European Journal of Clinical Microbiology & Infectious Diseases (2023) 42:883–893 https://doi.org/10.1007/s10096-023-04601-0 ORIGINAL ARTICLE Epidemiology and antimicrobial resistance profile of Neisseria gonorrhoeae in Catalonia, Spain, 2016–2019 Mercè Herrero1 · Sonia Broner1 · Adrià Cruells1 · Silvia Esteve1 · Lourdes Ferré1 · Jacobo Mendioroz1,2 · Mireia Jané1,3,4 · Pilar Ciruela1,3 · the working group at MRSC Received: 1 December 2022 / Accepted: 11 April 2023 / Published online: 10 May 2023 © The Author(s) 2023 Abstract Antimicrobial resistance data for Neisseria gonorrhoeae is globally sparse and resistant strains are emerging in Catalonia. We aim to describe epidemiological and antimicrobial resistance in all patients infected with N. gonorrhoeae during the period from 2016 to 2019, using available antimicrobial susceptibility data. We retrospectively analysed confirmed N. gonorrhoeae cases notified to Catalonia’s microbiological reporting system. Antibiotic susceptibility testing (azithromycin, cefixime, ceftriaxone, ciprofloxacin, penicillin, spectinomycin, and tetracycline) was assessed using clinical breakpoints published by the European Committee on Antimicrobial Susceptibility Testing. Incidence rates were calculated and proportions were compared using the χ2 test or Fisher’s exact test, and analysed using the Statistical Package for Social Sciences (SPSS 18.0). A total of 14,251 confirmed cases of N. gonorrhoeae were notified. Incidence increased from 30.7 cases/100,000 person-years (p < 0.001) in 2016 to 64.7 in 2019. Culture was available in 6,292 isolates (44.2%), of which 5,377 (85.5%) were resistant to at least one of the antibiotics tested. Azithromycin resistance rose from 6.1% in 2016 to 16% in 2019 (p < 0.001). Only 1.0% (45 cases) were resistant to ceftriaxone. Multidrug-resistant N. gonorrhoeae increased from 0.25% in 2016 to 0.42% in 2019 (p = 0.521). One case presented extensively drug-resistant N. gonorrhoeae. In Catalonia, 10% of the N. gonorrhoeae isolates were resistant to azithromycin in the 2016–2019 period. According to World Health Organization guidelines, resistance above 5% indicates an alert to review treatment guidelines. Antimicrobial susceptibility testing in clinical practice followed by surveillance and interventions are essential to monitor trends and prevent the spread of antimicrobial resistance. Keywords Neisseria gonorrhoeae · Multi-drug resistant · Ceftriaxone · Azithromycin · Antimicrobial resistance * Mercè Herrero Pilar Ciruela merce.herrerog@gencat.cat pilar.ciruela@gencat.cat Sonia Broner 1 Subdirectorate General for Public Health Surveillance sonia.broner@gencat.cat and Emergency Response, Catalan Public Health Agency, Adrià Cruells Government of Catalonia, 08005 Barcelona, Spain acruells100@gmail.com 2 Research Support Unit of Central Catalonia, Jordi Gol i Silvia Esteve Gurina University Research Institute for Primary Health silviaesteve@gencat.cat Care, 08272 Sant Fruitós de Bages, Spain 3 Lourdes Ferré CIBER Epidemiologia y Salud Pública (CIBERESP), Carlos lourdesferre@gencat.cat III Health Institute, 28029 Madrid, Spain 4 Jacobo Mendioroz Department of Medicine, University of Barcelona, Barcelona, jmendioroz@gencat.cat Spain Mireia Jané mireia.jane@gencat.cat 13 Vol.:(0123456789) 884 European Journal of Clinical Microbiology & Infectious Diseases (2023) 42:883–893 Abbreviations (WHO) recommends that local resistance data determine AMR Antimicrobial resistance the choice of therapy (both dual therapy and monotherapy). ECDC European Centre for Disease Prevention and In territories where local resistance data are unavailable, the Control guidelines suggest combining azithromycin and ceftriaxone- ESC Extended-spectrum cephalosporins based therapy or, alternatively, treating with cefixime prior GASP Gonococcal Antimicrobial Surveillance to monotherapy [5]. Programme Since 2009, the European Centre for Disease Prevention IR Incidence rate and Control (ECDC) has been coordinating the Gonococcal MDR Multi-drug resistant Antimicrobial Surveillance Programme (Euro-GASP), a spe- MRSC Microbiological reporting system of Catalonia cific epidemiological surveillance programme for antibiotic NAAT​ Nucleic acid amplification test resistance in Neisseria gonorrhoeae. Funded by an interna- NG  Neisseria gonorrhoeae, N. gonorrhoeae tional network, the programme is led by Public Health Eng- STI Sexually transmitted infection land in the UK and includes the Örebro University Hospital WHO World Health Organization in Sweden [6]. XDR Extensively-drug resistant According to the ECDC, incidence rates (IR) of gono- coccal infection have increased significantly in Europe over the years, rising from 