Research and analysis

GRASP report: data to June 2023

Updated 20 November 2023

This report includes Second-Generation Surveillance System (SGSS) data to June 2023.

Main findings

Between 2021 and 2022, characterisation of 1,460 Neisseria gonorrhoeae isolates collected through the gonococcal resistance to antimicrobials surveillance programme (GRASP) showed:

• the percentage of isolates with reduced susceptibility to ceftriaxone (minimum inhibitory concentration (MIC) >0.03 milligrams per litre (mg/L)), the current first-line therapy, remained low at 0.21% in 2022 compared to 0.07% in 2021
• the modal MIC for ceftriaxone remained at 0.015mg/L
• the modal ceftriaxone MIC for isolates from heterosexual men and women increased to meet that of gay, bisexual and other men who have sex with men (GBMSM) for the first time since 2017, similarly, the modal cefixime MIC for isolates from women increased to that of GBMSM for the first time since 2018
• cefixime resistance (MIC >0.125mg/L) increased slightly from 0.3% to 0.8%
• azithromycin resistance (MIC >0.5mg/L) and ciprofloxacin resistance (MIC >0.06mg/L) continued to increase rapidly (15.1% to 20.4% and 46.8% to 58.6% respectively)
• tetracycline resistance (MIC >1.0mg/L) decreased for the first time since monitoring began (74.8% to 61.8%)
• penicillin resistance (MIC >1.0mg/L) remained stable from 14.2% to 13.6%
• as in previous years, no spectinomycin resistance was detected and the modal gentamicin MIC remained low (4mg/L)
• over two-thirds of the isolates belonged to 10 multi-locus sequence types
• elevated MICs for cephalosporins were associated with expression of mosaic penA alleles, in particular penA-34

There were 14 cases of ceftriaxone resistance (MIC >0.125mg/L) identified by primary diagnostic testing and confirmed by the UK Health Security Agency (UKHSA) sexually transmitted infection (STI) reference laboratory (STIRL) from January 2022 to June 2023 compared to 2 cases in 2021 and no cases in 2020.

Prescribing data demonstrated excellent adherence to the UK guideline for managing infection with N. gonorrhoeae, with 97.7% of individuals receiving the recommended first-line of ceftriaxone 1g intramuscular (IM) monotherapy in 2022 (1).

The effectiveness of first-line treatment for gonorrhoea continues to be threatened by antimicrobial resistance, particularly given the recent reports of mainly travel-associated ceftriaxone resistance in England. Increases in the ceftriaxone and cefixime modal MICs among isolates from heterosexual men and women, as well as the growing number of resistant isolates referred to STIRL show that continual monitoring is essential.

Recommendations

All primary diagnostic laboratories should test gonococcal isolates for susceptibility to ceftriaxone.

Suspected ceftriaxone resistant isolates (MIC >0.125mg/L, European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoint) should be referred to STIRL for confirmatory testing and follow-up.

Primary diagnostic laboratories are encouraged to report test results and antimicrobial resistance (AMR) data to SGSS to facilitate real-time monitoring of trends in N. gonorrhoeae diagnoses and AMR in England.

Healthcare practitioners should ensure that all individuals diagnosed with gonorrhoea are treated and managed according to national guidelines and should be alert to changes in recommended first-line therapies.

Possible cases of ceftriaxone treatment failure should be reported to UKHSA via the HIV and STI Data Exchange. This has restricted access for authorised users only.

Introduction

Gonorrhoea, caused by the bacterium Neisseria gonorrhoeae, is the second-most commonly diagnosed STI in England. If untreated, gonorrhoea can lead to complications, such as chronic pelvic pain, pelvic inflammatory disease, ectopic pregnancy and infertility.

Gonorrhoea diagnoses in England have more than doubled in the last decade (31,177 in 2013 to 82,592 in 2022) (2, 3). Of note, the number of gonorrhoea diagnoses increased by 50.3% between 2021 and 2022 and was the largest annual number reported since records began in 1918 (4). Although this recent increase was reported across all age groups, cases of gonorrhoea nearly doubled among young people aged 15 to 24 years. Furthermore, diagnosis rates of gonorrhoea remain highest among specific population groups; gay, bisexual and other men who have sex with men (GBMSM) and people of black Caribbean ethnicity continue to experience disproportionately high rates of gonorrhoea (2).

Ceftriaxone is an extended-spectrum cephalosporin (ESC) that is currently recommended in the UK as the first-line therapy for gonorrhoea (1g IM monotherapy) (1). Where antimicrobial susceptibility is known prior to treatment, ciprofloxacin, a fluoroquinolone, is recommended as an alternative first-line therapy (500mg orally as a single dose). These antibiotics were recommended as first-line treatments in January 2019 in the UK by the British Association for Sexual Health and HIV (BASHH). The 2019 guidance represented a major change from the 2011 guidelines, which advised using dual therapy with ceftriaxone 500mg IM and azithromycin 1g orally as first-line treatment. ESCs are among few remaining antimicrobials that can be effectively used as first-line monotherapy for gonorrhoea.

Ongoing monitoring of AMR, comprising the culture of isolates, test-of-cure and the maintenance of comprehensive and enhanced surveillance is vital for the detection of emerging trends and to ensure that first-line treatments for gonorrhoea remain effective. Ineffective treatment facilitates onward transmission and the development of sequelae.

This report presents trends in gonococcal susceptibility to therapeutically relevant antimicrobials and explores the recent epidemiology of N. gonorrhoeae AMR in England and Wales. GRASP includes a suite of surveillance systems to detect and monitor AMR in N. gonorrhoeae and to record potential treatment failures; these include the GRASP sentinel surveillance system, analysis of real-time laboratory data and reports of suspected treatment failure.

The GRASP sentinel surveillance system

GRASP sentinel surveillance data is obtained annually from a network of sexual health services (SHSs) across England and Wales and their associated laboratories. In 2022, 26 SHSs (24 in England, 2 in Wales) and 20 laboratories participated in the programme. The geographical distribution of the 26 participating SHSs is shown in Figure 1.

Participating laboratories are requested to collect consecutive N. gonorrhoeae isolates over a 2 to 3 month period (usually between July to September). All collected N. gonorrhoeae isolates are sent to STIRL for antimicrobial susceptibility testing. Antimicrobial susceptibility results are linked securely to the pseudonymised GUMCAD STI surveillance system data to obtain demographic and clinical details. GUMCAD is a disaggregated, patient-level data set of all STI tests and diagnoses at SHSs in England (3). In addition, enhanced supplementary demographic, clinical and behavioural data is submitted by participating SHSs to enhance GUMCAD data. Two sample tests of proportion and Chi-square tests for trend are used to define recent and longitudinal antimicrobial susceptibility trends, respectively. All analyses are performed with Stata V.17.0 (StataCorp LP, College Station, Texas, USA).

Full details on the data sets and methodology used for the GRASP sentinel surveillance system are available online (5).

Figure 1. Map showing 26 sentinel sexual health services participating in GRASP 2022 across England and Wales and London (shown at larger scale)

Real-time laboratory data

Data from the GRASP sentinel surveillance system are supplemented year-round by real-time laboratory data, reported through SGSS and by STIRL (Appendix 1).

SGSS data

SGSS is an application that stores and manages laboratory data and notifications, capturing routine surveillance data on infectious diseases and AMR. Positive test results and AMR data is submitted on a voluntary basis from 147 laboratories who receive specimens from a range of healthcare providers, including SHSs, general practitioners and hospitals across England, Wales and Northern Ireland (6). Within GRASP, SGSS data is used to monitor real-time trends in N. gonorrhoeae diagnoses and AMR in England.

STI reference laboratory

Laboratories are asked to refer N. gonorrhoeae isolates with suspected ceftriaxone resistance (MIC >0.125mg/L, EUCAST breakpoint) to STIRL for antimicrobial susceptibility testing and confirmation. For cases of suspected treatment failure, residual nucleic acid amplification tests (NAATs) can be referred to STIRL for molecular detection of the penA-60 allele with the mutations most often associated with resistance to ceftriaxone. STIRL primarily acts as a reference and specialistic diagnostic service for laboratories in England, but also receives samples from Wales and Northern Ireland.

Treatment failures

Information on suspected treatment failures is reported to UKHSA via the HIV and STI Data Exchange. This has restricted access for authorised users only.

