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Significant increase in azithromycin “resistance” and susceptibility to ceftriaxone and cefixime in Neisseria gonorrhoeae isolates in 26 European countries, 2019

Significant increase in azithromycin “resistance” and susceptibility to ceftriaxone and cefixime... Background: The European Gonococcal Antimicrobial Surveillance Programme (Euro‑ GASP) performs annual senti‑ nel surveillance of Neisseria gonorrhoeae susceptibility to therapeutically relevant antimicrobials across the European Union/European Economic Area (EU/EEA). We present the Euro‑ GASP results from 2019 (26 countries), linked to patient epidemiological data, and compared with data from previous years. Methods: Agar dilution and minimum inhibitory concentration (MIC) gradient strip methodologies were used to determine the antimicrobial susceptibility (using EUCAST clinical breakpoints, where available) of 3239 N. gonorrhoeae isolates from 26 countries across the EU/EEA. Significance of differences compared with Euro ‑ GASP results in previous years was analysed using Z‑test and the Pearson’s χ2 test was used to assess significance of odds ratios for associations between patient epidemiological data and antimicrobial resistance. Results: European N. gonorrhoeae isolates collected between 2016 and 2019 displayed shifting MIC distributions for; ceftriaxone, with highly susceptible isolates increasing over time and occasional resistant isolates each year; cefixime, with highly‑susceptible isolates becoming increasingly common; azithromycin, with a shift away from lower MICs towards higher MICs above the EUCAST epidemiological cut‑ off (ECOFF); and ciprofloxacin which is displaying a simi‑ lar shift in MICs as observed for azithromycin. In 2019, two isolates displayed ceftriaxone resistance, but both isolates had MICs below the azithromycin ECOFF. Cefixime resistance (0.8%) was associated with patient sex, with resistance higher in females compared with male heterosexuals and men‑ who‑have ‑sex ‑ with‑men (MSM). The number of countries reporting isolates with azithromycin MICs above the ECOFF increased from 76.9% (20/26) in 2016 to 92.3% (24/26) in 2019. Isolates with azithromycin MICs above the ECOFF (9.0%) were associated with pharyngeal infection sites. Following multivariable analysis, ciprofloxacin resistance remained associated with isolates from MSM and het ‑ erosexual males compared with females, the absence of a concurrent chlamydial infection, pharyngeal infection sites and patients ≥ 25 years of age. Magnus Unemo and Michelle J. Cole joint senior authors *Correspondence: [email protected] UK Health Security Agency, London, UK Full list of author information is available at the end of the article © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecom‑ mons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Day et al. BMC Infectious Diseases (2022) 22:524 Page 2 of 10 Conclusions: Resistance to ceftriaxone and cefixime remained uncommon in EU/EEA countries in 2019 with a significant decrease in cefixime resistance observed between 2016 and 2019. The significant increase in azithro ‑ mycin “resistance” (azithromycin MICs above the ECOFF) threatens the effectiveness of the dual therapy (ceftriax ‑ one + azithromycin), i.e., for ceftriaxone‑resistant cases, currently recommended in many countries internationally and requires close monitoring. Keywords: Gonorrhoea, Treatment, Antimicrobial resistance, Ceftriaxone, Azithromycin, Surveillance, European Gonococcal Antimicrobial Surveillance Programme (Euro‑ GASP), Europe, European Union (EU), European Economic Area (EEA) Background As azithromycin is only recommended for use in dual The European Gonococcal Antimicrobial Surveillance therapy with another effective agent, the correlates Programme (Euro-GASP) is a sentinel surveillance sys- between azithromycin in  vitro susceptibility and treat- tem that since 2009 has been coordinated by the Euro- ment outcome are limited, and appropriate clinical treat- pean Centre for Disease Prevention and Control (ECDC) ment data to inform clinical breakpoints are lacking, and supported by a European network of microbiolo- the European Committee on Antimicrobial Susceptibil- gists and epidemiologists. The programme aims to pro - ity Testing (EUCAST) replaced their clinical resistance vide quality-assured antimicrobial susceptibility data to breakpoint with an epidemiological cut-off (ECOFF) inform European and other regional and national gonor- value of 1 mg/L in January 2019 [14]. This ECOFF value rhoea treatment guidelines as well as to detect emerging aims to detect strains with acquired macrolide resistance. antimicrobial resistance and monitor trends in antimi- Those with azithromycin MICs of ≤ 1  mg/L are consid- crobial resistance. ered “wild-type” [14]. Euro-GASP previously reported Decreasing levels of susceptibility to clinically relevant stable levels of azithromycin resistance (approx. 7%, antimicrobials along with verified treatment failures are using previous > 0.5 mg/L breakpoint) across the EU/EEA threatening the treatment and control of gonorrhoea in 2014–2016 [7]. internationally [1–9]. The European guideline for the In the present study, we describe the results from the diagnosis and treatment of gonorrhoea in adults was 2019 Euro-GASP sentinel surveillance, in conjunction updated in 2020 [10, 11]. The guideline now recommends with patients’ epidemiological data, and compare them for uncomplicated N. gonorrhoeae infections, 1  g ceftri- to the Euro-GASP results obtained from previous years axone (an increase from the 500 mg recommended in the (main focus on the published 2016 Euro-GASP data [7]). 2012 guidelines [12]) with 2  g azithromycin, or 1  g cef- triaxone alone in settings where in  vitro antimicrobial Methods susceptibility surveillance has shown lack of ceftriaxone European Gonococcal Antimicrobial Surveillance resistance, test of cure (TOC) is mandatory, and doxycy- Programme (Euro‑GASP) cline regimen is administered if Chlamydia trachomatis Annually, laboratories participating in Euro-GASP report infection has not been excluded [10]. Notably, in a most antimicrobial susceptibility profiles (using EUCAST clin - recent Euro-GASP survey of 26 EU/EEA countries only ical breakpoints, where available [14]) and patient epide- 19 (73.1%) countries used ceftriaxone plus azithromycin miological data for N. gonorrhoeae isolates collected in dual therapy with Ireland, Sweden, the Netherlands and their country as described previously [7, 15]. All gono- the United Kingdom (UK) having national guidelines that coccal isolates were cultured and preserved as part of the recommended use of ceftriaxone 1 g monotherapy [13]. routine diagnostics (standard care), and isolates or data In addition, cefixime (400  mg single dose) is recom - were submitted to the Euro-GASP surveillance study mended in the European guideline only as a substitute with no patient identification information, separate ethi - for ceftriaxone in dual therapy in cases where injections cal approval was therefore not required. are refused or contraindicated. Cefixime is not recom - In 2019, 26 countries participated in Euro-GASP, sub- mended for use in monotherapy. Ciprofloxacin (500  mg mitting total data for 4166  N. gonorrhoeae isolates (one single dose) is suggested as an alternative treatment isolate per patient per gonorrhoea episode) to The Euro - regime for those with history of severe hypersensitiv- pean Surveillance System (TESSy) at ECDC. Some coun- ity to any β-lactam antimicrobial or when injections are tries were over-represented in the complete 2019 TESSy contraindicated or refused, however, only where suscep- data set with Austria submitting data for 434 isolates, tibility has been confirmed phenotypically or molecularly France 243 isolates, the Netherlands 364 isolates and (gyrA-based resistance testing) [10]. Norway 641 isolates whereas other countries with lower Da y et al. BMC Infectious Diseases (2022) 22:524 Page 3 of 10 gonorrhoea incidence were under-represented with Table 1 Gonorrhoea patient characteristics in 2016 and 2019 Cyprus submitting data for two isolates, Latvia seven 2016 2019 isolates, Estonia eight isolates and Croatia nine isolates. N (%) N (%) The same imbalance was also present in previous years’ Total number of isolates 2559 3239 TESSy datasets. In order to reduce biases caused by high Sex isolate numbers from some countries, only data for the Male 2158 (84.7) 2676 (84.2) first 200 isolates with complete antimicrobial susceptibil - Female 391 (15.3) 502 (15.8) ity testing results submitted to TESSy in each year were Not reported 10 61 included in the analysis of the present paper including Age (years) data from 2016 which was used as the main comparator < 25 668 (26.5) 883 (28.4) for this publication unless otherwise stated. For compari- ≥ 25 1854 (73.5) 2223 (71.6) son of azithromycin MIC data, data collected prior to the Not reported 37 133 introduction of the ECOFF was converted to equal to or Sexual orientation and sex below the ECOFF (referred to as susceptible hereafter) Females 391 (24.4) 501 (25.6) or above the ECOFF (referred to