8.7 cases/100,000 persons in 2010 to Introduction 18.9/100,000 in 2016; 46% of these cases were registered as men who have sex with men [6]. In Spain, the gonococcal Gonorrhoea is one of the most common sexually transmitted infection incidence has increased from 2.02 cases/100,000 bacterial infections (STI) and an important cause of mor- persons in 2001 to 13.89/100,000 in 2016. Of 6,456 notified bidity worldwide. Without treatment, the disease can cause cases, 83.7% occurred in males, indicating a male/female severe complications such as pelvic inflammatory disease ratio of 5:1. and ectopic pregnancy in women, and infertility in both gen- With respect to age groups, the highest incidence ders. In addition, neonatal gonococcal conjunctivitis may occurs in 20 to 24-years-old (89.2/100,000 in males and lead to scarring and blindness [1]. 21.5/100,000 in women) in Europe and worldwide. In 2016, Laboratory diagnosis is determined by gram staining, the highest IR in Spain was in Catalonia, followed by Astu- conventional agar-based culture method, and/or nucleic acid rias and Madrid [7]. In Barcelona, between 2013 and 2017, amplification test (NAAT). In the case of gonococcus, it is the observed proportions of cases resistant to first-line treat- especially important to obtain a sample of urethral/cervical ments were 4.9% for cefixime, 0.9% for ceftriaxone, and exudate for culture before starting treatment; this sample 3.0% for azithromycin. However, the proportion of isolates will be used to perform an antibiogram, confirm the appro- showing resistance to all antibiotics was approximately 1% priate treatment and track changes in antimicrobial resist- of cases [8]. ance (AMR) [2]. In Catalonia, the Epidemiological Surveillance Network Antimicrobial resistance is a major public health prob- (Decree 203/2015 [9], of 15 September) was created in lem. Systematic epidemiological surveillance of AMR to N. 2015 to regulate reporting systems for notifiable diseases gonorrhoeae is essential for several reasons. First, to detect and epidemic outbreaks, and establish a microbiological emerging resistance to antimicrobials in strains circulating reporting system for Catalonia (MRSC) as a notifiable sys- among the population; second, to contribute to the design tem. Through the MRSC, microbiologists notify confirmed of action plans for the prevention and control of gonorrhoea cases of acute illnesses, enabling the study of microorgan- infection, and third, to allow professionals to evaluate its isms with antibiotic susceptibility and notifiable resistance extension worldwide and report on local and global strate- profiles. gies to control AMR to gonococcal disease. Current sur- In this study, we aim to describe the epidemiological veillance is often suboptimal and presents many challenges, characteristics of confirmed cases of N. gonorrhoeae and especially in countries with the highest burden of resistance antimicrobial susceptibility notified to the MRSC between [3]. 2016 and 2019. Treatment of gonococcal infection is currently affected by the appearance of strains resistant to almost all groups of antibiotics used, as well as by the recent reduced susceptibil- Methods ity appearing worldwide in third-generation cephalosporins [4]. Study population The study population considered all In order to reduce the risk of resistance to the use of patients notified to the MRSC who received treatment in antibiotic monotherapy, the World Health Organization hospitals and primary health care centres in Catalonia or 13 European Journal of Clinical Microbiology & Infectious Diseases (2023) 42:883–893 885 presented with a new confirmed episode of acute infection included in the Protocol for the Surveillance of Antimi- by N. gonorrhoeae between 2016 and 2019. crobial Resistance in Catalonia [12]. The clinical break- points (susceptible, resistant) were as follows: azithro- Data collection All data was processed by the Subdirec- mycin (MIC ≤ 0.25 mg/L, MIC > 0.5 mg/L); ceftriaxone torate General for Public Health Surveillance and Emer- and cefixime (MIC ≤ 0.125 mg/L, MIC > 0.125 mg/L); gency Response at the Catalonian Public Health Agency, ciprofloxacin (MIC ≤ 0.03 mg/L, MIC > 0.06 mg/L); peni- including the introduction, validation, cleaning and analysis cillin (MIC ≤ 0.06 mg/L, MIC > 1.0 mg/L); spectinomy- of data records according to the diagnostic criteria, ensur- cin (MIC ≤ 64 mg/L, MIC > 64 mg/L); and tetracycline ing that cases met the confirmed case definition in line (MIC ≤ 0.5 mg/L, MIC > 1.0 mg/L). The production strains with established criteria. The epidemiological, laboratory of beta-lactamase were also analysed. and clinical data collected included