Sentinel surveillance sample

Sampling frame

The 2022 GRASP collection took place between 1 July to 30 September 2022. Figure 2 shows that during this period, 8,368 gonorrhoea diagnoses were reported to GUMCAD by the 24 English SHSs participating in GRASP. Over the same period, 3,172 N. gonorrhoeae isolates were sent to STIRL for antimicrobial susceptibility testing from these SHSs (3,357 isolates including Welsh clinics), a 36% increase from the number received in 2021 across the same period (number (n) =2,324).

In 2022, the number of isolates received exceeded the target sample size required to achieve representativeness (see GRASP report 2021, Appendix 3) so only isolates collected during July and August were tested. Isolates were included in analyses if they, a) could be case-matched to a GRASP participating SHS within the GUMCAD STI surveillance system (n=1,629), and b) had been successfully tested for susceptibility to 8 therapeutically relevant antimicrobials by STIRL (n=1,460).

Figure 2. Sentinel surveillance sampling frame flowchart in GRASP 2022 [note 1]

Note for Figure 2:

Note 1: Due to an unprecedented number of isolates received during the GRASP 2022 collection period, only isolates collected in July and August (where case-matched to GUMCAD) were tested for antimicrobial susceptibility, for most clinics. Isolates collected in September were included for clinics that had fewer than 20 case-matched isolates collected in July and August.

Where more than one isolate was collected from an individual, a hierarchy for testing was applied as shown in Table 1. Of note, the 2021 GRASP collection was the first time that pharyngeal isolates have been prioritised ahead of all other sites due to concerns that resistance is most likely to emerge in this site (5). In 2020 and prior years, pharyngeal isolates were included within ‘any other site’ and were thus only tested if no specimens from other sites (rectal, urethral or cervical) were available. Among the 1,460 tested and case-matched isolates in 2022, the anatomical site of specimen collection was most commonly urethral (40.7%), followed by rectal (26.0%) and pharyngeal (20.6%). In comparison, pharyngeal isolates constituted only 7.7% of those included in the 2020 GRASP analysis.

Table 1. Anatomical site of specimen collection hierarchy and percentage of all isolates within respective GRASP collections, 2020 to 2022

Site of specimen collection	2020 (%)	2021 (%)	2022 (%)
Pharyngeal (highest priority)	7.7	20.2	20.6
Rectal	27.1	24.4	26
Urethral	47	43.5	40.7
Cervical	14.1	9.7	10.3
Any other site (lowest priority)	4.1	2.2	2.4

Sentinel surveillance sample

Among 1,460 individuals with a N. gonorrhoeae isolate included in the sentinel surveillance sample, 1,147 (78.6%) were male, of whom 74.3% (852 out of 1,147) were GBMSM (Table 2). Most individuals in the sentinel surveillance sample were white (56.5%), and the modal age group was 25 to 34 years (41.0%), with ages ranging from 15 to 76 years. Just under half (47.7%) were resident in London.

Among all individuals, 7.3% were living with HIV, and 92.5% (99 out of 107) of these were GBMSM. Nearly a third (32.6%) had been diagnosed with gonorrhoea previously and 21.4% were diagnosed with chlamydia at the time of their gonorrhoea diagnosis. Individuals most commonly reported having between 0 to 5 sexual partners in the 3 months prior to their gonorrhoea diagnosis, with 2.8% of all individuals reporting having had a sexual partner abroad (outside of the UK) in the same time interval. However, information on the number of sexual partners either in the UK or abroad was not reported for 30.9% of individuals.

Over half (57.0%) of individuals were reported to have received a test-of-cure, similar to 54.4% in 2021.

When the GRASP sample was compared to all individuals diagnosed with gonorrhoea nationally at all SHSs in GUMCAD over the same period (July to September 2022), women were under-represented in GRASP (17.1% versus 23.5%; probability (p) value <0.001), while GBMSM (58.4% versus 48.0%; p<0.001) and heterosexual men (20.2% versus 16.5%; p<0.001) were over-represented. London residents were particularly over-represented in the sentinel system relative to all diagnoses nationally (47.7% versus 39.8%; p<0.001) in large part due to increased diagnoses among residents outside London during this period in 2022 (data not shown).

Table 2. Characteristics of individuals in the GRASP sentinel surveillance system, by gender and sexual orientation, 2022

Characteristics	GBMSM (% of N)	Heterosexual men (% of N)	Women (% of N)	Not reported (% of N)	Total (% of N)
Number of individuals (N)	852	295	250	63	1460
Aged 13 to 19 years	14 (1.6%)	25 (8.5%)	41 (16.4%)	6 (9.5%)	86 (5.9%)
Aged 20 to 24 years	124 (14.6%)	109 (36.9%)	108 (43.2%)	17 (27.0%)	358 (24.5%)
Aged 25 to 34 years	392 (46.0%)	97 (32.9%)	82 (32.8%)	28 (44.4%)	599 (41.0%)
Aged 35 to 44 years	201 (23.6%)	46 (15.6%)	13 (5.2%)	10 (15.9%)	270 (18.5%)
Aged 45 years and over	121 (14.2%)	18 (6.1%)	6 (2.4%)	2 (3.2%)	147 (10.1%)
Ethnic group: white	556 (65.3%)	94 (31.9%)	145 (58.0%)	30 (47.6%)	825 (56.5%)
Ethnic group: black Caribbean	25 (2.9%)	28 (9.5%)	7 (2.8%)	1 (1.6%)	61 (4.2%)
Ethnic group: black African	27 (3.2%)	34 (11.5%)	6 (2.4%)	2 (3.2%)	69 (4.7%)
Ethnic group: black other	4 (0.5%)	8 (2.7%)	3 (1.2%)	2 (3.2%)	17 (1.2%)
Ethnic group: Asian (including Chinese)	51 (6.0%)	10 (3.4%)	10 (4.0%)	5 (7.9%)	76 (5.2%)
Ethnic group: other	33 (3.9%)	11 (3.7%)	5 (2.0%)	1 (1.6%)	50 (3.4%)
Ethnic group: mixed	63 (7.4%)	23 (7.8%)	12 (4.8%)	1 (1.6%)	99 (6.8%)
Ethnic group: not reported [note 1]	93 (10.9%)	87 (29.5%)	62 (24.8%)	21 (33.3%)	263 (18.0%)
Residence: outside London	316 (37.1%)	220 (74.6%)	194 (77.6%)	33 (52.4%)	763 (52.3%)
Residence: London	536 (62.9%)	75 (25.4%)	56 (22.4%)	30 (47.6%)	697 (47.7%)
HIV status: negative	738 (86.6%)	262 (88.8%)	216 (86.4%)	60 (95.2%)	1276 (87.4%)
HIV status: positive	99 (11.6%)	5 (1.7%)	1 (0.4%)	2 (3.2%)	107 (7.3%)
HIV status: not reported [note 1]	15 (1.8%)	28 (9.5%)	33 (13.2%)	1 (1.6%)	77 (5.3%)
Site of infection: genital [note 2]	329 (38.6%)	271 (91.9%)	218 (87.2%)	37 (58.7%)	855 (58.6%)
Site of infection: rectal [note 2]	572 (67.1%)	12 (4.1%)	44 (17.6%)	27 (42.9%)	655 (44.9%)
Site of infection: pharyngeal [note 2]	449 (52.7%)	25 (8.5%)	95 (38.0%)	19 (30.2%)	588 (40.3%)
Site of infection: other [note 2]	16 (1.9%)	18 (6.1%)	1 (0.4%)	3 (4.8%)	38 (2.6%)
Site of infection: multiple sites [note 2]	402 (47.2%)	36 (12.2%)	90 (36.0%)	19 (30.2%)	547 (37.5%)
Symptoms: no	481 (56.5%)	49 (16.6%)	125 (50.0%)	25 (39.7%)	680 (46.6%)
Symptoms: yes	367 (43.1%)	246 (83.4%)	125 (50.0%)	38 (60.3%)	776 (53.2%)
Symptom: not reported [note 1]	4 (0.5%)	0 (0.0%)	0 (0.0%)	0 (0.0%)	4 (0.3%)
Any concurrent STI: chlamydia [note 3]	182 (21.4%)	65 (22.0%)	51 (20.4%)	15 (23.8%)	313 (21.4%)
Any concurrent STI: syphilis [note 3]	7 (0.8%)	1 (0.3%)	0 (0.0%)	0 (0.0%)	8 (0.5%)
Any concurrent STI: herpes [note 3]	2 (0.2%)	1 (0.3%)	2 (0.8%)	0 (0.0%)	5 (0.3%)
Any concurrent STI: warts [note 3]	1 (0.1%)	1 (0.3%)	0 (0.0%)	0 (0.0%)	2 (0.1%)
Any concurrent STI: LGV [note 3]	1 (0.1%)	0 (0.0%)	0 (0.0%)	1 (1.6%)	2 (0.1%)
Previously diagnosed with gonorrhoea: no	307 (36.0%)	144 (48.8%)	139 (55.6%)	29 (46.0%)	619 (42.4%)
Previously diagnosed with gonorrhoea: yes	395 (46.4%)	37 (12.5%)	31 (12.4%)	13 (20.6%)	476 (32.6%)
Previously diagnosed with gonorrhoea: not reported [note 1]	150 (17.6%)	114 (38.6%)	80 (32.0%)	21 (33.3%)	365 (25.0%)
Total sexual partners (past 3 months): 0 to 1	151 (17.7%)	127 (43.1%)	149 (59.6%)	19 (30.2%)	446 (30.5%)
Total sexual partners (past 3 months): 2 to 5	256 (30.1%)	114 (38.6%)	61 (24.4%)	17 (27.0%)	448 (30.7%)
Total sexual partners (past 3 months): 6 to 10	53 (6.2%)	10 (3.4%)	5 (2.0%)	1 (1.6%)	69 (4.7%)
Total sexual partners (past 3 months): 11 and over	39 (4.6%)	4 (1.4%)	1 (0.4%)	2 (3.2%)	46 (3.2%)
Total sexual partners (past 3 months): not reported [note 1]	353 (41.4%)	40 (13.6%)	34 (13.6%)	24 (38.1%)	451 (30.9%)
Sex abroad (past 3 months): no	482 (56.6%)	243 (82.4%)	204 (81.6%)	39 (61.9%)	968 (66.3%)
Sex abroad (past 3 months): yes	17 (2.0%)	12 (4.1%)	12 (4.8%)	0 (0.0%)	41 (2.8%)
Sex abroad (past 3 months): not reported [note 1]	353 (41.4%)	40 (13.6%)	34 (13.6%)	24 (38.1%)	451 (30.9%)
Test of cure: no	267 (31.3%)	88 (29.8%)	48 (19.2%)	33 (52.4%)	436 (29.9%)
Test of cure: yes	503 (59.0%)	148 (50.2%)	164 (65.6%)	17 (27.0%)	832 (57.0%)
Test of cure: not reported [note 1]	82 (9.6%)	59 (20.0%)	38 (15.2%)	13 (20.6%)	192 (13.1%)
Sample origin: urethral	283 (33.2%)	270 (91.5%)	9 (3.6%)	32 (50.8%)	594 (40.7%)
Sample origin: cervical	3 (0.4%)	2 (0.7%)	142 (56.8%)	3 (4.8%)	150 (10.3%)
Sample origin: rectal	342 (40.1%)	4 (1.4%)	15 (6.0%)	18 (28.6%)	379 (26.0%)
Sample origin: pharyngeal	216 (25.4%)	16 (5.4%)	59 (23.6%)	10 (15.9%)	301 (20.6%)
Sample origin: high vaginal site	0 (0.0%)	0 (0.0%)	22 (8.8%)	0 (0.0%)	22 (1.5%)
Sample origin: other	1 (0.1%)	0 (0.0%)	1 (0.4%)	0 (0.0%)	2 (0.1%)
Sample origin: not reported [note 1]	7 (0.8%)	3 (1.0%)	2 (0.8%)	0 (0.0%)	12 (0.8%)