as resistant hereafter). Heterosexual males 539 (33.6) 545 (27.9)* Azithromycin MICs ≥ 256  mg/L will be discussed as Men who have sex with men 672 (41.9) 908 (46.5)* “high-level azithromycin resistant”. Not reported 957 1285 Site of infection Statistical analysis Urogenital 1745 (75.1) 2076 (71.5)* The Mann–Whitney test was used to analyse differences Pharyngeal 153 (6.6) 262 (9.0)* in age distribution and the Z-test was applied to compare Anorectal 329 (14.2) 475 (16.4)* proportions when analysing antimicrobial susceptibility Other 97 (4.2) 91 (3.1)* and epidemiological data. Associations between epidemi- Not reported 235 335 ological characteristics and antimicrobial susceptibility Previous gonorrhoea were assessed using odds ratios (OR) and 95% confidence Yes 163 (16.7) 228 (23.2)* intervals (CI); the Pearson’s χ test was used to measure if No 814 (83.3) 753 (76.8)* these odds ratios differed significantly from 1. For small Not reported 1582 2258 cell numbers (n < 5), Fisher’s exact test was performed. Concurrent sexually transmitted infection (STI) Statistical significance for all tests was assumed when Concurrent chlamydia infection 181 (23.5) 228 (21.2) p < 0.05. Statistical analysis was performed using Stata Concurrent other STI (not HIV ) 51 (6.6) 83 (7.7) v15 (StataCorp LP, Texas, USA). No concurrent STI 539 (69.9) 764 (71.1) Not reported 1788 2164 Results HIV status Using a maximum of 200 isolates per country, 3239  N. Positive 143 (15.8) 139 (13.1) gonorrhoeae isolates collected in 2019 from 3239 episodes Negative 760 (84.2) 926 (86.9) of gonorrhoea were compared to the Euro-GASP data Not reported 1656 2174 from 2016 (n = 2556) (Table  1). As in all previous years of Euro-GASP surveillance (starting in 2009), most iso- Total number of isolates includes a maximum of 200 isolates per country. Three countries exceeded the 200 isolate limit in 2016; The Netherlands, Spain and the lates in 2019 were from male patients (84.2%, 2676/3178), UK. In 2019 seven countries exceeded 200 isolates; Austria, Finland, France, The and male patients (median age 30 years) were older than Netherlands, Norway, Spain and the UK female patients (median age 26 years) (p < 0.0001). Over- *Bold letters indicate significant difference between 2016 and 2019 by Z-test (p < 0.05) all, patient ages ranged from 0 to 84 years with a median age of 29 years old. The anatomical site of collection was mainly urogenital (71.5%), however, there was a decrease infection which was an increase from 16.7% (163/976) in samples from this site compared to 2016 (75.1%, in 2016 (p < 0.002) and 21.2% (228/1075) had a con- p = 0.004, Table 1). current C. trachomatis infection which remained at a In contrast, there was an increase in both rectal level similar to that in 2016 (23.5%, 181/771) (Table  1). (14.2% vs. 16.4%, p = 0.02) and pharyngeal (6.6% vs. Among cases with known sexual orientation and 9.0%, p = 0.001) sites which is likely a consequence of sex (unknown for 31–43% of cases each year), 53.5% the significant increase in specimens from men-who- (1046/1954) of the N. gonorrhoeae infections were have-sex-with-men (MSM) in 2019 (41.9% vs. 46.5%, reported as heterosexually acquired (47.9% females p = 0.0002, Table  1). For cases where information was and 52.1% males). The proportion of heterosexual available, 23.2% (228/981) had a previous gonorrhoea Day et al. BMC Infectious Diseases (2022) 22:524 Page 4 of 10 males decreased from 33.6% in 2016 to 27.9% in 2019 the UK (one in 2017, six in 2019). The proportion of (p = 0.0002, Table 1). countries reporting isolates with azithromycin resistance In 2019 ceftriaxone resistance was detected in two uro- increased from 76.9% (20/26) in 2016 to 92.3% (24/26) in genital isolates, one in Belgium (MIC = 0.5  mg/L) and 2019 (p = 0.0007). The countries with the highest propor - one in Portugal (MIC = 0.25  mg/L). Both isolates were tion of azithromycin-resistant isolates in 2019 were Nor- also resistant to cefixime (MIC = 2  mg/L and = 0.5  mg/L, way (16%; 32/200), Poland (18.9%; 10/53), Iceland (20.4%; respectively) and ciprofloxacin (MIC > 32  mg/L and 11/54), Estonia (25%; 2/8), and Croatia (55.6%; 5/9). 4  mg/L, respectively) but were susceptible to azithro- Three of these countries, Estonia, Croatia and Poland did mycin (MIC 0.5  mg/L and 1  mg/L, respectively). For not report any azithromycin resistance in 2016, however, comparison, there were three urogenital isolates with cef- the number of isolates reported especially in Estonia and triaxone resistance identified in 2018 (two in Spain, one Croatia in both 2016 and 2019 were very low. Azithromy- in Germany), zero in 2017 and 2016. Despite the detec- cin resistance was associated with pharyngeal sites when tion of ceftriaxone-resistant isolates in both 2018 and compared to urogenital ones (Table 2). 2019, the proportion of gonococcal isolates that were There was an increase in resistance to ciprofloxacin most susceptible to ceftriaxone (MIC ≤ 0.016  mg/L) from 47.2% (1003/2124) in 2016 to 57.4% (1665/2884) in increased from 82.9% (2117/2555) in 2016 to 89.7% 2019 (p < 0.0002, Fig.  1d). The MIC distribution changed (2903/3238) in 2019 (p < 0.0002, Fig.  1a). In addition, the between 2016 and 2019 with decreases in lower MICs proportion of isolates with decreased susceptibility to (0.004–0.008  mg/L, p < 0.0002) and increases in lower ceftriaxone (MICs from 0.032 to 0.125  mg/L) decreased levels of resistance (0.5–4  mg/L, p < 0.0002, Fig.  1d). from 17.1% (438/2555) in 2016 to 10.3% (333/3238) in However, there was a decrease in high-level ciprofloxa - 2019 (p < 0.0002, Fig. 1a). cin resistance (MIC ≥ 32 mg/L) from 12.4% (264/2124) in Similarly to ceftriaxone, the proportion of isolates most 2016 to 7.7% in 2019 (223/2884, p < 0.0002). As in 2016, susceptible to cefixime (MIC ≤ 0.016  mg/L) increased ciprofloxacin resistance in 2019 was associated with from 74.9% (1805/2411) in 2016 to 80.9% (2621/3239) in male heterosexuals (compared to females) and previous 2019 (p < 0.0002, Fig. 1b). Furthermore, the percentage of gonorrhoea infection. In 2019 ciprofloxacin resistance isolates with decreased susceptibility to cefixime (MICs was also associated with MSM (compared to females), 0.032–0.125  mg/L) decreased from 22.9% (553/2411) in patient age ≥ 25  years (compared to < 25  years), anorec- 2016 to 18.3% (592/3239) in 2019 (p < 0.0002). The pro - tal and pharyngeal sites (compared to urogenital) and portion of cefixime-resistant isolates (MIC > 0.125 mg/L) with not having concurrent C. trachomatis infection also decreased from 2.2% (53/2411) in 2016 to 0.8% (Table  2). Following multivariable analysis, ciprofloxacin (26/3239) in 2019 (p < 0.0002, Fig.  1b). Of the 26 isolates resistance remained associated with isolates from MSM with cefixime resistance in 2019, only one had addi - (OR = 2.7, CI = 1.48–4.95, p < 0.01) and heterosexual tional azithromycin resistance (MIC = 16 mg/L). In 2019, males (OR = 2.24, CI = 1.24–4.05, p < 0.01) compared cefixime resistance was associated with patient sex and to females, the absence of a concurrent C. trachomatis sexual orientation with 1.6% resistance in females com- infection (OR = 1.9, CI = 1.14–3.18, p = 0.02), phar yn- pared with 0.7% in male heterosexuals and 0.3% in MSM geal sites (OR = 2.4, CI = 1.28–4.52, p < 0.01) and patient (p = 0.045, Fisher’s exact test, Table 2). age ≥ 25 years (OR = 1.62, CI = 1.05–2.50, p = 0.03). The percentage of isolates with azithromycin resist - ance (MICs above the ECOFF of 1  mg/L) increased Discussion from 3.8% (97/2532) in 2016 to 9.0% (284/3159) in 2019 Three distinct antimicrobial susceptibility patterns (p < 0.002, Fig.  1c). In contrast to what was observed for among N. gonorrhoeae isolates in the EU/EEA have ceftriaxone and cefixime (Fig.  1a and b), there was also emerged for ceftriaxone, cefixime and azithromycin a decrease in the proportion of gonococcal isolates with between 2016 and 2019. Ceftriaxone appears to be shift- the lowest azithromycin MICs (≤ 0.016 mg/L) from 1.1% ing towards higher susceptibility over time and resistant (27/2532) in 2016 to 0.4% (14/3159) in 2019 (p < 0.002, isolates continue to be rare. However, worryingly the Fig.  1c). The proportion of isolates with azithromycin clonally expanding and internationally spreading ceftri- MICs ≥ 256  mg/L (“high-level azithromycin resistance”) axone-resistant N. gonorrhoeae strain FC428 has been has not changed with 0.2% (5/2532) in 2016 and 0.3% identified in several EU/EEA countries such as Denmark in 2019 (10/3159, p = 0.381). Only five countries have [16], France [5], Ireland [17], and the UK [18], as well as reported isolates with azithromycin MICs ≥ 256  mg/L in in many additional countries worldwide, e.g., Japan [19], multiple years; Finland (two in 2016, one in 2017), Ireland Australia [20], Canada [21], and China [22]. (one in 2016, one in 2018, three in 2019), Iceland (two in Cefixime MICs are also shifting away from resistance 2016, two in 2019), Italy (two in 2016, one in 2018), and with highly susceptible isolates becoming increasingly Da y et al. BMC Infectious Diseases (2022) 22:524 Page 5 of 10 2016 2017 2018 2019 ≤0.016 0.032 0.064 