epidemiological data. The authors would also like to thank Kathy Attawell for her review of the manuscript. data, particularly data on country of birth, country of infection and sexual orientation and increasing the representativeness are Contributors CHR, GS and TN designed, initiated and coordinated the study. Euro-­GASP network members coordinated and performed the laboratory analyses. high priorities for Euro-­GASP.6 Patient data was supplied by the Euro-­GASP network members. CHR, GS, AM, VG, MJC and MU analysed and interpreted all the data, and wrote a first draft of the paper. MS and JC critically read and commented on the manuscript. All authors read, Conclusions commented and approved the final manuscript. Importation of AMR gonococcal strains into the EU/EEA from Funding The authors have not declared a specific grant for this research from any other geographic regions worldwide poses a threat for emer- funding agency in the public, commercial or not-­for-­profit sectors. gence and subsequent rapid spread of gonococcal AMR in Competing interests None declared. Europe. Effective disease-­control measures targeted towards Patient consent for publication Not required. foreign-­ born originating from countries with higher levels of gonococcal AMR and those returning to their country of Provenance and peer review Not commissioned; externally peer reviewed. birth to visit friends and relatives could be valuable. These Data availability statement All relevant data are included in the manuscript or results from Euro-­GASP demonstrate the public health value in the supplementary file. of quality-­assured surveillance of gonococcal AMR, which is Open access This is an open access article distributed in accordance with the required throughout the WHO European Region. Improving Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-­commercially, the completeness of demographic and risk factor data in and license their derivative works on different terms, provided the original work is Euro-­ GASP would provide strengthened information for properly cited, appropriate credit is given, any changes made indicated, and the use public health action. It is also essential to further strengthen is non-­commercial. See: http://​creativecommons.​org/​licenses/​by-​nc/​4.​0/. and expand the WHO Global GASP,7 particularly in regions ORCID iDs with very limited AMR data such as WHO EMR and WHO Michelle Jayne Cole http://​orcid.​org/​0000-​0002-​6707-​6910 AFR, but also in regions with high rates of AMR such as SEAR Magnus Unemo http://​orcid.​org/​0000-​0003-​1710-​2081 and especially WPR. Further research to improve the under- standing of sexual networks within foreign-­born and sexual tourism populations will help to inform effective tailor-­made References interventions. 1 Bignell C, Unemo M. European guideline on the diagnosis and treatment of Additional references can be found in the online supplemen- gonorrhoea in adults. Int J STD AIDS 2012;2013:85–92. tary file. 2 Unemo M, Shafer WM. Antimicrobial resistance in Neisseria gonorrhoeae in the 21st century: past, evolution, and future. Clin Microbiol Rev 2014;27:587–613. 3 European Centre for Disease Prevention and Control (ECDC). 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