Notes for Table 2:

Note 1: ‘not reported’ refers to instances where information was unknown or not stated.

Note 2: numerator: individuals in GRASP 2022 data set infected at site specified (by gender and sexual orientation). Denominator: all individuals in GRASP 2022 data set (by gender and sexual orientation). Not all individuals are tested for gonorrhoea at each site. Data reported are for individuals infected with at least the specified site, not exclusively this site. Percentages do not add to 100% as individuals can be infected at more than one site. Also note that these numbers differ to isolates tested by specimen site as only one site is tested per individual. For individuals with multiple sites of infection, the isolate sample tested followed the hierarchy described above.

Note 3: numerator: individuals in GRASP 2022 data set with any diagnosed concurrent STI (by gender and sexual orientation). Denominator: all individuals in GRASP 2022 data set (by gender and sexual orientation). Not all individuals are tested for each STI.

Whole genome sequencing

Genotyping

To understand which N. gonorrhoeae clones are driving AMR, whole genome sequencing (WGS) was performed on all isolates. Those isolates with good quality sequencing data (1,409 out of 1,460; 96.5%) were included in further analysis. To identify sequence types (STs) present in the sample, the following methods were used:

• multilocus sequence typing (MLST) detects variation between 7 housekeeping genes
• neisseria gonorrhoeae multiantigen sequence typing (NG-MAST) analyses differences in the porin B and transferrin-binding protein B genes
• neisseria gonorrhoeae sequence typing for antimicrobial resistance (NG-STAR) profiles alleles of 7 AMR associated loci

Sequence analysis identified a total of 93 different MLSTs, 10 of which accounted for more than two-thirds (974 out of 1,409, 69.1%) of the isolates (1,580 (n=224), 7,822 (n=121), 9,362 (n=110), 11,422 (n=97), 1,599 (n=79), 11,706 (n=77), 9,363 (n=73), 10,314 (n=71), 7,363 (n=64) and 1,583 (n=58)). STs were further subdivided into 217 and 401 NG-STAR and NG-MAST STs, respectively. Common associations between MLSTs, NG-STAR and NG-MAST types are shown in Figure 3. Further analysis of the yearly trends and epidemiological data associated with these STs is ongoing and will be published at a later date.

Figure 3. Association between MLST, NG-STAR and NG-MAST among sequenced isolates in 2022 [note 1]

Note for Figure 3:

Note 1: only STs with more than 3 representatives are shown. Segments are scaled according to the numbers of isolates belonging to each type. The inner circle represents the STs, the middle circle the NG-STAR types in relation to each ST and the outer circle the NG-MAST types in relation to each NG-STAR type.

Antimicrobial resistance

N. gonorrhoeae has developed resistance to all classes of antimicrobials recommended to treat gonorrhoea. Table 3 shows the AMR definitions used in GRASP. Antimicrobial susceptibility results were interpreted using current EUCAST breakpoints (7), as well as some previous EUCAST breakpoints for continuity. Figure 4 and Table 4 show trends in the percentage of gonococcal isolates collected through the GRASP sentinel surveillance system with resistance to selected antimicrobials since the inception of the programme (2000 to 2022) then with a focus on more recent trends (2018 to 2022), respectively. Appendix 2 shows resistance to selected antimicrobials by individuals’ characteristics for GBMSM, heterosexual men, and women.

Table 3. Antimicrobial resistance definitions

Antimicrobial	Minimum inhibitory concentration breakpoint for resistance (mg/L)
Ceftriaxone	>0.125
Azithromycin [note 1]	>0.5
High-level azithromycin [note 2]	≥256.0
Cefixime	>0.125
Ciprofloxacin	>0.06
Penicillin	>1.0 and/or β-lactamase positive
Tetracycline [note 3]	>1.0
Tetracycline (2023)	>0.5
Spectinomycin	>64.0
Gentamicin [note 4]	Not applicable

Notes for Table 3:

Note 1: until 2018, EUCAST had set a breakpoint of MIC 0.5mg/L for N. gonorrhoeae azithromycin resistance. This has since been replaced with an ‘epidemiological cut-off’ of 1.0mg/L (7). For continuity with previous GRASP reports, the previous breakpoint of 0.5mg/L is retained as a historic reference point.

Note 2: high-level azithromycin resistance is not defined by EUCAST, but the definition of ≥256mg/L is internationally recognised.

Note 3: in 2023 EUCAST updated the tetracycline resistance breakpoint for N. gonorrhoeae from 1.0mg/L to 0.5mg/L. For continuity, the previous breakpoint of 1.0mg/L has been retained.