0.125 0.25 0.5 Ceriaxone MIC (mg/L) 2016 2017 2018 2019 ≤0.016 0.032 0.064 0.125 0.25 0.5 1≥2 Cefixime MIC (mg/L) Fig. 1 Minimum inhibitory concentration (MIC; mg/L) distribution in European Neisseria gonorrhoeae isolates (2016–2019) for a ceftriaxone, b cefixime, c azithromycin, and d ciprofloxacin Percentage Percentage Day et al. BMC Infectious Diseases (2022) 22:524 Page 6 of 10 2016 2017 2018 2019 ≤0.016 0.032 0.064 0.125 0.25 0.5 1248 16 32 64 ≥256 Azithromycin MIC (mg/L) 2016 2017 2018 2019 ≤0.002 0.004 0.008 0.016 0.032 0.064 0.125 0.25 0.51 24 816≥32 Ciprofloxacin MIC (mg/L) Fig. 1 continued common between 2016 and 2019. This increase in cefix - years in the EU/EEA countries. The same shift towards ime susceptibility might be due to the use of recom- cefixime susceptibility was observed in the United States mended ceftriaxone/azithromycin dual therapy since (US) between 2014 and 2018 with the proportion of iso- 2012 or ceftriaxone monotherapy (500–1000 mg), which lates with decreased susceptibility to cefixime (MIC has become increasingly common in the most recent 0.032–0.125 mg/L) decreasing from 37.8 to 29.9% and the Percentage Percentage Da y et al. BMC Infectious Diseases (2022) 22:524 Page 7 of 10 Table 2 Univariate association of cefixime, azithromycin and ciprofloxacin resistance/susceptibility and patient characteristics, 2019 Cefixime resistance Azithromycin resistance Ciprofloxacin resistance N (%, 95% CI) Odds ratio 95% CI p value N (%, 95% CI) Odds ratio 95% CI p value N (%, 95% CI) Odds ratio 95% CI p value Site of infection (n = 2904) Urogenital (2076) 18 (0.9, 0.5–1.4) 0.40* 171 (8.2, 7.1–9.5) 1 1152 (55.5, 53.4–57.6) 1 Anorectal (475) 1 (0.2, 0.0–1.2) 48 (10.1, 7.7–13.1) 1.25 0.89–1.75 0.19 298 (62.7, 58.3–67.0) 1.35 1.09–1.66 < 0.01 Pharyngeal (262) 2 (0.8, 0.2–2.7) 35 (13.4, 9.8–18.0) 1.72 1.16–2.54 < 0.01 163 (62.5, 56.4–68.1) 1.33 1.02–1.74 0.03 Other (91) 1 (1.1, 0.2–2.7) 9 (9.9, 5.3–17.7) 1.22 0.60–2.48 0.58 56 (61.5, 51.3–70.9) 1.28 0.83–1.97 0.26 Sexual orientation and sex (n = 1955) MSM (908) 3 (0.3, 0.1–1.0) 0.045* 75 (8.3, 6.6–10.2) 1 542 (59.7, 56.5–62.8) 1.9 1.54–2.42 < 0.01 Male heterosexual (545) 4 (0.7, 0.3–1.9) 40 (7.3, 5.4–9.8) 0.88 0.59–1.31 0.53 285 (52.3, 48.1–56.5) 1.4 1.12–1.83 < 0.01 Female (502) 8 (1.6, 0.8–3.1) 35 (7.0, 5.0–9.5) 0.83 0.59–1.26 0.39 217 (43.4, 39.1–47.8) 1 Previous gonorrhoea (n = 981) Yes (228) 1 (0.4, 0.0–2.4) 0.41* 18 (7.9, 6.0–9.8) 1.03 0.59–1.78 0.92 138 (60.5, 54.1–66.6) 1.68 1.24–2.28 < 0.01 No (753) 1 (0.1, 0.0–0.8) 58 (7.7, 5.1–12.1) 1 359 (47.7, 44.1–51.2) 1 Concurrent chlamydia (n = 1075) Yes (228) 2 (0.9, 0.2–3.1) 0.20* 20 (8.8, 5.8–13.2) 1.02 0.61–1.71 0.94 95 (41.7, 35.5–48.2) 1 No (847) 2 (0.2, 0.0–0.9) 73 (8.6, 7.0–10.7) 1 502 (59.3, 55.9–62.5) 2 1.51–2.75 < 0.01 HIV status (n = 1065) Positive (139) 0 (0.0, 0.0–2.7) 1.00* 15 (10.8, 6.6–17.0) 1.25 0.70–2.23 0.46 81 (59.3, 50.0–66.1) 1.2 0.84–1.72 0.32 Negative (926) 3 (0.3, 0.1–0.9) 82 (8.9, 7.2–10.9) 1 498 (53.8, 50.6–57.0) 1 Age (n = 3106) < 25 years (883) 7 (0.8, 0.4–1.6) 1 0.72 75 (8.5, 6.8–10.5) 1 457 (51.9, 48.6–55.2) 1 ≥ 25 years (2223) 15 (0.7, 0.4–1.1) 0.85 0.35–2.09 193 (8.7, 7.6–9.9) 1.02 0.77–1.35 0.87 1307 (58.8, 56.7–60.8) 1.3 1.13–1.55 < 0.01 MSM men who have sex with men. Bold letters indicate significance *Fishers exact test (n < 5) One isolate had no ciprofloxacin result Two isolates had no ciprofloxacin results Day et al. BMC Infectious Diseases (2022) 22:524 Page 8 of 10 proportion of cefixime-resistant isolates decreasing from isolates are available from many of these cases, the major- 0.7 to 0.3% (recalculated from data presented in [23]). ity of examined N. gonorrhoeae isolates are obtained from In the US, new gonorrhoea treatment guidelines were urogenital sites and the number of isolates from rec- issued in 2015 recommending dual therapy with ceftriax- tal and pharyngeal sites are more limited, and in many one 500 mg and azithromycin 1 g for uncomplicated gon- countries the completeness of reported epidemiological orrhoea [24], which may have had a role in the increase in data (particularly of sexual orientation) is suboptimal. cefixime susceptibility. However, despite these limitations a previous representa- Azithromycin MICs are, in contrast to those observed tiveness analysis showed that Euro-GASP appropriately for ceftriaxone and cefixime, shifting towards MICs reflects the antimicrobial resistance situation for N. gon - above the azithromycin ECOFF, and this has been orrhoeae in the EU/EEA [36]. recently reported in many countries internationally [8, 9, 25]. High levels of azithromycin resistance are of concern Conclusions not just for N. gonorrhoeae but for also for other bacte- Resistance in N. gonorrhoeae to the third-generation rial STIs. The same increase in higher MICs (> 1  mg/L) cephalosporins ceftriaxone and cefixime remained was observed in the US between 2014 and 2018 although uncommon in 2019 in EU/EEA countries with a signifi - less pronounced than in Europe with an increase from cant decrease in cefixime resistance observed between 2.4 to 4.6% (recalculated from data presented in [23]). 2016 and 2019. The significant increase in the propor - By contrast, the Australian gonococcal surveillance pro- tion of isolates with azithromycin resistance is concern- gramme has observed a decrease in the percentage of iso- ing for the future effectiveness of any ceftriaxone plus lates with azithromycin MICs > 1  mg/L after the peak of azithromycin dual therapy, particularly if ceftriaxone 9.3% was reached in 2017 to 4.6% in 2019 [26]. In the vast resistance starts to spread more widely. It is imperative majority of Australian settings, dual therapy with ceftri- that the MICs for N. gonorrhoeae isolates continue to be axone 500  mg and azithromycin 1  g (2  g for pharyngeal monitored very closely over the next years, particularly of gonorrhoea) is recommended for uncomplicated gonor- azithromycin and ceftriaxone. rhoea [27]. This may indicate a high adherence to recom - mended treatment, less and more controlled macrolide use for other infections (particularly Chlamydia tra- Abbreviations AD: Agar dilution method; CI: Confidence interval; ECDC: European Centre chomatis and Mycoplasma genitalium infections), and/or for Disease Prevention and Control; ECOFF: Epidemiological cut‑ off; EEA: replacement of some major azithromycin-resistant gono- European Economic Area; EU: European Union; EUCAST: European Commit‑ coccal clones with more azithromycin-susceptible clones. tee on Antimicrobial Susceptibility Testing; Euro‑ GASP: European Gonococcal Antimicrobial Surveillance Programme; MIC: Minimum inhibitory concentra‑ In the Euro-GASP 2009–2016 data, ciprofloxacin tion; MSM: Men who have sex with men; No.: Number; OR: Odds ratio; STI: resistance was significantly associated with urogenital Sexually transmitted infection; TESSy: The European Surveillance System; UK: sites [28], in 2019 both ciprofloxacin and azithromycin United Kingdom. resistance were significantly associated with pharyngeal Acknowledgements infections. Pharyngeal infections are considered to have We are grateful to the European STI surveillance network for its contribution to a major role in the development of resistance to sev- developing and implementing Euro‑ GASP and submitting gonococcal isolates and epidemiological data. eral antimicrobials, such as beta-lactam antimicrobials. The Euro‑ GASP Network: The presence of other commensal Neisseria species in Austrian Agency for Health and Food Safety, Wien, Austria: Claudia Eder, the pharynx often with previous exposure to antibiotics Sonja Pleininger, Steliana Huhlescu; Institute of Tropical Medicine, Antwer‑ pen, Belgium: Irith de Baetselier; Croatian National Institute Of Public Health, allows for horizontal transfer of resistance genes to N. Zagreb, Croatia: Blaženka Hunjak, Tatjana Nemeth Blažić; Nicosia General gonorrhoeae [29–33]. Pharyngeal infections are also more Hospital, Nicosia, Cyprus: Panagiota Maikanti‑ Charalampous, Despo Pieridou; difficult to eradicate with most antimicrobials due to sub- The National Institute of Public Health, Prague, The Czech Republic: Hana Zákoucká, Helena Žemličková; Statens Serum Institut, Copenhagen, Denmark: optimal antibiotic concentrations at this site which adds Steen Hoffmann, Susan Cowan; Health Board, Tallinn, Estonia: Rita Peetso, to the selective pressure of gonococcal clones with higher Jelena Viktorova; Hospital Saint Louis, Paris, France: Ndeindo Ndeikoundam, MICs [34, 35]. Beatrice Bercot; Helsinki University Central Hospital, Helsinki, Finland: Anu Patari Sampo, Vesa Kirjavainen; Vivantes Klinikum Neukolln, Berlin, Germany: The limitations of Euro-GASP and, accordingly, the Susanne Buder, Klaus Jansen; Hellenic Pasteur Institute, Athens, Greece: present study have been previously described in detail [7, Vivi Miriagou; National Centre for Epidemiology, Budapest, Hungary: Eszter 28, 36, 37]. These limitations include, for example, that Balla, Mária Dudás; Landspitali University Hospital, Reykjavik, Iceland: Guðrún Sigmundsdóttir, Lena Ros Asmundsdottir; St James’s Hospital, Dublin, Ireland: a limited number of gonorrhoea patients and