the age and sex of the The criteria for this study were adapted from Tapsall patient, anatomical site of infection, previous gonorrhoea et al. (2009), when definitions were established for multi- diagnosis, diagnostic technique, type of centre, coinfection drug-resistant gonococci (MDR-NG) and extensively drug- with other STIs, and antibiotic sensitivity in isolated strains. resistant gonococci (XDR-NG) [13]. The site of infection was classified as urethral/balanopre- Multi-drug resistant gonococci are strains resistant to one putial, vaginal/endocervix, pharynx, anorectal, urine and category I antibiotic – extended spectrum cephalosporins others (broadly categorized under genital/anorectal area (ESC) or spectinomycin – plus at least two other antibiotics and non-genital area). The age groups were split as fol- in category II (penicillin, ciprofloxacin and azithromycin). lows: 0–11 years, 12–19 years, 20–29 years, 30–39 years, Extensively drug-resistant gonococci strains are resistant to 40–49 years, and ≥ 50 years. two or more category I antibiotics (ESC and spectinomycin); A case was considered laboratory-confirmed when at and to three or more in category II (penicillin, ciprofloxacin, least one of the following diagnostic criteria was met [10]: azithromycin, aminoglycosides and carbapenem). In our definition of MDR-NG, we used cefixime and cef- • isolation of N. gonorrhoeae in a clinical sample triaxone as ESC or XDR-NG and did not consider amino- • detection of nucleic acids from N. gonorrhoeae in a clini- glycosides and carbapenem. cal sample We reviewed patient files for studied cases present- • observation of intracellular gram-negative diplococcus ing multi-drug resistant and extensively drug-resistant obtained in a smear of male’s urethral material (direct gonococci. microscopy) Co-infections with other STIs were studied, considering a three-week window period between the gonorrhoea infec- Data analysis A descriptive analysis of the study variables tion and other STIs. Analyses of all cases of N. gonorrhoeae was conducted. With regard to statistical analysis, IR per (14,251) were conducted to determine whether other STIs 100,000 person-years were calculated according to demo- (chlamydia, trichomonas, herpes or syphilis) were present graphic data delivered by the Institute of Statistics of Cata- during the three-week period from the initial diagnosis of lonia [11] for the studied age groups and sex. Proportions N. gonorrhoeae. were compared using the χ2 test or Fisher’s exact test, as Reinfection episodes were studied for each confirmed appropriate. Incidence rates were calculated and changes case of N. gonorrhoeae subsequent to the first infection. N. were assessed according to IR ratios and expressed as the gonorrhoeae positive tests within 60 days of a previous posi- percentage change in incidence. Two-sided p-values < 0.05 tive confirmed case were considered a single episode. were considered statistically significant. Analyses were conducted using the Statistical Package for Social Sciences (SPSS 18.0). Results Antimicrobial susceptibility The determination of anti- microbial susceptibility testing was studied for seven Between 2016 and 2019, a total of 14,251 confirmed cases of antibiotics: azithromycin, cefixime, ceftriaxone, cipro- N. gonorrhoeae were reported in Catalonia. In Table 1, we floxacin, penicillin, spectinomycin, and tetracycline. The summarize the case incidence according to year, age group laboratories used an “antibiogram kit”; where not avail- and sex; and diagnosis technique, anatomical site of infec- able, manual susceptibility testing was performed for each tion and origin of the sample (clinical setting). antibiotic. For the study of resistance for each antibiotic, Overall incidence was 46.9 cases/100,000 persons/year, the breakpoints recommended by the European Commit- with an increase of 110.7% in 2019 compared to the rate in tee on Antimicrobial Susceptibility Testing (version 6.0) 2016 (IR: 30.7 cases/100,000 persons/year in 2016; and 64.7 were used, with the consensus of the MRSC working group cases/100,000 persons/year in 2019 (p < 0.001). 