Note 4: gentamicin does not have a resistance breakpoint.

Figure 4. Percentage of N. gonorrhoeae isolates in the GRASP sentinel surveillance system that were resistant to selected antimicrobials, England and Wales, 2000 to 2022 [note 1]

Note for Figure 4:

Note 1: due to changes in the diagnostic sensitivity medium used to test antimicrobial susceptibility of sentinel surveillance isolates, MICs for the 2015 to 2022 collections are not directly comparable with those from previous years. Trends from 2000 to 2014 compared to 2015 to 2022 must be interpreted with caution (point of change indicated by vertical dashed black line), particularly for azithromycin and tetracycline (data for tetracycline is only included from 2015 onwards due to this issue) (8). For continuity, the previous breakpoint of 1.0mg/L for tetracycline has been retained. The 5% threshold (≥5% of infections resistant to the first-line therapy) at which the World Health Organization (WHO) recommends that first-line monotherapy guidelines should be changed is indicated by the horizontal dashed red line. In 2021, pharyngeal isolates were prioritised ahead of all other sites for the first time, resulting in a substantial change in the distribution of specimen sites from 2021 onwards.

Table 4. Number and percentage of N. gonorrhoeae isolates in the GRASP sentinel surveillance system that were resistant to selected antimicrobials, England and Wales, 2018 to 2022

Antimicrobial MIC resistance breakpoint (mg/L)	2018 N=1,457	2019 N=1,701	2020 N=1,534	2021 N=1,459	2022 N=1,460
Ceftriaxone (>0.125) [note 1]	0 (0.0%)	0 (0.0%)	0 (0.0%)	0 (0.0%)	0 (0.0%)
Azithromycin (>0.5) [note 2]	142 (9.8%)	158 (9.3%)	134 (8.7%)	221 (15.2%)	298 (20.4%)
Azithromycin (>1.0) [note 2]	101 (6.9%)	52 (3.1%)	64 (4.2%)	74 (5.1%)	99 (6.8%)
Cefixime (>0.125)	32 (2.2%)	14 (0.8%)	9 (0.6%)	4 (0.3%)	11 (0.8%)
Ciprofloxacin (>0.06)	579 (39.8%)	727 (42.7%)	679 (44.3%)	683 (46.8%)	855 (58.6%)
Penicillin (>1.0)	181 (12.4%)	305 (17.9%)	147 (9.6%)	207 (14.2%)	198 (13.6%)
Tetracycline (>0.5) [note 3]	Not applicable	Not applicable	Not applicable	Not applicable	1,228 (84.1%)
Tetracycline (>1.0) [note 3]	769 (52.8%)	1,070 (62.9%)	999 (65.1%)	1,092 (74.8%)	902 (61.8%)
Spectinomycin (>64.0)	0 (0.0%)	0 (0.0%)	0 (0.0%)	0 (0.0%)	0 (0.0%)

Notes for Table 4:

Note 1: although no ceftriaxone-resistant cases were detected in GRASP sentinel surveillance, cases have been confirmed through direct referrals to the UKHSA STIRL national reference laboratory: 3 in 2018, 3 in 2019, 0 in 2020, 2 in 2021, 10 in 2022, 4 in 2023 (up to June)

Note 2: until 2018, EUCAST had a resistance breakpoint of 0.5mg/L for azithromycin against N. gonorrhoeae (7). This has since been removed and replaced with an ‘epidemiological cut-off’ of 1.0mg/L. For continuity with previous GRASP reports, the previous breakpoint of >0.5mg/L is retained as a historic reference.

Note 3: in 2023, EUCAST updated the resistance breakpoint for tetracycline against N. gonorrhoeae from 1.0mg/L to 0.5mg/L. For continuity with previous GRASP reports, the previous breakpoint of 1.0mg/L is retained as a historic reference. Breakpoint plates at 0.5mg/L were introduced in 2022; therefore, no data for this breakpoint is available prior to 2022.

Ceftriaxone

Sentinel surveillance system sample

Among 1,460 isolates included in the sentinel surveillance sample in 2022, none were resistant to ceftriaxone (MIC >0.125mg/L) (Table 4). The proportion of isolates with reduced susceptibility (defined here as an MIC >0.03mg/L) to ceftriaxone remained low at 0.07% (1 out of 1,459) in 2021 and 0.21% (3 out of 1,460) in 2022 (p=0.31) (Figure 5). If a lower threshold for reduced susceptibility to ceftriaxone with MIC >0.015mg/L is considered, the 2022 data shows a significant increase compared to 2021 (24.1% versus 9.2% respectively; p<0.001), the first time an increase has been seen since 2018.

Figure 5. Percentage of N. gonorrhoeae isolates in the GRASP sentinel surveillance system with reduced susceptibility to ceftriaxone, England and Wales, 2004 to 2022 [note 1]

Note for Figure 5:

Note 1: due to changes in the diagnostic sensitivity medium used to test antimicrobial susceptibility of sentinel surveillance isolates, MICs for the 2015 to 2022 collections are not directly comparable with those from previous years. Trends from 2004 to 2014 compared to 2015 to 2022 must be interpreted with caution (point of change indicated by vertical dashed black line) (8). Changes to the UK national guidance for the management of infection with N. gonorrhoeae are indicated by vertical dashed black lines with bold text. CRO: ceftriaxone; CFM: cefixime; SPT: spectinomycin; AZM: azithromycin. In 2021, pharyngeal isolates were prioritised ahead of all other sites for the first time, resulting in a substantial change in the distribution of specimen sites from 2021 onwards.

In 2022, the proportion of isolates with a ceftriaxone MIC of 0.015mg/L was more than double the proportion with an MIC ≤0.008mg/L. This was a greater upward shift in the modal MIC than seen in 2021, an indication that a greater proportion of the isolates are less susceptible to ceftriaxone (Figure 6). Furthermore, the modal MIC increased to 0.015mg/L among isolates from heterosexual men and women to meet that of isolates from GBMSM for the first time since 2017 (Figure 7). The proportion of isolates with an MIC of 0.03mg/L remains higher in GBMSM compared to heterosexual men (p<0.001) and women (p<0.001).

Figure 6. Distribution of ceftriaxone MICs (mg/L) for N. gonorrhoeae isolates in the GRASP sentinel surveillance system, England and Wales, 2018 to 2022 [note 1]

Note for Figure 6:

Note 1: in 2021, pharyngeal isolates were prioritised ahead of all other sites for the first time, resulting in a substantial change in the distribution of specimen sites from 2021 onwards.

Figure 7. Distribution of ceftriaxone MICs (mg/L) for N. gonorrhoeae isolates in the GRASP sentinel surveillance system, by gender and sexual orientation, England and Wales, 2022

Genotyping

The penA gene encodes penicillin-binding protein 2 and is a key lethal target of β-lactam antibiotics. Alterations in penA constitute a significant mechanism of ceftriaxone and cefixime resistance, either by specific mutations in the penA or by mosaic patterns that have arisen from horizontal DNA transfer, mainly from commensal Neisseria species.

A total of 25 penA variants were detected in sequenced genomes, of which, the non-mosaic penA-2 (30.7%, 433 out of 1,409) and penA-5 (21.1%, 298 out of 1,409) variants were most common (Figure 8). However, mosaic penA-34 subtypes (34.001 and 34.007) associated with ceftriaxone MICs 0.015 to 0.06mg/L ranked third, being identified in 245 genomes. Some of the isolates with ceftriaxone MICs of ≥0.015mg/L expressed the mosaic penA-93 (n=82) and penA-8 (n=5). Overall, the majority of mosaic penA variants were detected in a small number of MLSTs, notably ST1580, ST7363, ST9362, ST8123 and ST1583 (Figure 8).

Figure 8. Distribution of mosaic penA variants among STs in 2022 [note 1]

Note for Figure 8:

Note 1: each circle represents a unique ST. The size of the circle reflects the number of samples from each ST. The solid line connecting the circles shows single-locus variants.

Real-time laboratory data

Since 2015, UKHSA has extracted N. gonorrhoeae AMR data from SGSS on a weekly basis for the real-time follow-up of ceftriaxone-resistant N. gonorrhoeae. When a case of ceftriaxone-resistant N. gonorrhoeae is reported, the primary laboratory is contacted and asked to refer the isolate to the STIRL for confirmatory testing if the isolate has not been referred already.