N. gonor- Sinead Saab, Brendan Crowley; Istituto Superiore di Sanita, Rome, Italy: Anna rhoeae isolates (~ 3% of all reported gonorrhoea cases Carannante, Paola Stefanelli; Riga East University Hospital, Riga, Latvia: Gatis in the EU/EEA) from many diverse countries are exam- Pakarna, Violeta Mavcutko; Mater Dei Hospital, Msida, Malta: Robert Cassar, Christopher Barbara, Francesca Vella; The Public Health Service of Amsterdam, ined, many gonorrhoea cases in the EU/EEA are diag- Amsterdam, The Netherlands: Alje Van Dam, Ineke Linde; Domain of Infec‑ nosed with molecular diagnostics and no N. gonorrhoeae tious Disease Control and Environmental Health, Oslo, Norway: Dominique Da y et al. BMC Infectious Diseases (2022) 22:524 Page 9 of 10 Caugant, Hilde Kløvstad; Medical University of Warsaw, Warsaw, Poland: Beata resistance and decreased ceftriaxone susceptibility, Hawaii, 2016. Clin Mlynarczyk‑Bonikowska; Instituto Nacional de Saude Dr Ricardo Jorge, Lisboa, Infect Dis. 2017;65(6):918–23. Portugal: Maria‑ José Borrego; Medirex a.s., Bratislava, Slovak Republic: Peter 4. Morita‑Ishihara T, Unemo M, Furubayashi K, Kawahata T, Shimuta Pavlik; Institut za mikrobiologijo in imunologijo, Univerza v Ljubljani Medicin‑ K, Nakayama S, et al. Treatment failure with 2 g of azithromycin ska fakulteta, Ljubljana, Slovenia: Irena Klavs, Tanja Kustec; National Institute (extended‑release formulation) in gonorrhoea in Japan caused by the of Health Carlos III, Madrid, Spain: Julio Vazquez, Asuncion Diaz, Raquel Abad international multidrug‑resistant ST1407 strain of Neisseria gonor - Torreblanca; Public Health Agency of Sweden, Stockholm, Sweden: Inga rhoeae. J Antimicrob Chemother. 2014;69(8):2086–90. Velicko, Magnus Unemo; Royal Infirmary of Edinburgh, Edinburgh, UK: Helen 5. Poncin T, Fouere S, Braille A, Camelena F, Agsous M, Bebear C, et al. Fifer, Kate Templeton. Multidrug‑resistant Neisseria gonorrhoeae failing treatment with cef‑ triaxone and doxycycline in France, November 2017. Eurosurveillance. Author contributions 2018;23(21). MC, MD, GS, BB, SJ, NW, MJvdW, AAG and MU designed, initiated and 6. Yan J, Chen Y, Yang F, Ling X, Jiang S, Zhao F, et al. High percentage of coordinated the study. SJ, MD, CK, NS and Network members coordinated the ceftriaxone‑resistant Neisseria gonorrhoeae FC428 clone among and performed the laboratory analyses. Patient data was supplied by the isolates from a single hospital in Hangzhou, China. J Antimicrob Chem‑ Network members. MD, MC, GS, BB, SJ, NW, MJvdW, AAG and MU analysed and other. 2021;76(4):936–9. interpreted all the data, and wrote a first draft of the paper. MD, MC, CK, NS, 7. Day MJ, Spiteri G, Jacobsson S, Woodford N, Amato‑ Gauci AJ, Cole MJ, GS, BB, SJ, NW, MJvdW, AAG and MU read, commented and approved the final et al. Stably high azithromycin resistance and decreasing ceftriaxone manuscript. All authors read and approved the final manuscript. susceptibility in Neisseria gonorrhoeae in 25 European countries, 2016. BMC Infect Dis. 2018;18(1):609. Funding 8. Unemo M, Lahra MM, Cole M, Galarza P, Ndowa F, Martin I, et al. World The study was funded by the European Centre for Disease Prevention Health Organization Global Gonococcal Antimicrobial Surveillance and Control (Framework Contract No. ECDC/2017/004). The funding body Program ( WHO GASP): review of new data and evidence to inform designed, initiated and coordinated the study as well as assisted in the inter‑ international collaborative actions and research efforts. Sex Health. pretation of the data, development and final approval of the manuscript. 2019;16(5):412–25. 9. Unemo M LM, Escher M, Eremin S, Cole MJ, Galarza P, Ndowa F, Martin Availability of data and materials I, Dillon JR, Galas M, Ramon‑Pardo P, Weinstock H, Wi T. WHO global The data that support the findings of this study are available from the Euro ‑ antimicrobial resistance surveillance for Neisseria gonorrhoeae 2017–18: pean Centre for Disease Prevention and Control but restrictions apply to the a retrospective observational study. The Lancet Microbe. 2021; https:// availability of these data, which were used under license for the current study, www. thela ncet. com/ action/ showP df? pii= S2666‑ 5247% 2821% 29001 and so are not publicly available. Data are, however, available from the authors 71‑3. upon reasonable request and with permission of the European Centre for 10. Unemo M, Ross J, Serwin AB, Gomberg M, Cusini M, Jensen JS. Back‑ Disease Prevention and Control. ground review for the ‘2020 European guideline for the diagnosis and treatment of gonorrhoea in adults.’ Int J STD AIDS. 2021;32(2):108–26. 11. Unemo M, Ross J, Serwin AB, Gomberg M, Cusini M, Jensen JS. Declarations European guideline for the diagnosis and treatment of gonorrhoea in adults. Int J STD AIDS. 2020;2020:956462420949126. Ethics approval and consent to participate 12. Bignell C, Unemo M. 2012 European guideline on the diagnosis and All examined gonococcal isolates were cultured and preserved as part of the treatment of gonorrhoea in adults. Int J STD AIDS. 2013;24(2):85–92. routine diagnostics (standard care), and isolates or data were submitted to 13. European Centre for Disease Control. Response plan to control and the Euro‑ GASP surveillance study with no patient identification information. manage the threat of multi‑ and extensively drug‑resistant gonorrhoea Separate ethical approval was therefore not required. in Europe—Indicator monitoring 2019. https:// www. ecdc. europa. eu/ sites/ defau lt/ files/ docum ents/ TRP‑ 20201 125‑ 1523. pdf . 2021. Consent for publication 14. The European Committee on Antimicrobial Susceptibility Testing. Not applicable. Breakpoint tables for interpretation of MICs and zone diameters. Ver‑ sion 9.0. http:// www. eucast. org. 2019. Competing interests 15. European Centre for Disease Control. Gonococcal antimicrobial The authors declare that they have no competing interests. susceptibility surveillance in the European Union/European Economic Area Summary of results for 2019. https:// www. ecdc. europa. eu/ sites/ Author details defau lt/ files/ docum ents/ Gonoc occal‑ antim icrob ial‑ susce ptibi lity‑ surve 1 2 UK Health Security Agency, London, UK. WHO Collaborating Centre for Gon‑ illan ce‑ 2019. pdf . 2021. orrhoea and Other STIs, Örebro University, Örebro, Sweden. European Centre 16. Terkelsen D, Tolstrup J, Johnsen CH, Lund O, Larsen HK, Worning P, et al. for Disease Prevention and Control, Stockholm, Sweden. Universit y College Multidrug‑resistant Neisseria gonorrhoeae infection with ceftriaxone London (UCL), London, UK. resistance and intermediate resistance to azithromycin, Denmark, 2017. Eurosurveillance. 2017;22(42). Received: 7 March 2022 Accepted: 27 May 2022 17. Golparian D, Rose L, Lynam A, Mohamed A, Bercot B, Ohnishi M, et al. Multidrug‑resistant Neisseria gonorrhoeae isolate, belonging to the internationally spreading Japanese FC428 clone, with ceftriaxone resistance and intermediate resistance to azithromycin, Ireland, August 2018. Eurosurveillance. 2018;23(47). 18. Eyre DW, Town K, Street T, Barker L, Sanderson N, Cole MJ, et al. Detec‑ tion in the United Kingdom of the Neisseria gonorrhoeae FC428 clone, References with ceftriaxone resistance and intermediate resistance to azithromy‑ 1. Eyre DW, Sanderson ND, Lord E, Regisford‑Reimmer N, Chau K, Barker L, cin, October to December 2018. Eurosurveillance. 2019;24(10). et al. Gonorrhoea treatment failure caused by a Neisseria gonorrhoeae 19. Nakayama S, Shimuta K, Furubayashi K, Kawahata T, Unemo M, Ohnishi strain with combined ceftriaxone and high‑level azithromycin resistance, M. New Ceftriaxone‑ and multidrug‑resistant Neisseria gonorrhoeae England, February 2018. Eurosurveillance. 2018;23(27). strain with a novel Mosaic penA gene isolated in Japan. Antimicrob 2. Fifer H, Natarajan U, Jones L, Alexander S, Hughes G, Golparian D, et al. Agents Chemother. 2016;60(7):4339–41. Failure of dual antimicrobial therapy in treatment of gonorrhea. N Engl J 20. Lahra MM, Martin I, Demczuk W, Jennison AV, Lee KI, Nakayama Med. 2016;374(25):2504–6. SI, et al. Cooperative recognition of internationally disseminated 3. Katz AR, Komeya AY, Kirkcaldy RD, Whelen AC, Soge OO, Papp JR, et al. ceftriaxone‑resistant Neisseria gonorrhoeae strain. Emerg Infect Dis. Cluster of Neisseria gonorrhoeae isolates with high‑level azithromycin 2018;24(4):735–40. Day et al. BMC Infectious Diseases (2022) 22:524 Page 10 of 10 21. Lefebvre B, Martin I, Demczuk W, Deshaies L, Michaud S, Labbé AC, et al. Ceftriaxone‑resistant Neisseria gonorrhoeae, Canada, 2017. Emerg Infect Dis. 2018;24(2):381–3. 22. Chen SC, Han Y, Yuan LF, Zhu XY, Yin YP. Identification of internationally disseminated ceftriaxone‑resistant Neisseria gonorrhoeae strain FC428, China. Emerg Infect Dis. 2019;25(7):1427–9. 23. Centers for Disease Control and Prevention. Sexually Transmitted Disease Surveillance 2018. https:// www. cdc. gov/ std/ stats 18/ STDSu rveil lance 2018‑ full‑ report. pdf . 2019. 24. Workowski KA, Bolan GA. Sexually transmitted diseases treatment guide‑ lines, 2015. MMWR Recommendations Reports. 2015;64(03):1–137. 