13 886 European Journal of Clinical Microbiology & Infectious Diseases (2023) 42:883–893 Table 1  Characteristics of confirmed cases of Neisseria gonorrhoeae. Catalonia, Spain, 2016−2019 (n = 14,251 cases) Characteristics 2016 (n=2,308) 2017 (n=3,319) 2018 (n=3,659) 2019 (n=4,965) Total* (n=14,251) n % IR n % IR n % IR n % IR n % IR Age Group* 0−11 years 4 0.2 0.4 1 0.0 0.1 1 0.0 0.1 7 0.1 0.8 13 0.1 0.3 12−19 years 160 6.9 27.6 212 6.4 35.6 297 8.1 48.4 391 7.9 61.5 1,060 7.4 43.7 20−29 years 948 41.1 121.9 1,466 44.2 187.7 1,487 40.6 187.9 1,964 39.6 242.5 5,865 41.2 185.6 30−39 years 743 32.2 63.9 1,023 30.8 91.4 1,088 29.7 100.7 1,488 30.0 141.0 4,342 30.5 98.3 40−49 years 316 13.7 25.3 443 13.3 35.0 549 15.0 42.8 777 15.6 59.8 2085 14.6 40.9 ≥ 50 years 137 5.9 4.9 173 5.2 6.1 235 6.4 8.1 335 6.7 11.4 880 6.2 7.7 Total 2,308 100 30.7 3,319 100 43.9 3,659 100 48.1 4,965 100 64.7 14,251 100 46.9 Sex Women 402 17.4 10.5 597 18 15.5 742 20.3 19.2 1,116 22.5 28.6 2,857 20 18.5 Men 1,906 82.6 51.6 2,722 82 73.4 2,917 79.7 78.2 3,849 77.5 102.1 11,394 80 76.4 Diagnosis Culture 1,101 47.7 1,346 40.6 1,713 46.8 2,132 42.9 6,292 44.2 PCR 1,207 52.3 1,970 59.4 1,946 53.2 2,832 57 7,955 55.8 Direct microscopy 0 0.0 3 0.0 0 0.0 1 0.0 4 0.0 Specimen** Urethral/balanopreputial 1,254 47.0 1,724 44.9 1,942 47.4 2,261 40.4 7,181 44.3 Anorectal 418 15.7 626 16.3 626 15.3 900 16.1 2,570 15.9 Endocervical/vaginal 369 13.8 522 13.6 664 16.2 941 16.8 2,496 15.4 Pharynx 377 14.1 628 16.4 454 11.1 909 16.2 2,368 14.6 Urine 222 8.3 317 8.3 374 9.1 538 9.6 1,451 9.0 Others*** 29 1.1 22 0.6 35 0.9 50 0.9 136 0.8 Clinical setting Hospital 877 38 1,368 41.2 2,173 59.4 2,951 59.4 7,369 51.7 Primary care 1,431 62 1,951 58.8 1,486 40.6 2,014 40.6 6,882 48.3 IR incidence rate per 100,000 habitants *In 6 cases age was unknown **Some cases have more than one specimen ***Genital - anorectal area [Abscess (1); Penis abscess (1); Bartholin abscess (2); Endometrium (3); Douglas sack exudate (4); Genital swab (4); Glans (2); Penis (1); Pelvis pus (1); Genital ulcer (3); Genital chancre (27); Sperm (26)]. Non-genitalia area [Lymph node biopsy (1); Conjunctival exudate (7); Non-surgical exudate (2); Articular fluid (4); Peritoneal fluid (3); Blood (1); Conjunctival secretion (4); Serum (38)]; Not informed (1) Age and sex were available for almost all cases (age was (Table 1 and Fig. 1). Laboratory culture decreased slightly, from missing in only six cases). Over 80% of cases were males. Over- 47.7% in 2016 to 42.9% in 2019, but not significantly, due to all ratio of male cases to female cases was 4:1, with this distri- the shift from use of bacterial culture to NAAT for diagnosis of bution exhibiting a diminishing trend over time, from 4.7:1 in gonorrhoea. Of 16,202 samples, 12,322 (76.1%) were of genital- 2016 to 3.4:1 in 2019 (p < 0.001). The incidence rose by 98% anorectal origin, 2,368 samples (14.6%) were pharyngeal, 1,451 in males and by 172% in females between 2016 and 2019. The samples (9.0%) were from urine, and 61 samples (0.4%) were median age was 30 years (with a range of 0 to 89 years), with from other anatomical site. In one case, site of infection was not 31 years for males and 25 years for females. Sex and age distri- reported. Confirmed cases of gonococcal infection came both butions were similar throughout the period, with a high increase from primary care (48.3%) and hospital care (51.7%). in female incidence in 2019 compared to 2016 (10.5 cases per 100,000 persons in 2016; and 28.6 cases/100,000 persons in Antimicrobial susceptibility and resistance profiles 2019; p < 0.001). The highest incidence occurred in the 20–29 of Neisseria gonorrhoeae isolates age group (185.6 cases/100,000 persons/year), followed by the 30–39 age group (98.3 cases/100,000 persons/year). The antimicrobial susceptibility study was carried out on Regarding diagnostic technique, culture was available in 5,377 (85.5%) strains of 6,292 culture-diagnosed cases 6,292 cases (44.2%); 7,955 (55.8%) cases were analysed only by (Fig. 1). The percentage of antimicrobial susceptibility PCR and 4 of these (0.03%) were analysed by direct microscopy studied among culture-diagnosed cases and declared to the 13 European Journal of Clinical Microbiology & Infectious Diseases (2023) 42:883–893 887 Fig. 1  Flowchart for determining index events for inclusion in outcome analyses. Catalonia, Spain, 2016–2019. Abbreviations: ATB, Antibiotic; PCR, Polymerase chain reaction; ESC, extended-spectrum cephalosporins; R, resistant public system has increased in recent years, from 74.5% in (42.3%). Of the penicillin-resistant strains (n = 1,027), only 2016 to 90.1% in 2019 (p < 0.001). 