From January to June 2023, 16,361 N. gonorrhoeae isolates were reported to SGSS by laboratories across England, a 29.2% increase relative to the same period in 2022 (11,584 isolates). The percentage of N. gonorrhoeae isolates tested for susceptibility to ceftriaxone (or cefuroxime as a proxy, see Appendix 1 in laboratories across England, as reported via SGSS, remained high (Table 5).

The percentage of isolates that were reported as resistant to ceftriaxone in SGSS increased from 0.19% in 2022 to 0.28% in 2023 (p=0.05) (Table 5). From January to June 2023, only 15.6% (7 out of 45) of isolates reported as resistant to ceftriaxone by laboratories across England were referred to STIRL for confirmation, despite the recommendation in the national management guidelines that all isolates with suspected ceftriaxone resistance should be referred (1). This is a decrease in the number of isolates that were referred compared to the same period in 2022 (41.6%, 10 out of 24). However, follow-up of all isolates reported as resistant but not initially referred to STIRL showed that all were misclassified by the primary laboratory as resistant and were incorrectly reported as resistant in SGSS. The number of misclassifications increased, with 25 misclassified isolates in the first 6 months of 2023, compared to 20 isolates misclassified across the whole of 2022.

In 2022, there were 10 confirmed cases of ceftriaxone-resistant N. gonorrhoeae (including those made through direct referral to STIRL rather than real-time follow-up through SGSS) (9). In comparison, no cases were detected in 2020 and 2 cases were detected in 2021 (Table 5). Infection was likely acquired in the Asia-Pacific region for 5 of these individuals with the remaining 5 infections resulting from limited onward transmission in the UK. WGS of the resistant isolates from 8 of the 10 cases showed they were MLST ST8123 harbouring mosaic penA-60 alleles. Isolates from the remaining 2 cases belonged to MLST ST1901 and ST16406 with mosaic penA-237 and penA-60 alleles respectively (9). As the source of infection was unclear for some cases and not all partners were contactable, a National Standard Incident Management Team was convened by UKHSA to coordinate the public health response to these cases and contain further transmission.

In the first 6 months of 2023, 4 cases of ceftriaxone-resistant N. gonorrhoeae were detected through direct referral to UKHSA. These comprised of one partnership and 2 individuals who were not epidemiologically linked. All were associated with travel to the Asia-Pacific region. WGS showed MLST ST13871, and presence of the mosaic penA-60 allele in 2 isolates from the partnership. Isolates from the other 2 individuals belonged to MLST ST8123 and a novel sequence type (single locus variant of ST7363) both with mosaic penA-60 alleles.

Table 5. Ceftriaxone susceptibility testing and referral of N. gonorrhoeae isolates: data from primary diagnostic laboratories reported via SGSS and the UKHSA STIRL national reference laboratory, 2019 to 2023

N. gonorrhoeae isolates reported to	2019	2020	2021	2022	2023 [note 1]
N. gonorrhoeae isolates reported to SGSS	32,387	18,310	16,230	27,395	16,361
N. gonorrhoeae isolates reported in SGSS that were tested for ceftriaxone susceptibility (%)	32,216 (99.5%)	18,195 (99.4%)	16,110 (99.3%)	27,056 (98.8%)	16,062 (98.2%)
N. gonorrhoeae isolates reported as ceftriaxone-resistant in SGSS (% of N. gonorrhoeae isolates tested)	57 (0.18%)	42 (0.23%)	23 (0.14%)	51 (0.19%)	45 (0.28%)
N. gonorrhoeae isolates reported as ceftriaxone-resistant in SGSS and referred to STIRL (% of total reported as ceftriaxone-resistant in SGSS)	14 (24.6%)	7 (16.7%)	6 (26.1%)	15 (29.4%)	7 (15.6%)
Referred N. gonorrhoeae isolates confirmed as resistant by STIRL (% of total referred N. gonorrhoeae isolates)	0 (0.0%)	0 (0.0%)	1 (16.7%)	2 (13.3%)	0 (0.0%)
All N. gonorrhoeae isolates confirmed as resistant by STIRL [note 2]	3	0	2	10	4

Notes for Table 5:

Note 1: data to June 2023.

Note 2: data sourced from both SGSS referrals and referrals made directly to STIRL from laboratories not using SGSS. Primary diagnostic laboratories report isolate test results to SGSS on a voluntary basis and therefore not all isolates received at STIRL have been reported to SGSS. The proportion of all isolates confirmed as resistant by STIRL is not presented due to the unavailability of an accurate denominator.

Cefixime

There was a continuous decline in cefixime resistant (MIC >0.125mg/L) isolates from 2.2% in 2018 to 0.3% in 2021 (p<0.001). This year, however, the percentage of resistant isolates remained stable at 0.8% (p=0.07) (Figure 4; Table 4). In 2022, the modal cefixime MIC remained at 0.03mg/L, as it was in 2021 (Figure 9). However, the proportion of isolates with an MIC of 0.125mg/L, only one dilution below the EUCAST threshold for resistance, doubled for the second year in a row from 8.2% (120 out of 1,459) in 2021 to 16.8% (245 out of 1,460) in 2022.

The modal cefixime MIC for isolates from GBMSM and women were the same for the first time since 2018 (0.03mg/L), while isolates from heterosexual men had a lower modal MIC (0.015mg/L) (Figure 10). As only 5 isolates from GBMSM and 2 each from women and heterosexual men displayed cefixime resistance (MIC >0.125mg/L), the proportion resistant among GBMSM (0.6%) was not significantly different from that of women (0.8%) (p=0.73) or heterosexual men (0.7%) (p=0.85).

Figure 9. Distribution of cefixime MICs (mg/L) for N. gonorrhoeae isolates in the GRASP sentinel surveillance system, England and Wales, 2015 to 2022 [note 1]

Note for Figure 9:

Note 1: in 2021, pharyngeal isolates were prioritised ahead of all other sites for the first time, resulting in a substantial change in the distribution of specimen sites from 2021 onwards.

Figure 10. Distribution of cefixime MICs (mg/L) for N. gonorrhoeae isolates in the GRASP sentinel surveillance system, by gender and sexual orientation, England and Wales, 2022

Genotyping

The majority of isolates exhibiting cefixime MICs of ≥0.125mg/L (96.4%, 242 out of 251) expressed mosaic penA, including the penA-34 (n=231), penA-10 (n=5), penA-166 (n=3), penA-101 (n=2) and penA-268 (n=1) variants.

Azithromycin

Resistance breakpoints for azithromycin were removed by EUCAST in 2019 and replaced with an epidemiological cut-off of 1.0mg/L (Table 2) (7). For continuity with previous GRASP reports, the previous breakpoint of 0.5mg/L is retained as a historic reference point.

Between 2021 and 2022, the proportion of isolates included in the sentinel surveillance sample with azithromycin MICs >0.5mg/L increased from 15.2% to 20.4% (p<0.001) (Figure 11). The modal azithromycin MIC has remained at 0.125mg/L since an increase in 2021. The proportion of isolates with azithromycin MICs at the epidemiological cut-off of >1.0mg/L slightly increased from 5.1% in 2021 to 6.8% in 2022 (p=0.05). The proportion of isolates with azithromycin MICs ≥256mg/L, an internationally recognised measure of high-level resistance, remained stable from 0.6% (9 isolates) in 2021 to 0.3% (4 isolates) (p=0.23) in 2022, having previously decreased from a peak of 1.2% in 2019 (20 isolates). Isolates with high-level resistance were widely geographically distributed and detected at 4 GRASP clinics in 2022.

Figure 11. Distribution of azithromycin MICs (mg/L) for N. gonorrhoeae isolates in the GRASP sentinel surveillance system, England and Wales, 2015 to 2022 [note 1]

Note for Figure 11:

Note 1: in 2021, pharyngeal isolates were prioritised ahead of all other sites for the first time, resulting in a substantial change in the distribution of specimen sites from 2021 onwards.