25. Selb R, Buder S, Dudareva S, Tamminga T, Bremer V, Banhart S, et al. Markedly decreasing azithromycin susceptibility of Neisseria gonorrhoeae, Germany, 2014 to 2021. Eurosurveillance. 2021;26(31). 26. Lahra MM, Shoushtari M, George CRR, Armstrong BH, Hogan TR. Austral‑ ian gonococcal surveillance programme annual report, 2019. Commun Dis Intell. 2018;2020:44. 27. Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine (ASHM). Australian STI management guidelines for use in primary care. http:// www. stigu ideli nes. org. au/ sexua lly‑ trans missi ble‑ infec tions/ gonor rhoea/. 2016. 28. Jacobsson S, Cole MJ, Spiteri G, Day M, Unemo M. Associations between antimicrobial susceptibility/resistance of Neisseria gonorrhoeae isolates in European Union/European Economic Area and patients’ gender, sexual orientation and anatomical site of infection, 2009–2016. BMC Infect Dis. 2021;21(1):273. 29. Dong HV, Pham LQ, Nguyen HT, Nguyen MXB, Nguyen TV, May F, et al. Decreased cephalosporin susceptibility of oropharyngeal Neisseria spe‑ cies in antibiotic‑using men who have sex with men in Hanoi, Vietnam. Clin Infect Dis. 2020;70(6):1169–75. 30. Furuya R, Onoye Y, Kanayama A, Saika T, Iyoda T, Tatewaki M, et al. Anti‑ microbial resistance in clinical isolates of Neisseria subflava from the oral cavities of a Japanese population. J Infect Chemother. 2007;13(5):302–4. 31. Laumen JGE, Van Dijck C, Abdellati S, Manoharan‑Basil SS, De Baetselier I, Martiny D, et al. Markedly reduced azithromycin and ceftriaxone suscep‑ tibility in commensal Neisseria species in clinical samples from Belgian men who have sex with men. Clin Infect Dis. 2021;72(2):363–4. 32. Spratt BG, Bowler LD, Zhang QY, Zhou J, Smith JM. Role of interspecies transfer of chromosomal genes in the evolution of penicillin resist‑ ance in pathogenic and commensal Neisseria species. J Mol Evol. 1992;34(2):115–25. 33. Unemo M, Shafer WM. Antimicrobial resistance in Neisseria gonorrhoeae in the 21st century: past, evolution, and future. Clin Microbiol Rev. 2014;27(3):587–613. 34. Lewis DA. Will targeting oropharyngeal gonorrhoea delay the further emergence of drug‑resistant Neisseria gonorrhoeae strains? Sex Transm Infect. 2015;91(4):234–7. 35. Kong FYS, Horner P, Unemo M, Hocking JS. Pharmacokinetic con‑ siderations regarding the treatment of bacterial sexually transmit‑ ted infections with azithromycin: a review. J Antimicrob Chemother. 2019;74(5):1157–66. 36. Cole MJ, Quinten C, Jacobsson S, Day M, Amato‑ Gauci AJ, Woodford N, et al. The European gonococcal antimicrobial surveillance programme (Euro‑ GASP) appropriately reflects the antimicrobial resistance situation for Neisseria gonorrhoeae in the European Union/European Economic Area. BMC Infect Dis. 2019;19(1):1040. 37. Harris SR, Cole MJ, Spiteri G, Sánchez‑Busó L, Golparian D, Jacobs‑ Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? Choose BMC and benefit from om: : son S, et al. Public health surveillance of multidrug‑resistant clones of Neisseria gonorrhoeae in Europe: a genomic survey. 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Significant increase in azithromycin “resistance” and susceptibility to ceftriaxone and cefixime in Neisseria gonorrhoeae isolates in 26 European countries, 2019

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Abstract

Background: The European Gonococcal Antimicrobial Surveillance Programme (Euro‑ GASP) performs annual senti‑ nel surveillance of Neisseria gonorrhoeae susceptibility to therapeutically relevant antimicrobials across the European Union/European Economic Area (EU/EEA). We present the Euro‑ GASP results from 2019 (26 countries), linked to patient epidemiological data, and compared with data from previous years. Methods: Agar dilution and minimum inhibitory concentration (MIC) gradient strip methodologies were used to determine the antimicrobial susceptibility (using EUCAST clinical breakpoints, where available) of 3239 N. gonorrhoeae isolates from 26 countries across the EU/EEA. Significance of differences compared with Euro ‑ GASP results in previous years was analysed using Z‑test and the Pearson’s χ2 test was used to assess significance of odds ratios for associations between patient epidemiological data and antimicrobial resistance. Results: European N. gonorrhoeae isolates collected between 2016 and 2019 displayed shifting MIC distributions for; ceftriaxone, with highly susceptible isolates increasing over time and occasional resistant isolates each year; cefixime, with highly‑susceptible isolates becoming increasingly common; azithromycin, with a shift away from lower MICs towards higher MICs above the EUCAST epidemiological cut‑ off (ECOFF); and ciprofloxacin which is displaying a simi‑ lar shift in MICs as observed for azithromycin. In 2019, two isolates displayed ceftriaxone resistance, but both isolates had MICs below the azithromycin ECOFF. Cefixime resistance (0.8%) was associated with patient sex, with resistance higher in females compared with male heterosexuals and men‑ who‑have ‑sex ‑ with‑men (MSM). The number of countries reporting isolates with azithromycin MICs above the ECOFF increased from 76.9% (20/26) in 2016 to 92.3% (24/26) in 2019. Isolates with azithromycin MICs above the ECOFF (9.0%) were associated with pharyngeal infection sites. Following multivariable analysis, ciprofloxacin resistance remained associated with isolates from MSM and het ‑ erosexual males compared with females, the absence of a concurrent chlamydial infection, pharyngeal infection sites and patients ≥ 25 years of age. Magnus Unemo and Michelle J. Cole joint senior authors *Correspondence: [email protected] UK Health Security Agency, London, UK Full list of author information is available at the end of the article © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecom‑ mons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Day et al. BMC Infectious Diseases (2022) 22:524 Page 2 of 10 Conclusions: Resistance to ceftriaxone and cefixime remained uncommon in EU/EEA countries in 2019 with a significant decrease in cefixime resistance observed between 2016 and 2019. The significant increase in azithro ‑ mycin “resistance” (azithromycin MICs above the ECOFF) threatens the effectiveness of the dual therapy (ceftriax ‑ one + azithromycin), i.e., for ceftriaxone‑resistant cases, currently recommended in many countries internationally and requires close monitoring. Keywords: Gonorrhoea, Treatment, Antimicrobial resistance, Ceftriaxone, Azithromycin, Surveillance, European Gonococcal Antimicrobial Surveillance Programme (Euro‑ GASP), Europe, European Union (EU), European Economic Area (EEA) Background As azithromycin is only recommended for use in dual The European Gonococcal Antimicrobial Surveillance therapy with another effective agent, the correlates Programme (Euro-GASP) is a sentinel surveillance sys- between azithromycin in  vitro susceptibility and treat- tem that since 2009 has been coordinated by the Euro- ment outcome are limited, and appropriate clinical treat- pean Centre for Disease Prevention and Control (ECDC) ment data to inform clinical breakpoints are lacking, and supported by a European network of microbiolo- the European Committee on Antimicrobial Susceptibil- gists and epidemiologists. The programme aims to pro - ity Testing (EUCAST) replaced their clinical resistance vide quality-assured antimicrobial susceptibility data to breakpoint with an epidemiological cut-off (ECOFF) inform European and other regional and national gonor- value of 1 mg/L in January 2019 [14]. This ECOFF value rhoea treatment guidelines as well as to detect emerging aims to detect strains with acquired macrolide resistance. antimicrobial resistance and monitor trends in antimi- Those with azithromycin MICs of ≤ 1  mg/L are consid- crobial resistance. ered “wild-type” [14]. Euro-GASP previously reported Decreasing levels of susceptibility to clinically relevant stable levels of azithromycin resistance (approx. 7%, antimicrobials along with verified treatment failures are using previous > 0.5 mg/L breakpoint) across the EU/EEA threatening the treatment and control of gonorrhoea in 2014–2016 [7]. internationally [1–9]. The European guideline for the In the present study, we describe the results from the diagnosis and treatment of gonorrhoea in adults was 2019 Euro-GASP sentinel surveillance, in conjunction updated in 2020 [10, 11]. The guideline now recommends with patients’ epidemiological data, and compare them for uncomplicated N. gonorrhoeae infections, 1  g ceftri- to the Euro-GASP results obtained from previous years axone (an increase from the 500 mg recommended in the (main focus on the published 2016 Euro-GASP data [7]). 