410 (39.9%) yielded beta-lactamase production data and, of The antibiotic with the highest number of isolates studied these, 298 (72.7%) were positive for beta-lactamase. was ciprofloxacin (5,315/6,292 or 84.5%); followed by pen- Resistance to azithromycin rose significantly over time, icillin (5,165/6,292 or 82.1%); azithromycin (4,401/6,292 from 6.1% in 2016 to 16% in 2019 (p < 0.001). However, or 69.9%); ceftriaxone (4,361/6,292 or 69.3%); cefixime resistance to ceftriaxone did not increase significantly, from (2,806/6,292 or 44.6%); spectinomycin (2,290/6,292 or 0.5% in 2016 to 0.9% in 2019 ( p = 0.793). For cefixime, 36.4%) and tetracycline (2,028 /6,292 or 32.2%). Almost overall resistance decreased from 3% in 2016 to 1.9% in 50% of the isolates were tested for five antibiotics and close 2019 ( p = 0.013), as shown in Table 2, Fig. 2. to 26% for six or seven antibiotics. Of 5,377 N. gonorrhoeae isolates tested for antibiotic sensi- Multi‑resistant strains A total of 19 cases (0.4%) were identi- tivity, 3,508 (65.2%) presented resistance to at least one of the fied as multi-drug resistant N. gonorrhoeae (MDR-NG); 79% antibiotics analysed. The prevalence of resistance among the iso- of these occurred in males and 21% in females (Figs. 1 and 2). lates tested for ciprofloxacin was 57.1% (3,033/5,315). Among those tested for tetracycline, penicillin and azithromycin, preva- Extensively drug‑resistant N. gonorrhoeae (XDR-NG). Only lence was 32.3% (656/2,028), 19.9% (1,027/5,165), and 10.3% one case presented XDR-GC in 2019. The case was resistant (455/4,401), respectively. Between 2016 and 2019, percentages to ceftriaxone, cefixime, azithromycin, penicillin and tetracy- of resistance to ciprofloxacin, tetracycline and penicillin were cline and was only sensitive to spectinomycin (Figs. 1 and 2). relatively high and stable. Of the 4,361 strains analysed against When the characteristics of the 20 patients with MDR-NG ceftriaxone, 45 (1.0%) were resistant, while 71 (2.5%) out of and XDR-NG were further analysed, twelve of the patients 2,806 strains were resistant to cefixime. Seven (0.3%) out of were of Spanish origin, three were from Morocco, two from 2,290 strains were resistant to spectinomycin (Table 2). South America and three patients had no recorded origin. Of the strains with penicillin sensitivity data (n = 5,165), The median age of these patients was 31 years old (with a beta-lactamase production data was available in 2,187 range from 22 to 60 years) (Figs. 1 and 2). 13 888 European Journal of Clinical Microbiology & Infectious Diseases (2023) 42:883–893 Table 2  Antimicrobial Antimicrobials Percentage of*: Susceptible/Susceptible, increase exposure/Resistant susceptibility in Neisseria gonorrhoeae isolates. Catalonia, 2016 2017 2018 2019 Total Spain, 2016 − 2019 Ceftriaxone 99.5/NA/0.5 98.5/NA/1.5 98.9/NA/1.1 99.1/NA/0.9 99.0/NA/1.0 (n = 645) (n = 888) (n = 1,220) (n = 1,608) (n = 4,361) Cefixime 97.0/NA/3 95.4/NA/4.6 97.7/NA/2.3 98.1/NA/1.9 97.5/NA/2.5 (n = 164) (n = 434) (n = 1,042) (n = 1,166) (n = 2,806) Spectinomycin 99.8/NA/0.2 100/NA/0 99.3/NA/0.7 99.3/NA/0.7 99.7/NA/0.3 (n = 576) (n = 821) (n = 460) (n = 433) (n = 2,290) Ciprofloxacin 44.7/0.7/54.5 45.9/2.3/51.8 42.5/1.0/56.5 37.1/1.2/61.7 41.6/1.3/57.1 (n = 807) (n = 1.120) (n = 1,492) (n = 1,896) (n = 5,315) Penicillin 10.5/67.6/21.9 10/74.4/15.6 11.1/68.3/20.6 13.2/65.9/21.0 11.5/68.6/19.9 (n = 802) (n = 1,080) (n = 1,429) (n = 1,854) (n = 5,165) Tetracycline 38.5/28.2/33.3 45.7/23.4/30.9 54.8/12.8/32.4 49.6/17.7/32.7 48.7/19.0/32.3 (n = 291) (n = 411) (n = 564) (n = 762) (n = 2,028) Azithromycin 89.2/4.8/6.1 89.4/4.9/5.8 81.3/10.4/8.3 77.6/6.4/16.0 82.7/7.0/10.3 (n = 627) (n = 903) (n = 1,217) (n = 1,654) (n = 4,401) Abbreviations: NA, not applicable * The clinical breakpoints (susceptible, resistant) were as follows: ceftriaxone and cefixime (MIC ≤ 0.125 mg/L, MIC > 0.125 mg/L); ciprofloxacin (MIC ≤ 0.03 mg/L, MIC > 0.06 mg/L); spectino- mycin (MIC ≤ 64 mg/L, MIC > 64 mg/L); penicillin (MIC ≤ 0.06 mg/L, MIC > 1.0 mg/L); tetracycline (MIC ≤ 0.5 mg/L, MIC > 1.0 mg/L); azithromycin (MIC ≤ 0.25 mg/L, MIC > 0.5 mg/L) Fig. 2  Multidrug-resistant and extensively drug-resistant Neisseria drug-resistant gonococci. *Percentages based on total number of gonorrhoeae. Catalonia, Spain, 2016–2019. Abbreviations: n, num- isolates of ceftriaxone by year (2016: 807 cases; 2017: 1,120 cases; ber; MDR-NG, multidrug-resistant gonococci; XDR-NG, extensively 2018: 1,492 cases; 2019: 1,896 cases) 13 European Journal of Clinical Microbiology & Infectious Diseases (2023) 42:883–893 889 Table 3  Number of Neisseria gonorrhoeae reinfections in one-year period since first episode by sex. Catalonia, Spain, 2016–2019 2016 2017 2018 2019 Total F M F M F M F M F M n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) All cases 402 1,906 597 2,722 742 2,917 1,116 3,849 2,857 11,394 Time to next infection < 3 mo 2 (0.5) 27 (1.4) 3 (0.5) 29 (1.1) 2 (0.3) 16 (0.5) 6 (0.5) 43 (1.1) 13 (0.5) 115 (1.0) 3-< 6 mo 2 (0.5) 26 (1.4) 2 (0.3) 87 (3.2) 5 (0.7) 58 (2.0) 11 (1) 93 (2.4) 20 (0.7) 264 (2.3) 6-< 9 mo 0 (0.0) 27 (1.4) 2 (0.3) 83 (3) 2 (0.3) 43 (1.5) 10 (0.9) 84 (2.2) 14 (0.5) 237 (2.1) 9-< 12 mo 0 (0.0) 6 (0.3) 1 (0.2) 57 (2.1) 1 (0.1) 58 (2) 2 (0.2) 81 (2.1) 4 (0.1) 