Azithromycin MICs >0.5mg/L were more common among isolates from GBMSM (25.2%) compared to those from heterosexual men (16.3%; p=0.002) and women (11.2%; p<0.001) (Figure 12). High-level resistance to azithromycin (MIC ≥256mg/L) was identified in isolates taken from heterosexual men (0.7%; 2 isolates) and women (0.8%; 2 isolates). The distribution of azithromycin MICs was more positively skewed for heterosexual men and women, with low modal MICs of either ≤0.06mg/L or 0.125mg/L (Figure 12). However, for GBMSM, the modal MIC increased to 0.25mg/L compared to 0.125mg/L in 2021.

Figure 12. Distribution of azithromycin MICs (mg/L) for N. gonorrhoeae isolates in the GRASP sentinel surveillance system, by gender and sexual orientation, England and Wales, 2022

Genotyping

Over-expression of the mtr (multiple transferable resistance) efflux pump due to mutations in mtr genes and/or its repressor mtrR (mtr repressor), known to be associated with low levels of resistance (MIC >1.0mg/L) to azithromycin, were detected in most sequenced genomes. In particular, the presence of mosaic mtrR and mtrD (mtr inner membrane transport protein) sequences were associated with increased azithromycin MICs in 27.9% (393 out of 1,409) of genomes. Of these, the majority (81.2%, 319 out of 393) belonged to only 3 MLSTs, namely ST1580 (n=150), ST11422 (n=97) and ST7822 (n=72). Moderate and high levels of resistance to azithromycin (MICs ranging from 4 to ≥256mg/L) were associated with mutations A2045G and C2597T in one to 4 copies of 23S rRNA (ribosomal ribonucleic acid) gene.

Gentamicin

Antimicrobial susceptibility testing in the GRASP sentinel surveillance system has included gentamicin since 2019. Only 2.9% of all isolates in 2022 had a gentamicin MIC of 8.0mg/L (Figure 13), an increase compared to 1.1% in 2021 but a decrease compared to 23.0% in 2020. The modal MIC for gentamicin has remained stable at 4.0mg/L between 2019 and 2022. In 2022, the modal MIC of 4.0mg/L was consistent across sexual orientations, and all had similar proportions of isolates with an MIC of 2.0mg/L, compared to 2021 where isolates from GBMSM had lower susceptibility to gentamicin.

Figure 13. Distribution of gentamicin MICs (mg/L) for N. gonorrhoeae isolates in the GRASP sentinel surveillance system, by gender and sexual orientation, England and Wales, 2022

Tetracycline, penicillin, ciprofloxacin and spectinomycin

In 2022, there was a decrease in the percentage of tetracycline-resistant isolates for the first time since 2016 (61.8% in 2022 compared to 74.8% in 2021; p<0.001). When the updated 2023 EUCAST breakpoint of MIC >0.5mg/L is applied, tetracycline resistance was 84.1% in 2022 (Figure 4), however, this data cannot be compared with previous years as 2022 is the first year 0.5mg/L breakpoint plates were included.

Among isolates found to be resistant to tetracycline in 2022, the proportion of isolates with low-level chromosomally mediated resistance (MIC 2 to 8mg/L, according to the previous breakpoint) decreased to 43.5% for the first time since 2018. High-level plasmid-mediated tetracycline resistance (MIC >8mg/L) has fluctuated between a low of 11.9% in 2015 and a high of 28.5% in 2019 (Figure 14). The presence of the tet(M) gene was detected in 255 genomes, explaining high levels of resistance in tetracycline (MIC >8mg/L).

The proportion of isolates resistant to penicillin remained stable (14.2% in 2021 then 13.4% in 2022; p=0.53) (Table 4). In 2022, 97.5% (193 out of 198) of penicillin-resistant isolates were penicillinase-producing N. gonorrhoeae (PPNG), which is plasmid-mediated resistance, a 2.0% decrease from 2021 (p=0.1).

Resistance to ciprofloxacin in sequenced isolates was associated with alterations at amino acid positions 91 and 95 in GyrA and positions 86 and 87 in ParC. Rates of mutations associated with resistance in sequenced genomes (58.9%, 830 out of 1,409) aligned with those identified by phenotypic testing (58.6%). Interestingly of 93 MLSTs, most resistance (626 out of 830, 75.4%) was associated with the 7 most common, including ST1580 (n=131), ST7822 (n=121), ST9362 (n=110), ST11706 (n=77), ST10314 (n=71), ST7363 (n=59) and ST1583 (n=57). The increase in levels of resistance to ciprofloxacin in 2022 might be the result of expansion of some of these resistant STs (Figure 15).

There has been a continuous increase in ciprofloxacin resistance each year since 2016 (p<0.001), however there was a steep increase in resistance between 2021 and 2022 with 46.8% of isolates resistant in 2021 compared to 58.6% in 2022 (p<0.001) (Figure 4, Table 4). Ciprofloxacin resistance varied by gender and sexual orientation; 73.9% of isolates were resistant among GBMSM, compared to 40.3% among heterosexual men and 29.2% among women (Appendix 2).

As was the case between 2000 and 2021, no isolates were resistant to spectinomycin in 2022.

Figure 14. Percentage of N. gonorrhoeae isolates in the GRASP sentinel surveillance system with low versus high-level tetracycline resistance, England and Wales, 2018 to 2022 [note 1]

Note for Figure 14:

Note 1: In 2021, pharyngeal isolates were prioritised ahead of all other sites for the first time, resulting in a substantial change in the distribution of specimen sites from 2021 onwards.

Figure 15. Resistance to ciprofloxacin among STs in 2022 [note 1]

Note for Figure 15:

Note 1: each circle represents a unique ST. The size of the circle reflects the number of samples from each ST. The solid line connecting the circles shows single-locus variants.

Prescribing practices

Antimicrobial prescribing data was reported for 1,628 individuals diagnosed with gonorrhoea at SHSs participating in GRASP in 2022, irrespective of whether a N. gonorrhoeae isolate was available for antimicrobial susceptibility testing.

Of these, 97.7% (1,591 out of 1,628) received ceftriaxone (1g IM), in accordance with BASHH first-line treatment recommendations, and was similar for GBMSM (98.3%), heterosexual men (96.9%) and women (97.1%). Ciprofloxacin 500mg orally is recommended when antimicrobial susceptibility is known prior to treatment; however in 2022, only 2 individuals were prescribed ciprofloxacin.

The remaining 33 individuals were prescribed second-line treatments (1). Of these 13 (39.4%) received azithromycin 2g monotherapy and 9 (27.3%) received gentamicin and azithromycin.

Discussion

No cases of ceftriaxone resistance were observed among N. gonorrhoeae isolates captured within the GRASP sentinel surveillance system in 2022. We therefore assessed trends in reduced susceptibility to ceftriaxone (MIC >0.03mg/L), which has remained low at 0.21% in 2022. However, for the first time since 2018, reduced susceptibility to ceftriaxone has stabilised instead of decreased. Despite this, the MIC distribution of ceftriaxone shifted towards higher MICs in 2022. Indeed, those with a MIC >0.015mg/L increased by 14.9% in the last year. This is also the first year the modal ceftriaxone MICs for isolates from heterosexual men and women have increased to meet that of GBMSM since 2017.

A similar pattern was observed for cefixime, an ESC recommended in the UK as an alternative regimen for gonorrhoea if IM treatment is contraindicated or refused. Although resistance to cefixime remained low at 0.8% in 2022, the proportion of isolates with cefixime MICs >0.06mg/L (one doubling dilution below the EUCAST breakpoint) increased from 8.2% in 2021 to 16.8% in 2022 and has doubled each year since 2019 (2.1%). Moreover, the modal cefixime MIC among isolates from women rose to the same level as those from GBMSM for the first time since 2018. Most of the isolates with reduced susceptibility to the ESCs belonged to a small number of STs expressing mosaic penA alleles.

The proportion of isolates with azithromycin MICs >0.5mg/L more than doubled, from 8.7% in 2020 to 20.4% in 2022, following steady levels since 2017. The increase continues to be driven by the number of isolates with MICs at 1.0mg/L, just above the historical breakpoint. There also continues to be an overall shift towards higher MICs since the modal azithromycin MIC increased by one dilution to 0.125mg/L in the year prior.

Tetracycline resistance has decreased for the first time following successive increases since 2016, despite its lack of use as a treatment option for gonorrhoea. However, resistance remains above 60%, possibly due to the use of doxycycline for the treatment of other STIs (10). The increasing trend in previous years appeared to be driven by low-level tetracycline resistance (MIC 2 to 8mg/L) and both low-level and high-level tetracycline resistance decreased in 2022. Ciprofloxacin, penicillin, tetracycline and azithromycin resistance continue to be more common among isolates from GBMSM compared to those from heterosexual men and women.