2012 guidelines [12]) with 2  g azithromycin, or 1  g cef- triaxone alone in settings where in  vitro antimicrobial Methods susceptibility surveillance has shown lack of ceftriaxone European Gonococcal Antimicrobial Surveillance resistance, test of cure (TOC) is mandatory, and doxycy- Programme (Euro‑GASP) cline regimen is administered if Chlamydia trachomatis Annually, laboratories participating in Euro-GASP report infection has not been excluded [10]. Notably, in a most antimicrobial susceptibility profiles (using EUCAST clin - recent Euro-GASP survey of 26 EU/EEA countries only ical breakpoints, where available [14]) and patient epide- 19 (73.1%) countries used ceftriaxone plus azithromycin miological data for N. gonorrhoeae isolates collected in dual therapy with Ireland, Sweden, the Netherlands and their country as described previously [7, 15]. All gono- the United Kingdom (UK) having national guidelines that coccal isolates were cultured and preserved as part of the recommended use of ceftriaxone 1 g monotherapy [13]. routine diagnostics (standard care), and isolates or data In addition, cefixime (400  mg single dose) is recom - were submitted to the Euro-GASP surveillance study mended in the European guideline only as a substitute with no patient identification information, separate ethi - for ceftriaxone in dual therapy in cases where injections cal approval was therefore not required. are refused or contraindicated. Cefixime is not recom - In 2019, 26 countries participated in Euro-GASP, sub- mended for use in monotherapy. Ciprofloxacin (500  mg mitting total data for 4166  N. gonorrhoeae isolates (one single dose) is suggested as an alternative treatment isolate per patient per gonorrhoea episode) to The Euro - regime for those with history of severe hypersensitiv- pean Surveillance System (TESSy) at ECDC. Some coun- ity to any β-lactam antimicrobial or when injections are tries were over-represented in the complete 2019 TESSy contraindicated or refused, however, only where suscep- data set with Austria submitting data for 434 isolates, tibility has been confirmed phenotypically or molecularly France 243 isolates, the Netherlands 364 isolates and (gyrA-based resistance testing) [10]. Norway 641 isolates whereas other countries with lower Da y et al. BMC Infectious Diseases (2022) 22:524 Page 3 of 10 gonorrhoea incidence were under-represented with Table 1 Gonorrhoea patient characteristics in 2016 and 2019 Cyprus submitting data for two isolates, Latvia seven 2016 2019 isolates, Estonia eight isolates and Croatia nine isolates. N (%) N (%) The same imbalance was also present in previous years’ Total number of isolates 2559 3239 TESSy datasets. In order to reduce biases caused by high Sex isolate numbers from some countries, only data for the Male 2158 (84.7) 2676 (84.2) first 200 isolates with complete antimicrobial susceptibil - Female 391 (15.3) 502 (15.8) ity testing results submitted to TESSy in each year were Not reported 10 61 included in the analysis of the present paper including Age (years) data from 2016 which was used as the main comparator < 25 668 (26.5) 883 (28.4) for this publication unless otherwise stated. For compari- ≥ 25 1854 (73.5) 2223 (71.6) son of azithromycin MIC data, data collected prior to the Not reported 37 133 introduction of the ECOFF was converted to equal to or Sexual orientation and sex below the ECOFF (referred to as susceptible hereafter) Females 391 (24.4) 501 (25.6) or above the ECOFF (referred to as resistant hereafter). Heterosexual males 539 (33.6) 545 (27.9)* Azithromycin MICs ≥ 256  mg/L will be discussed as Men who have sex with men 672 (41.9) 908 (46.5)* “high-level azithromycin resistant”. Not reported 957 1285 Site of infection Statistical analysis Urogenital 1745 (75.1) 2076 (71.5)* The Mann–Whitney test was used to analyse differences Pharyngeal 153 (6.6) 262 (9.0)* in age distribution and the Z-test was applied to compare Anorectal 329 (14.2) 475 (16.4)* proportions when analysing antimicrobial susceptibility Other 97 (4.2) 91 (3.1)* and epidemiological data. Associations between epidemi- Not reported 235 335 ological characteristics and antimicrobial susceptibility Previous gonorrhoea were assessed using odds ratios (OR) and 95% confidence Yes 163 (16.7) 228 (23.2)* intervals (CI); the Pearson’s χ test was used to measure if No 814 (83.3) 753 (76.8)* these odds ratios differed significantly from 1. For small Not reported 1582 2258 cell numbers (n < 5), Fisher’s exact test was performed. Concurrent sexually transmitted infection (STI) Statistical significance for all tests was assumed when Concurrent chlamydia infection 181 (23.5) 228 (21.2) p < 0.05. Statistical analysis was performed using Stata Concurrent other STI (not HIV ) 51 (6.6) 83 (7.7) v15 (StataCorp LP, Texas, USA). No concurrent STI 539 (69.9) 764 (71.1) Not reported 1788 2164 Results HIV status Using a maximum of 200 isolates per country, 3239  N. Positive 143 (15.8) 139 (13.1) gonorrhoeae isolates collected in 2019 from 3239 episodes Negative 760 (84.2) 926 (86.9) of gonorrhoea were compared to the Euro-GASP data Not reported 1656 2174 from 2016 (n = 2556) (Table  1). As in all previous years of Euro-GASP surveillance (starting in 2009), most iso- Total number of isolates includes a maximum of 200 isolates per country. Three countries exceeded the 200 isolate limit in 2016; The Netherlands, Spain and the lates in 2019 were from male patients (84.2%, 2676/3178), UK. In 2019 seven countries exceeded 200 isolates; Austria, Finland, France, The and male patients (median age 30 years) were older than Netherlands, Norway, Spain and the UK female patients (median age 26 years) (p < 0.0001). Over- *Bold letters indicate significant difference between 2016 and 2019 by Z-test (p < 0.05) all, patient ages ranged from 0 to 84 years with a median age of 29 years old. The anatomical site of collection was mainly urogenital (71.5%), however, there was a decrease infection which was an increase from 16.7% (163/976) in samples from this site compared to 2016 (75.1%, in 2016 (p < 0.002) and 21.2% (228/1075) had a con- p = 0.004, Table 1). current C. trachomatis infection which remained at a In contrast, there was an increase in both rectal level similar to that in 2016 (23.5%, 181/771) (Table  1). (14.2% vs. 16.4%, p = 0.02) and pharyngeal (6.6% vs. Among cases with known sexual orientation and 9.0%, p = 0.001) sites which is likely a consequence of sex (unknown for 31–43% of cases each year), 53.5% the significant increase in specimens from men-who- (1046/1954) of the N. gonorrhoeae infections were have-sex-with-men (MSM) in 2019 (41.9% vs. 46.5%, reported as heterosexually acquired (47.9% females p = 0.0002, Table  1). For cases where information was and 52.1% males). The proportion of heterosexual available, 23.2% (228/981) had a previous gonorrhoea Day et al. BMC Infectious Diseases (2022) 22:524 Page 4 of 10 males decreased from 33.6% in 2016 to 27.9% in 2019 the UK (one in 2017, six in 2019). The proportion of (p = 0.0002, Table 1). countries reporting isolates with azithromycin resistance In 2019 ceftriaxone resistance was detected in two uro- increased from 76.9% (20/26) in 2016 to 92.3% (24/26) in genital isolates, one in Belgium (MIC = 0.5  mg/L) and 2019 (p = 0.0007). The countries with the highest propor - one in Portugal (MIC = 0.25  mg/L). Both isolates were tion of azithromycin-resistant isolates in 2019 were Nor- also resistant to cefixime (MIC = 2  mg/L and = 0.5  mg/L, way (16%; 32/200), Poland (18.9%; 10/53), Iceland (20.4%; respectively) and ciprofloxacin (MIC > 32  mg/L and 11/54), Estonia (25%; 2/8), and Croatia (55.6%; 5/9). 4  mg/L, respectively) but were susceptible to azithro- Three of these countries, Estonia, Croatia and Poland did mycin (MIC 0.5  mg/L and 1  mg/L, respectively). For not report any azithromycin resistance in 2016, however, comparison, there were three urogenital isolates with cef- the number of isolates reported especially in Estonia and triaxone resistance identified in 2018 (two in Spain, one Croatia in both 2016 and 2019 were very low. Azithromy- in Germany), zero in 2017 and 2016. Despite the detec- cin resistance was associated with pharyngeal sites when tion of ceftriaxone-resistant isolates in both 2018 and compared to urogenital ones (Table 2). 2019, the proportion of gonococcal isolates that were There was an increase in resistance to ciprofloxacin most susceptible to ceftriaxone (MIC ≤ 0.016  mg/L) from 47.2% (1003/2124) in 2016 to 57.4% (1665/2884) in increased from 82.9% (2117/2555) in 2016 to 89.7% 2019 (p < 0.0002, Fig.  1d). The MIC distribution changed (2903/3238) in 2019 (p < 0.0002, Fig.  1a). In addition, the between 2016 and 2019 with decreases in lower MICs proportion of isolates with decreased susceptibility to (0.004–0.008  mg/L, p < 0.0002) and increases in lower ceftriaxone (MICs from 0.032 to 0.125  mg/L) decreased levels of resistance (0.5–4  mg/L, p < 0.0002, Fig.  1d). from 17.1% (438/2555) in 2016 to 10.3% (333/3238) in However, there was a decrease in high-level ciprofloxa - 2019 (p < 0.0002, Fig. 1a). cin resistance (MIC ≥ 32 mg/L) from 12.4% (264/2124) in Similarly to ceftriaxone, the proportion of isolates most 2016 to 7.7% in 2019 (223/2884, p < 0.0002). As in 2016, susceptible to cefixime (MIC ≤ 0.016  mg/L) increased ciprofloxacin resistance in 2019 was associated with from 74.9% (1805/2411) in 2016 to 80.9% (2621/3239) in male heterosexuals (compared to females) and previous 2019 (p < 0.0002, Fig. 1b). Furthermore, the percentage of gonorrhoea infection. In 2019 ciprofloxacin resistance isolates with decreased susceptibility to cefixime (MICs was also associated with MSM (compared to females), 0.032–0.125  mg/L) decreased