202 (1.8) Total 4 (1.0) 86 (4.5) 8 (1.3) 256 (9.4) 10 (1.3) 175 (6) 29 (2.6) 301 (7.8) 51 (1.8) 818 (7.2) Abbreviations: F female, M male, mo months Co‑infection of gonorrhoea with other STIs We found other Reinfection Reinfection rates were 12.2% (1,738 out of STIs present in 2,833 (19.9%) of 14,251 cases of gonococcal 14,251 cases) for the study period from 2016 to 2019. infection (Fig. 1). Co-infection increased slightly between Among males, the median time since the first infection was 2016 and 2019 (from 19.7% to 21%). Chlamydia trachoma- 12.2 months (0.3–46 months), compared to 7.4 months (1.7– tis was the most frequent co-infection (86.0%), followed by 36 months) among females and globally, reinfections ocurred Treponema pallidum (8.5%), Trichomonas vaginalis (3.6%), more in males than in females (7.2 versus 1.8%) (Table 3). and the herpes virus (1.9%). Females were more likely to be The boxplot in Fig. 3 represents the number of patients that co-infected than males (30.4% versus 15.1%; p < 0.001) for had between one and seven reinfection episodes subsequent all microorganisms, but not for Treponema pallidum (0.3% to the first primary infection. For each episode, the median versus 2.0%; p < 0.001). time elapsed in months is shown. In females, the median Fig. 3  Neisseria gonorrhoeae reinfection episodes since primary infection by sex. Catalonia, Spain, 2016–2019 13 890 European Journal of Clinical Microbiology & Infectious Diseases (2023) 42:883–893 time between one infection and the next was shorter through- for gonorrhoea diagnosis. This trend has also been attested out the period. The distribution of reinfections shows 8.9% to in Canada, where 21.8% of gonococcal infections are (n = 1,273) cases with one reinfection, and 2.2% (n = 316) diagnosed through culture [24]. This is a concern, as cul- with two. In 149 cases (1.1%) there were three or more rein- tures are required for antimicrobial susceptibility testing fections, including one patient with seven reinfections. and to monitor AMR. In 2015–16, the WHO’s Gonococ- cal Antimicrobial Surveillance Programme (WHO-GASP) documented sustained high levels of ciprofloxacin resist- ance [25]. And although the resistance rate to ciprofloxacin Discussion observed (57.1%) is similar to that of neighbouring Euro- pean countries (53%), it is notably higher than that reported This study describes microbiological surveillance data, in Portugal (46%) or the Netherlands (36%) [26]. coinfections and reinfections of 14.251 confirmed N. gon- Combination therapy is now recommended for treating non- orrhoeae cases in Catalonia over a four-year period. Anti- complicated gonorrhoea, given the growing resistance to ceph- microbial susceptibility was performed on 5,377 strains. To alosporins described for N. gonorrhoeae in recent years [27] our knowledge, this is the first study conducted in Spain to and treatment failures detected. Health professionals therefore describe AMR of such a considerable amount of N. gonor- need to be made aware of the importance of performing a cure rhoeae isolates, previously published works [8, 14] having test in cases where symptoms do not improve [5]. studied far fewer strains. During the period of our study, we observed a decrease The results indicate a rise in the incidence of gonococ- in the resistance rate for cefixime, especially during the later cal infection in our region in 2019 (IR = 64.7 cases/100,000 years (2018–2019). One probable explanation could be the persons) compared to 2016 (IR = 30.7 cases/100,000 per- low number of strains studied for this antibiotic, affecting sons). This increase can be explained in part by improved the relevance of continued monitoring. It has been suggested STIs diagnosis, in addition to public health campaigns and [28] that cefixime could be reconsidered as an alternative an increase in access to rapid point-of-care testing. Fur- to ceftriaxone in first-line dual therapy if this decrease is thermore, Catalonia is a reception site for sex tourism [15]. sustained over time. Recent studies conducted in Europe, the Netherlands and The increase in resistance to azithromycin observed in the United Kingdom [16, 17] describe that the use of sub- Catalonia, from 6.1% in 2016 to 16% in 2019, is compara- stances that facilitate chemsex and other high-risk group ble to a similar increase in Germany (from 1.3% in 2014 to sex activities has contributed to an increased incidence of 12.2% in 2020) [29], but higher than that observed in Canada STIs. Pre-exposure prophylaxis (PrEP) for HIV does not (from 0.8% in 2012 to 7.2% in 2016) [24]. Azithromycin protect against other infections, and the use of condoms is resistance in N. gonorrhoeae