Prescribing data collected through the sentinel surveillance system demonstrates excellent compliance with the UK guidelines, with nearly all individuals receiving the recommended first-line therapy of ceftriaxone 1g IM monotherapy. There were no confirmed treatment failures reported in 2022.

Outside of the GRASP sentinel surveillance system, STIRL confirmed 10 cases of ceftriaxone resistance in 2022, and 4 in 2023 (up to June) upon direct referral from primary diagnostic laboratories, compared to a total of 11 between 2015 and 2021. Of the 14 cases in 2022 and 2023, most had travel links with the Asia-Pacific region, which has been shown to have the highest prevalence of ceftriaxone-resistant N. gonorrhoeae globally (11). However, as not all partners could be contacted in addition to some cases having no travel links, there may be ongoing local transmission within the UK. With only 2 out of these 14 cases reported in SGSS by the primary diagnostic laboratory, increased reporting of test results and antimicrobial resistance data to SGSS could strengthen real-time monitoring of antimicrobial resistance among N. gonorrhoeae diagnoses in England (12).

Conclusion

The effectiveness of first-line treatment for gonorrhoea continues to be threatened by the development and importation of AMR, despite the current low levels of reduced susceptibility to ceftriaxone and cefixime resistance. Furthermore, the stabilising of ceftriaxone resistance and the upward shift of the MICs may indicate that susceptibility to these ESCs is gradually decreasing at a population-level.

Concerningly, there have been large increases in ciprofloxacin and azithromycin resistance despite their infrequent use for gonorrhoea treatment. This may have future implications for the development of resistance-guided treatment (particularly for ciprofloxacin) and their use as alternative first and second-line treatments, respectively.

It is also worrying that the number of ceftriaxone-resistant cases between 2022 and June 2023 exceeded the total number reported in the 7 years since the first case detected in 2015. A high level of vigilance is required to facilitate the timely detection of emerging trends in resistance and ensure the continued effectiveness of first-line treatments. Culture and antimicrobial susceptibility testing of isolates, test-of-cure, and notification and management of sexual partners remain vital. Continued strong adherence to treatment guidelines and referral of isolates to STIRL for confirmatory antimicrobial susceptibility testing, where isolates are locally identified to be ceftriaxone-resistant, are also essential.

Appendices

Appendix 1. Real-time laboratory data

Data on N. gonorrhoeae isolates tested for antimicrobial susceptibility from January 2022 to June 2023 was retrieved from SGSS. SGSS is a centralised repository of communicable disease test results for every specimen tested by laboratories in England, Northern Ireland and Wales, including those of N. gonorrhoeae.

There are 2 sub-repositories within SGSS that hold data on antimicrobial susceptibility:

• communicable disease reporting (CDR)
• antimicrobial resistance (AMR)

Data was extracted from both repositories and duplicate records were removed (where the same record was found in both the CDR and AMR repository).

Episodes of infection were defined and enumerated after removing reports for multiple specimens and specimen sites within a 6-week period per patient. If more than one isolate was collected from a patient, where resistance or antimicrobial susceptibility testing profiles differed, the resistant code was preferentially kept. Isolates with an ocular specimen site were removed prior to restricting isolates to one episode per 6-week period.

In primary diagnostic laboratories, ceftriaxone and cefixime susceptibility is occasionally inferred by testing cefuroxime as a proxy cephalosporin. If a gonococcus is found to be susceptible to cefuroxime it may thus be reported susceptible to ceftriaxone or cefixime. If, conversely, the isolate is resistant to cefuroxime, resistance to ceftriaxone or cefixime cannot be inferred and laboratories should use a gradient strip method to determine the ceftriaxone or cefixime MIC. Therefore, where the ceftriaxone or cefixime susceptibility results were missing and cefuroxime susceptibility was reported, susceptibility to ceftriaxone or cefixime result was recorded. Where the ceftriaxone or cefixime susceptibility results were missing and resistance to cefuroxime was reported, the ceftriaxone or cefixime result was recorded as missing since there was no way to verify whether ceftriaxone resistance was present.

Isolates reported to SGSS as ceftriaxone-resistant by laboratories across England were linked to the STIRL database based on available patient information. This was used to calculate the percentage of isolates successfully referred to and confirmed as resistant (or not) by STIRL.

Appendix 2. Methods for WGS

Genomic DNA was extracted and prepared for sequencing using the Nextera DNA library preparation kits. Sequencing was performed using the standard 2 × 101 base pairs (bp) protocol on Illumina sequencing instruments. The generated reads were quality filtered and had Illumina adapters removed using Trimmomatic. Good-quality reads were screened with Kraken to detect contaminations and de novo assembled with St. Petersburg genome assembler (SPAdes) using default parameters. MLST, NG-MAST and NG-STAR types of sequenced isolates were determined with an in-house pipeline that uses a Blast-based approach to interrogate the assembled genomes with publicly available reference sequences (Public databases for molecular typing and microbial genome diversity (PubMLST) and NG-STAR).

PenA alleles were determined according to the NG-STAR database. Known antimicrobial resistance determinants (AMRFinderPlus - Pathogen Detection developed by the National Center for Biotechnology Information (NCBI) were searched against assembled genomes using Blastn and confirmed with a mapping-based approach.

Appendix 3. Antimicrobial resistance by individuals’ characteristics

Table 6. Antimicrobial resistance by individuals’ characteristics for GBMSM, GRASP sentinel surveillance system, 2022 [note 1]

Characteristics	Total GBMSM	Azithromycin	Ciprofloxacin	Penicillin	Tetracycline
Resistant isolates	852	215	630	134	584
Aged 15 to 19 years	14	3 (21.4%)	9 (64.3%)	0 (0.0%)	9 (64.3%)
Aged 20 to 24 years	124	27 (21.8%)	92 (74.2%)	16 (12.9%)	77 (62.1%)
Aged 25 to 34 years	392	103 (26.3%)	290 (74.0%)	62 (15.8%)	271 (69.1%)
Aged 35 to 44 years	201	41 (20.4%)	155 (77.1%)	37 (18.4%)	137 (68.2%)
Aged 45 years and over	121	41 (33.9%)	84 (69.4%)	19 (15.7%)	90 (74.4%)
Ethnic group: white	556	150 (27.0%)	413 (74.3%)	84 (15.1%)	382 (68.7%)
Ethnic group: black Caribbean	25	5 (20.0%)	16 (64.0%)	4 (16.0%)	15 (60.0%)
Ethnic group: black African	27	6 (22.2%)	15 (55.6%)	5 (18.5%)	16 (59.3%)
Ethnic group: black other	4	0 (0.0%)	3 (75.0%)	0 (0.0%)	2 (50.0%)
Ethnic group: Asian (including Chinese)	51	6 (11.8%)	45 (88.2%)	12 (23.5%)	32 (62.7%)
Ethnic group: other	33	9 (27.3%)	29 (87.9%)	5 (15.2%)	26 (78.8%)
Ethnic group: mixed	63	17 (27.0%)	42 (66.7%)	8 (12.7%)	49 (77.8%)
Ethnic group: not reported	93	22 (23.7%)	67 (72.0%)	16 (17.2%)	62 (66.7%)
Residence: outside London	316	96 (30.4%)	245 (77.5%)	46 (14.6%)	221 (69.9%)
Residence: London	536	119 (22.2%)	385 (71.8%)	88 (16.4%)	363 (67.7%)
HIV status: negative	738	184 (24.9%)	547 (74.1%)	117 (15.9%)	505 (68.4%)
HIV status: positive	99	26 (26.3%)	72 (72.7%)	14 (14.1%)	68 (68.7%)
HIV status: not reported	15	5 (33.3%)	11 (73.3%)	3 (20.0%)	11 (73.3%)
Symptoms: no discharge and/or dysuria	481	121 (25.2%)	348 (72.3%)	84 (17.5%)	330 (68.6%)
Symptoms: yes (discharge and/or dysuria)	367	93 (25.3%)	278 (75.7%)	49 (13.4%)	250 (68.1%)
Symptom: not reported	4	1 (25.0%)	4 (100.0%)	1 (25.0%)	4 (100.0%)
Previously diagnosed with gonorrhoea: no	307	84 (27.4%)	218 (71.0%)	45 (14.7%)	220 (71.7%)
Previously diagnosed with gonorrhoea: yes	395	98 (24.8%)	298 (75.4%)	61 (15.4%)	263 (66.6%)
Previously diagnosed with gonorrhoea: not reported	150	33 (22.0%)	114 (76.0%)	28 (18.7%)	101 (67.3%)
Total sexual partners (past 3 months): 0 to 1	151	49 (32.5%)	122 (80.8%)	18 (11.9%)	96 (63.6%)
Total sexual partners (past 3 months): 2 to 5	256	66 (25.8%)	193 (75.4%)	41 (16.0%)	177 (69.1%)
Total sexual partners (past 3 months): 6 to 10	53	12 (22.6%)	45 (84.9%)	13 (24.5%)	43 (81.1%)
Total sexual partners (past 3 months): 11 and over	39	11 (28.2%)	28 (71.8%)	2 (5.1%)	30 (76.9%)
Total sexual partners (past 3 months): not reported	353	77 (21.8%)	242 (68.6%)	60 (17.0%)	238 (67.4%)
Sex abroad (past 3 months): no	482	132 (27.4%)	376 (78.0%)	72 (14.9%)	332 (68.9%)
Sex abroad (past 3 months): yes	17	6 (35.3%)	12 (70.6%)	2 (11.8%)	14 (82.4%)
Sex abroad (past 3 months): not reported	353	77 (21.8%)	242 (68.6%)	60 (17.0%)	238 (67.4%)