from 22.9% (553/2411) in patient age ≥ 25  years (compared to < 25  years), anorec- 2016 to 18.3% (592/3239) in 2019 (p < 0.0002). The pro - tal and pharyngeal sites (compared to urogenital) and portion of cefixime-resistant isolates (MIC > 0.125 mg/L) with not having concurrent C. trachomatis infection also decreased from 2.2% (53/2411) in 2016 to 0.8% (Table  2). Following multivariable analysis, ciprofloxacin (26/3239) in 2019 (p < 0.0002, Fig.  1b). Of the 26 isolates resistance remained associated with isolates from MSM with cefixime resistance in 2019, only one had addi - (OR = 2.7, CI = 1.48–4.95, p < 0.01) and heterosexual tional azithromycin resistance (MIC = 16 mg/L). In 2019, males (OR = 2.24, CI = 1.24–4.05, p < 0.01) compared cefixime resistance was associated with patient sex and to females, the absence of a concurrent C. trachomatis sexual orientation with 1.6% resistance in females com- infection (OR = 1.9, CI = 1.14–3.18, p = 0.02), phar yn- pared with 0.7% in male heterosexuals and 0.3% in MSM geal sites (OR = 2.4, CI = 1.28–4.52, p < 0.01) and patient (p = 0.045, Fisher’s exact test, Table 2). age ≥ 25 years (OR = 1.62, CI = 1.05–2.50, p = 0.03). The percentage of isolates with azithromycin resist - ance (MICs above the ECOFF of 1  mg/L) increased Discussion from 3.8% (97/2532) in 2016 to 9.0% (284/3159) in 2019 Three distinct antimicrobial susceptibility patterns (p < 0.002, Fig.  1c). In contrast to what was observed for among N. gonorrhoeae isolates in the EU/EEA have ceftriaxone and cefixime (Fig.  1a and b), there was also emerged for ceftriaxone, cefixime and azithromycin a decrease in the proportion of gonococcal isolates with between 2016 and 2019. Ceftriaxone appears to be shift- the lowest azithromycin MICs (≤ 0.016 mg/L) from 1.1% ing towards higher susceptibility over time and resistant (27/2532) in 2016 to 0.4% (14/3159) in 2019 (p < 0.002, isolates continue to be rare. However, worryingly the Fig.  1c). The proportion of isolates with azithromycin clonally expanding and internationally spreading ceftri- MICs ≥ 256  mg/L (“high-level azithromycin resistance”) axone-resistant N. gonorrhoeae strain FC428 has been has not changed with 0.2% (5/2532) in 2016 and 0.3% identified in several EU/EEA countries such as Denmark in 2019 (10/3159, p = 0.381). Only five countries have [16], France [5], Ireland [17], and the UK [18], as well as reported isolates with azithromycin MICs ≥ 256  mg/L in in many additional countries worldwide, e.g., Japan [19], multiple years; Finland (two in 2016, one in 2017), Ireland Australia [20], Canada [21], and China [22]. (one in 2016, one in 2018, three in 2019), Iceland (two in Cefixime MICs are also shifting away from resistance 2016, two in 2019), Italy (two in 2016, one in 2018), and with highly susceptible isolates becoming increasingly Da y et al. BMC Infectious Diseases (2022) 22:524 Page 5 of 10 2016 2017 2018 2019 ≤0.016 0.032 0.064 0.125 0.25 0.5 Ceriaxone MIC (mg/L) 2016 2017 2018 2019 ≤0.016 0.032 0.064 0.125 0.25 0.5 1≥2 Cefixime MIC (mg/L) Fig. 1 Minimum inhibitory concentration (MIC; mg/L) distribution in European Neisseria gonorrhoeae isolates (2016–2019) for a ceftriaxone, b cefixime, c azithromycin, and d ciprofloxacin Percentage Percentage Day et al. BMC Infectious Diseases (2022) 22:524 Page 6 of 10 2016 2017 2018 2019 ≤0.016 0.032 0.064 0.125 0.25 0.5 1248 16 32 64 ≥256 Azithromycin MIC (mg/L) 2016 2017 2018 2019 ≤0.002 0.004 0.008 0.016 0.032 0.064 0.125 0.25 0.51 24 816≥32 Ciprofloxacin MIC (mg/L) Fig. 1 continued common between 2016 and 2019. This increase in cefix - years in the EU/EEA countries. The same shift towards ime susceptibility might be due to the use of recom- cefixime susceptibility was observed in the United States mended ceftriaxone/azithromycin dual therapy since (US) between 2014 and 2018 with the proportion of iso- 2012 or ceftriaxone monotherapy (500–1000 mg), which lates with decreased susceptibility to cefixime (MIC has become increasingly common in the most recent 0.032–0.125 mg/L) decreasing from 37.8 to 29.9% and the Percentage Percentage Da y et al. BMC Infectious Diseases (2022) 22:524 Page 7 of 10 Table 2 Univariate association of cefixime, azithromycin and ciprofloxacin resistance/susceptibility and patient characteristics, 2019 Cefixime resistance Azithromycin resistance Ciprofloxacin resistance N (%, 95% CI) Odds ratio 95% CI p value N (%, 95% CI) Odds ratio 95% CI p value N (%, 95% CI) Odds ratio 95% CI p value Site of infection (n = 2904) Urogenital (2076) 18 (0.9, 0.5–1.4) 0.40* 171 (8.2, 7.1–9.5) 1 1152 (55.5, 53.4–57.6) 1 Anorectal (475) 1 (0.2, 0.0–1.2) 48 (10.1, 7.7–13.1) 1.25 0.89–1.75 0.19 298 (62.7, 58.3–67.0) 1.35 1.09–1.66 < 0.01 Pharyngeal (262) 2 (0.8, 0.2–2.7) 35 (13.4, 9.8–18.0) 1.72 1.16–2.54 < 0.01 163 (62.5, 56.4–68.1) 1.33 1.02–1.74 0.03 Other (91) 1 (1.1, 0.2–2.7) 9 (9.9, 5.3–17.7) 1.22 0.60–2.48 0.58 56 (61.5, 51.3–70.9) 1.28 0.83–1.97 0.26 Sexual orientation and sex (n = 1955) MSM (908) 3 (0.3, 0.1–1.0) 0.045* 75 (8.3, 6.6–10.2) 1 542 (59.7, 56.5–62.8) 1.9 1.54–2.42 < 0.01 Male heterosexual (545) 4 (0.7, 0.3–1.9) 40 (7.3, 5.4–9.8) 0.88 0.59–1.31 0.53 285 (52.3, 48.1–56.5) 1.4 1.12–1.83 < 0.01 Female (502) 8 (1.6, 0.8–3.1) 35 (7.0, 5.0–9.5) 0.83 0.59–1.26 0.39 217 (43.4, 39.1–47.8) 1 Previous gonorrhoea (n = 981) Yes (228) 1 (0.4, 0.0–2.4) 0.41* 18 (7.9, 6.0–9.8) 1.03 0.59–1.78 0.92 138 (60.5, 54.1–66.6) 1.68 1.24–2.28 < 0.01 No (753) 1 (0.1, 0.0–0.8) 58 (7.7, 5.1–12.1) 1 359 (47.7, 44.1–51.2) 1 Concurrent chlamydia (n = 1075) Yes (228) 2 (0.9, 0.2–3.1) 0.20* 20 (8.8, 5.8–13.2) 1.02 0.61–1.71 0.94 95 (41.7, 35.5–48.2) 1 No (847) 2 (0.2, 0.0–0.9) 73 (8.6, 7.0–10.7) 1 502 (59.3, 55.9–62.5) 2 1.51–2.75 < 0.01 HIV status (n = 1065) Positive (139) 0 (0.0, 0.0–2.7) 1.00* 15 (10.8, 6.6–17.0) 1.25 0.70–2.23 0.46 81 (59.3, 50.0–66.1) 1.2 0.84–1.72 0.32 Negative (926) 3 (0.3, 0.1–0.9) 82 (8.9, 7.2–10.9) 1 498 (53.8, 50.6–57.0) 1 Age (n = 3106) < 25 years (883) 7 (0.8, 0.4–1.6) 1 0.72 75 (8.5, 6.8–10.5) 1 457 (51.9, 48.6–55.2) 1 ≥ 25 years (2223) 15 (0.7, 0.4–1.1) 0.85 0.35–2.09 193 (8.7, 7.6–9.9) 1.02 0.77–1.35 0.87 1307 (58.8, 56.7–60.8) 1.3 1.13–1.55 < 0.01 MSM men who have sex with men. Bold letters indicate significance *Fishers exact test (n < 5) One isolate had no ciprofloxacin result Two isolates had no ciprofloxacin results Day et al. BMC Infectious Diseases (2022) 22:524 Page 8 of 10 proportion of cefixime-resistant isolates decreasing from isolates are available from many of these cases, the major- 0.7 to 0.3% (recalculated from data presented in [23]). ity of examined N. gonorrhoeae isolates are obtained from In the US, new gonorrhoea treatment guidelines were urogenital sites and the number of isolates from rec- issued in 2015 recommending dual therapy with ceftriax- tal and pharyngeal sites are more limited, and in many one 500 mg and azithromycin 1 g for uncomplicated gon- countries the completeness of reported epidemiological orrhoea [24], which may have had a role in the increase in data (particularly of sexual orientation) is suboptimal. cefixime susceptibility. However, despite these limitations a previous representa- Azithromycin MICs are, in contrast to those observed tiveness analysis showed that Euro-GASP appropriately for ceftriaxone and cefixime, shifting towards MICs reflects the antimicrobial resistance situation for N. gon - above the azithromycin ECOFF, and this has been orrhoeae in the EU/EEA [36]. recently reported in many countries internationally [8, 9, 25]. High levels of azithromycin resistance are of concern Conclusions not just for N. gonorrhoeae but for also for other bacte- Resistance in N. gonorrhoeae to the third-generation rial STIs. The same increase in higher MICs (> 1  mg/L) cephalosporins ceftriaxone and cefixime remained was observed in the US between 2014 and 2018 although uncommon in 2019 in EU/EEA countries with a signifi - less pronounced than in Europe with an increase from cant decrease in cefixime resistance observed between 2.4 to 4.6% (recalculated from data presented in [23]). 