is established and spreading in frequently abandoned during these practices [18]. Catalonia, exceeding the 5% threshold at which WHO guide- Among our study population, roughly 48.7% of cases lines recommend a review to determine whether a particular were aged 29 or younger, and 30.5% were aged 30 to 39 at antimicrobial is the appropriate treatment. the time of diagnosis (similar to the Spanish national data In our study, however, the rate of resistance to ceftriaxone profile) [19]. In our dataset, the overall ratio of male cases remains low and stable, and AMR has led a number of Euro- to female cases was 4:1, higher than the overall European pean countries to adopt high-dose ceftriaxone monotherapy ratio of 3.2:1 [6]. in recent years (ECDC, 2019) [30]. Therefore, close AMR It is not surprising that a large proportion of our popula- surveillance following gonococcal culture is urgently needed. tion with N. gonorrhoeae was coinfected with other STDs Diminishing azithromycin susceptibility combined (gonorrhoea and chlamydia being the most frequent associa- with ceftriaxone resistance is a major concern and tion), especially among young women [20]. This supports threatens the effectiveness of the currently highly effec- the findings of previous Spanish studies [21] and Spanish tive dual therapy regimen of ceftriaxone in conjunction national guidelines that gonorrhoea infections should be with azithromycin. Even though resistance to cefixime treated with combination therapy (ceftriaxone or cefixime was decreasing in our region in 2019, cefixime resistance with azithromycin) to target both infections, in accordance needs to be monitored closely, particularly because gono- with ECDC guidance [22]. Cervical ectopy of young women coccal strains resistant to both cefixime and ceftriaxone (< 25 years old) has been identified as a risk factor for chla- continue to spread internationally [30]. mydia and gonorrhoea co-infection [23]. We have also detected four multidrug-resistant strains Antimicrobial surveillance data was available from the that are resistant to azithromycin and ceftriaxone and 6,292 (44.2%) culture isolates studied. Laboratory culture cefixime, and similar evidence has emerged in other coun- slightly decreased from 47.7% in 2016 to 42.9% in 2019, tries where the first cases of MDR-NG appeared in Feb- due to the shift from the use of bacterial culture to NAAT ruary 2018 (1 case in England and 2 cases in Australia) 13 European Journal of Clinical Microbiology & Infectious Diseases (2023) 42:883–893 891 [31]. These strains are a sign of the growing threat of Members of the Working Group of MRSC Miguel Ángel Benítez (Con- multidrug-resistant gonococcal strains in the context of sorci Laboratori Intercomarcal de l’Alt Penedès, Garraf i Anoia); Jordi Bosch, Cristina Pitart (Hospital Clínic i Provincial de Barcelona); Fred- limited therapeutic alternatives, lack of a vaccine and lim- eric Ballester (Hospital Universitari de Sant Joan de Reus); Ana Cal- ited surveillance capacity in many regions of the world. derón, Teresa Falgueras (Hospital Municipal de Badalona); Carmina Most reinfections occurred between 3 to 6 months Martí, Mª Àngeles Pulido (Hospital General de Granollers); Margarida after the first episode and were more common in males. Curriu (Hospital Comarcal de Sant Bernabé); Ester Sanfeliu (Hos- pital d'Olot Comarcal de la Garrotxa); Percy Juan Ayala (Clínica de A recent study of 9,241 cases conducted in New Zealand Terres de l’Ebre); Carme Gallés, Elisenda Capdevila, Pilar Hernández showed that, of the 34% (3,151) retested at 6 weeks and (Corporació de Salut del Maresme i la Selva); Paula Gassiot, Carme 6 months, 21% tested positive [32]. Given that reinfection Mora (Hospital de Figueres); Frederic Gómez (Hospital Universitari with chlamydia or gonorrhea is common and can lead to Joan XXIII de Tarragona); Araceli González (Hospital General del Parc Sanitari Sant Joan de Déu); Màrius Juanpere Aixalà (Hospital de significant reproductive health complications, testing for Móra d’Ebre); Eduardo Padilla (Laboratori de Referència Catalunya); reinfection after treatment might be recommended despite Amadeu Gené (Hospital Sant Joan de Déu, Esplugues de Llobregat); individual and social characteristics associated with gon- Ferran Navarro, Alba Rivera, Ferran Sánchez (Hospital de la Santa orrhea patients limiting the success of this strategy [33]. Creu i Sant Pau); Gloria Trujillo, Joan López (Hospital Sant Joan de Déu, Manresa-Fundació Althaia); Montserrat Olsina (Hospital Univer- The present study has a number of limitations. First, sitari General de Catalunya); Pepa Pérez (CatLab Centre Analítiques we are aware of a possible