2016 and 2019. The significant increase in the propor - By contrast, the Australian gonococcal surveillance pro- tion of isolates with azithromycin resistance is concern- gramme has observed a decrease in the percentage of iso- ing for the future effectiveness of any ceftriaxone plus lates with azithromycin MICs > 1  mg/L after the peak of azithromycin dual therapy, particularly if ceftriaxone 9.3% was reached in 2017 to 4.6% in 2019 [26]. In the vast resistance starts to spread more widely. It is imperative majority of Australian settings, dual therapy with ceftri- that the MICs for N. gonorrhoeae isolates continue to be axone 500  mg and azithromycin 1  g (2  g for pharyngeal monitored very closely over the next years, particularly of gonorrhoea) is recommended for uncomplicated gonor- azithromycin and ceftriaxone. rhoea [27]. This may indicate a high adherence to recom - mended treatment, less and more controlled macrolide use for other infections (particularly Chlamydia tra- Abbreviations AD: Agar dilution method; CI: Confidence interval; ECDC: European Centre chomatis and Mycoplasma genitalium infections), and/or for Disease Prevention and Control; ECOFF: Epidemiological cut‑ off; EEA: replacement of some major azithromycin-resistant gono- European Economic Area; EU: European Union; EUCAST: European Commit‑ coccal clones with more azithromycin-susceptible clones. tee on Antimicrobial Susceptibility Testing; Euro‑ GASP: European Gonococcal Antimicrobial Surveillance Programme; MIC: Minimum inhibitory concentra‑ In the Euro-GASP 2009–2016 data, ciprofloxacin tion; MSM: Men who have sex with men; No.: Number; OR: Odds ratio; STI: resistance was significantly associated with urogenital Sexually transmitted infection; TESSy: The European Surveillance System; UK: sites [28], in 2019 both ciprofloxacin and azithromycin United Kingdom. resistance were significantly associated with pharyngeal Acknowledgements infections. Pharyngeal infections are considered to have We are grateful to the European STI surveillance network for its contribution to a major role in the development of resistance to sev- developing and implementing Euro‑ GASP and submitting gonococcal isolates and epidemiological data. eral antimicrobials, such as beta-lactam antimicrobials. The Euro‑ GASP Network: The presence of other commensal Neisseria species in Austrian Agency for Health and Food Safety, Wien, Austria: Claudia Eder, the pharynx often with previous exposure to antibiotics Sonja Pleininger, Steliana Huhlescu; Institute of Tropical Medicine, Antwer‑ pen, Belgium: Irith de Baetselier; Croatian National Institute Of Public Health, allows for horizontal transfer of resistance genes to N. Zagreb, Croatia: Blaženka Hunjak, Tatjana Nemeth Blažić; Nicosia General gonorrhoeae [29–33]. Pharyngeal infections are also more Hospital, Nicosia, Cyprus: Panagiota Maikanti‑ Charalampous, Despo Pieridou; difficult to eradicate with most antimicrobials due to sub- The National Institute of Public Health, Prague, The Czech Republic: Hana Zákoucká, Helena Žemličková; Statens Serum Institut, Copenhagen, Denmark: optimal antibiotic concentrations at this site which adds Steen Hoffmann, Susan Cowan; Health Board, Tallinn, Estonia: Rita Peetso, to the selective pressure of gonococcal clones with higher Jelena Viktorova; Hospital Saint Louis, Paris, France: Ndeindo Ndeikoundam, MICs [34, 35]. Beatrice Bercot; Helsinki University Central Hospital, Helsinki, Finland: Anu Patari Sampo, Vesa Kirjavainen; Vivantes Klinikum Neukolln, Berlin, Germany: The limitations of Euro-GASP and, accordingly, the Susanne Buder, Klaus Jansen; Hellenic Pasteur Institute, Athens, Greece: present study have been previously described in detail [7, Vivi Miriagou; National Centre for Epidemiology, Budapest, Hungary: Eszter 28, 36, 37]. These limitations include, for example, that Balla, Mária Dudás; Landspitali University Hospital, Reykjavik, Iceland: Guðrún Sigmundsdóttir, Lena Ros Asmundsdottir; St James’s Hospital, Dublin, Ireland: a limited number of gonorrhoea patients and N. gonor- Sinead Saab, Brendan Crowley; Istituto Superiore di Sanita, Rome, Italy: Anna rhoeae isolates (~ 3% of all reported gonorrhoea cases Carannante, Paola Stefanelli; Riga East University Hospital, Riga, Latvia: Gatis in the EU/EEA) from many diverse countries are exam- Pakarna, Violeta Mavcutko; Mater Dei Hospital, Msida, Malta: Robert Cassar, Christopher Barbara, Francesca Vella; The Public Health Service of Amsterdam, ined, many gonorrhoea cases in the EU/EEA are diag- Amsterdam, The Netherlands: Alje Van Dam, Ineke Linde; Domain of Infec‑ nosed with molecular diagnostics and no N. gonorrhoeae tious Disease Control and Environmental Health, Oslo, Norway: Dominique Da y et al. BMC Infectious Diseases (2022) 22:524 Page 9 of 10 Caugant, Hilde Kløvstad; Medical University of Warsaw, Warsaw, Poland: Beata resistance and decreased ceftriaxone susceptibility, Hawaii, 2016. Clin Mlynarczyk‑Bonikowska; Instituto Nacional de Saude Dr Ricardo Jorge, Lisboa, Infect Dis. 2017;65(6):918–23. Portugal: Maria‑ José Borrego; Medirex a.s., Bratislava, Slovak Republic: Peter 4. Morita‑Ishihara T, Unemo M, Furubayashi K, Kawahata T, Shimuta Pavlik; Institut za mikrobiologijo in imunologijo, Univerza v Ljubljani Medicin‑ K, Nakayama S, et al. Treatment failure with 2 g of azithromycin ska fakulteta, Ljubljana, Slovenia: Irena Klavs, Tanja Kustec; National Institute (extended‑release formulation) in gonorrhoea in Japan caused by the of Health Carlos III, Madrid, Spain: Julio Vazquez, Asuncion Diaz, Raquel Abad international multidrug‑resistant ST1407 strain of Neisseria gonor - Torreblanca; Public Health Agency of Sweden, Stockholm, Sweden: Inga rhoeae. J Antimicrob Chemother. 2014;69(8):2086–90. Velicko, Magnus Unemo; Royal Infirmary of Edinburgh, Edinburgh, UK: Helen 5. Poncin T, Fouere S, Braille A, Camelena F, Agsous M, Bebear C, et al. Fifer, Kate Templeton. Multidrug‑resistant Neisseria gonorrhoeae failing treatment with cef‑ triaxone and doxycycline in France, November 2017. Eurosurveillance. Author contributions 2018;23(21). MC, MD, GS, BB, SJ, NW, MJvdW, AAG and MU designed, initiated and 6. Yan J, Chen Y, Yang F, Ling X, Jiang S, Zhao F, et al. High percentage of coordinated the study. SJ, MD, CK, NS and Network members coordinated the ceftriaxone‑resistant Neisseria gonorrhoeae FC428 clone among and performed the laboratory analyses. Patient data was supplied by the isolates from a single hospital in Hangzhou, China. J Antimicrob Chem‑ Network members. MD, MC, GS, BB, SJ, NW, MJvdW, AAG and MU analysed and other. 2021;76(4):936–9. interpreted all the data, and wrote a first draft of the paper. MD, MC, CK, NS, 7. Day MJ, Spiteri G, Jacobsson S, Woodford N, Amato‑ Gauci AJ, Cole MJ, GS, BB, SJ, NW, MJvdW, AAG and MU read, commented and approved the final et al. Stably high azithromycin resistance and decreasing ceftriaxone manuscript. All authors read and approved the final manuscript. susceptibility in Neisseria gonorrhoeae in 25 European countries, 2016. BMC Infect Dis. 2018;18(1):609. Funding 8. Unemo M, Lahra MM, Cole M, Galarza P, Ndowa F, Martin I, et al. World The study was funded by the European Centre for Disease Prevention Health Organization Global Gonococcal Antimicrobial Surveillance and Control (Framework Contract No. ECDC/2017/004). The funding body Program ( WHO GASP): review of new data and evidence to inform designed, initiated and coordinated the study as well as assisted in the inter‑ international collaborative actions and research efforts. Sex Health. pretation of the data, development and final approval of the manuscript. 2019;16(5):412–25. 9. Unemo M LM, Escher M, Eremin S, Cole MJ, Galarza P, Ndowa F, Martin Availability of data and materials I, Dillon JR, Galas M, Ramon‑Pardo P, Weinstock H, Wi T. WHO global The data that support the findings of this study are available from the Euro ‑ antimicrobial resistance surveillance for Neisseria gonorrhoeae 2017–18: pean Centre for Disease Prevention and Control but restrictions apply to the a retrospective observational study. The Lancet Microbe. 2021; https:// availability of these data, which were used under license for the current study, www. thela ncet. com/ action/ showP df? pii= S2666‑ 5247% 2821% 29001 and so are not publicly available. Data are, however, available from the authors 71‑3. upon reasonable request and with permission of the European Centre for 10. Unemo M, Ross J, Serwin AB, Gomberg M, Cusini M, Jensen JS. Back‑ Disease Prevention and Control. ground review for the ‘2020 European guideline for the diagnosis and treatment of gonorrhoea in adults.’ Int J STD AIDS. 2021;32(2):108–26. 11. Unemo M, Ross J, Serwin AB, Gomberg M, Cusini M, Jensen JS. Declarations European guideline for the diagnosis and treatment of gonorrhoea in adults. Int J STD AIDS. 2020;2020:956462420949126. Ethics approval and consent to participate 12. Bignell C, Unemo M. 2012 European guideline on the diagnosis and All examined gonococcal isolates were cultured and preserved as part of the treatment of gonorrhoea in adults. Int J STD AIDS. 2013;24(2):85–92. routine diagnostics (standard care), and isolates or data were submitted to 13. European Centre for Disease Control. 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Cole MJ, Quinten C, Jacobsson S, Day M, Amato‑ Gauci AJ, Woodford N, et al. The European gonococcal antimicrobial surveillance programme (Euro‑ GASP) appropriately reflects the antimicrobial resistance situation for Neisseria gonorrhoeae in the European Union/European Economic Area. BMC Infect Dis. 2019;19(1):1040. 37. Harris SR, Cole MJ, Spiteri G, Sánchez‑Busó L, Golparian D, Jacobs‑ Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? Choose BMC and benefit from om: : son S, et al. Public health surveillance of multidrug‑resistant clones of Neisseria gonorrhoeae in Europe: a genomic survey. 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Journal

BMC Infectious Diseases – Springer Journals

Published: Jun 7, 2022

Keywords: Gonorrhoea; Treatment; Antimicrobial resistance; Ceftriaxone; Azithromycin; Surveillance; European Gonococcal Antimicrobial Surveillance Programme (Euro-GASP); Europe; European Union (EU); European Economic Area (EEA)

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