under-notification of cases, as Terrassa); Mar Olga Pérez (Hospital Verge de la Cinta de Tortosa); notification is reliant on a passive system. However, the Joan Manel Ramírez (Hospital Universitari de Girona Dr. Josep Tru- MRSC conducts a search for suspected cases reported by eta); Xavier Raga, Judith Lucena (Hospital de Sant Pau i Santa Tecla); Jesús Aramburu (Hospital Universitari Arnau de Vilanova de Lleida); health professionals, which are then validated by epide- Esther Sanfeliu Riera (Hospital d'Olot Comarcal de la Garrotxa); Gore- miologists and confirmed by microbiology laboratories. tti Sauca, Inés Valle (Consorci Sanitari del Maresme); Anna Vilamala Second, cultures were carried out for less than half of the (Hospital General de Vic); Yannick Hoyos (Hospital Universitari de samples analysed, probably because of the comparative la Vall d’Hebron); Jordi Cámara, Jordi Niubó, Graciela Rodríguez, Fe Tubau (Hospital Universitari de Bellvitge); Maria Dolores Quesada (H. speed of diagnosis afforded by the molecular test. Universitari Germans Trias i Pujol, Badalona); Nuria Torrellas, Natàlia The low percentage of cultures, as shown in the study, Claver (Fundació Hospital de Palamós); Teresa Bastida, Rosalia Santos is hampering the monitoring and evaluation of AMR and (Fundació Hospital Esperit Sant); Olga González-Moreno (SYNLAB facilitating the spread of infection. Lastly, antibiotic sen- Diagnósticos Globales SAU). sitivity detection rates are often low (samples arriving Authors’ contributions M.H., S.B. and P.C. conceptualized and designed late to the laboratory are no longer viable, rendering anti- the study and drafted the manuscript. S.E. and L.F. made substantial biotic susceptibility testing impossible), indicating that a contributions to the data collection process. S.B. performed the statistical far larger number of samples is needed to build cultures analysis; M.H. and A.C. reviewed the scientific literature and checked the manuscript. P.C., M.J. and J.M. collaborated on the critical review and tests for antibiotic sensitivity. and validation of the final manuscript. The working group of MRSC reported the data collection and approved the final manuscript. All the authors have read and agreed to the published version of the manuscript. Conclusion Funding The authors declare that no funds, grants or other support were received during the preparation of this manuscript. In Catalonia, 10% of the N. gonorrhoeae isolates studied between 2016 and 2019 were resistant to azithromycin. Data availability All the data used in the analysis was collected during According to the WHO, resistance above 5% indicates an routine public health surveillance activities, as part of the legislated mandate of the Health Department of Catalonia, the competent author- alert to review treatment guidelines. Resistance to cipro- ity for the surveillance of communicable diseases, which is officially floxacin, tetracycline and penicillin was relatively high and authorized to receive, treat and temporarily store personal data on cases stable, while resistance to ceftriaxone and cefixime remained of infectious diseases. All data was fully anonymized. low; and multidrug-resistant strains of N. gonorrhoeae increased throughout the period. Epidemiological surveil- Declarations lance of N. gonorrhoeae must be enhanced, paying particular Ethics approval Both ethical approval and informed consent require- attention to improving the culture of strains and AMR data. ments for the study were waived by the Ethics Committee of the Insti- tutional Review Board at the Public Health Agency of Catalonia. All Acknowledgments We are grateful to Sergi Mendoza, Carolina Fer- study methods were carried out in accordance with Declaration of rer, Lorena Coronas, Glòria Patsi and Montserrat Piqué at the Public Helsinki guidelines and other relevant guidelines. Health Agency of Catalonia, and to Alba Ferran and Ferran Navarro at the Microbiology Service at the Santa Creu and Sant Pau Hospital, Competing interests The authors have no relevant financial or non- for their scrutiny and support. We also wish to thank Shannon Leigh financial interests to disclose. O’Brien for the English language revision. 13 892 European Journal of Clinical Microbiology & Infectious Diseases (2023) 42:883–893 Open Access This article is licensed under a Creative Commons Attri- 12. 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European Centre for Disease Prevention and Control (2021) Gono- Publisher's Note Springer Nature remains neutral with regard to coccal antimicrobial susceptibility surveillance in the European jurisdictional claims in published maps and institutional affiliations. 13