Note for Table 6:

Note 1: no isolates were resistant to ceftriaxone or spectinomycin in the 2022 sentinel surveillance collection. Data not included for cefixime due to small numbers (n=2). Percentages are row % however, as individuals can have isolates resistant to more than one antimicrobial, they will not equal 100%.

Table 7. Antimicrobial resistance by individuals’ characteristics for heterosexual men, GRASP sentinel surveillance system, 2022 [note 1]

Characteristics	Total heterosexual men	Azithromycin	Ciprofloxacin	Penicillin	Tetracycline
Resistant isolates	295	48	119	39	161
Aged 15 to 19 years	25	4 (16.0%)	4 (16.0%)	0 (0.0%)	10 (40.0%)
Aged 20 to 24 years	109	9 (8.3%)	42 (38.5%)	13 (11.9%)	54 (49.5%)
Aged 25 to 34 years	97	16 (16.5%)	42 (43.3%)	17 (17.5%)	59 (60.8%)
Aged 35 to 44 years	46	14 (30.4%)	18 (39.1%)	5 (10.9%)	25 (54.3%)
Aged 45 years and over	18	5 (27.8%)	13 (72.2%)	4 (22.2%)	13 (72.2%)
Ethnic group: white	94	16 (17.0%)	36 (38.3%)	12 (12.8%)	47 (50.0%)
Ethnic group: black Caribbean	28	6 (21.4%)	10 (35.7%)	2 (7.1%)	12 (42.9%)
Ethnic group: black African	34	3 (8.8%)	15 (44.1%)	6 (17.6%)	24 (70.6%)
Ethnic group: black other	8	1 (12.5%)	2 (25.0%)	1 (12.5%)	2 (25.0%)
Ethnic group: Asian (including Chinese)	10	1 (10.0%)	3 (30.0%)	3 (30.0%)	8 (80.0%)
Ethnic group: other	11	2 (18.2%)	2 (18.2%)	0 (0.0%)	5 (45.5%)
Ethnic group: mixed	23	3 (13.0%)	10 (43.5%)	4 (17.4%)	13 (56.5%)
Ethnic group: not reported	87	16 (18.4%)	41 (47.1%)	11 (12.6%)	50 (57.5%)
Residence: outside London	220	35 (15.9%)	87 (39.5%)	30 (13.6%)	121 (55.0%)
Residence: London	75	13 (17.3%)	32 (42.7%)	9 (12.0%)	40 (53.3%)
HIV status: negative	262	37 (14.1%)	104 (39.7%)	38 (14.5%)	138 (52.7%)
HIV status: positive	5	1 (20.0%)	3 (60.0%)	0 (0.0%)	3 (60.0%)
HIV status: not reported	28	10 (35.7%)	12 (42.9%)	1 (3.6%)	20 (71.4%)
Symptoms: no discharge and/or dysuria	49	5 (10.2%)	18 (36.7%)	3 (6.1%)	23 (46.9%)
Symptoms: yes (discharge and/or dysuria)	246	43 (17.5%)	101 (41.1%)	36 (14.6%)	138 (56.1%)
Previously diagnosed with gonorrhoea: no	144	23 (16.0%)	50 (34.7%)	20 (13.9%)	78 (54.2%)
Previously diagnosed with gonorrhoea: yes	37	8 (21.6%)	18 (48.6%)	2 (5.4%)	21 (56.8%)
Previously diagnosed with gonorrhoea: not reported	114	17 (14.9%)	51 (44.7%)	17 (14.9%)	62 (54.4%)
Total sexual partners (past 3 months): 0 to 1	127	21 (16.5%)	49 (38.6%)	18 (14.2%)	71 (55.9%)
Total sexual partners (past 3 months): 2 to 5	114	19 (16.7%)	47 (41.2%)	15 (13.2%)	62 (54.4%)
Total sexual partners (past 3 months): 6 to 10	10	2 (20.0%)	0 (0.0%)	0 (0.0%)	3 (30.0%)
Total sexual partners (past 3 months): 11 and over	4	1 (25.0%)	2 (50.0%)	1 (25.0%)	0 (0.0%)
Total sexual partners (past 3 months): not reported	40	5 (12.5%)	21 (52.5%)	5 (12.5%)	25 (62.5%)
Sex abroad (past 3 months): no	243	38 (15.6%)	93 (38.3%)	32 (13.2%)	129 (53.1%)
Sex abroad (past 3 months): yes	12	5 (41.7%)	5 (41.7%)	2 (16.7%)	7 (58.3%)
Sex abroad (past 3 months): not reported	40	5 (12.5%)	21 (52.5%)	5 (12.5%)	25 (62.5%)

Note for Table 7:

Note 1: no isolates were resistant to ceftriaxone or spectinomycin in the 2022 sentinel surveillance collection. Data not included for cefixime due to small numbers (n=2). Percentages are row % however, as individuals can have isolates resistant to more than one antimicrobial, they will not equal 100%.

Table 8. Antimicrobial resistance by individuals’ characteristics for women, GRASP sentinel surveillance system, 2022 [note 1]

Characteristics	Total women	Azithromycin	Ciprofloxacin	Penicillin	Tetracycline
Resistant isolates	250	28	73	17	119
Aged 15 to 19 years	41	4 (9.8%)	7 (17.1%)	0 (0.0%)	19 (46.3%)
Aged 20 to 24 years	108	13 (12.0%)	29 (26.9%)	7 (6.5%)	43 (39.8%)
Aged 25 to 34 years	82	7 (8.5%)	29 (35.4%)	8 (9.8%)	45 (54.9%)
Aged 35 to 44 years	13	2 (15.4%)	7 (53.8%)	2 (15.4%)	9 (69.2%)
Aged 45 years and over	6	2 (33.3%)	1 (16.7%)	0 (0.0%)	3 (50.0%)
Ethnic group: white	145	20 (13.8%)	36 (24.8%)	8 (5.5%)	66 (45.5%)
Ethnic group: black Caribbean	7	0 (0.0%)	0 (0.0%)	0 (0.0%)	3 (42.9%)
Ethnic group: black African	6	0 (0.0%)	3 (50.0%)	1 (16.7%)	4 (66.7%)
Ethnic group: black other	3	0 (0.0%)	1 (33.3%)	0 (0.0%)	1 (33.3%)
Ethnic group: Asian (including Chinese)	10	1 (10.0%)	6 (60.0%)	2 (20.0%)	9 (90.0%)
Ethnic group: other	4	2 (50.0%)	1 (25.0%)	0 (0.0%)	3 (75.0%)
Ethnic group: mixed	12	0 (0.0%)	3 (25.0%)	1 (8.3%)	4 (33.3%)
Ethnic group: not reported	63	5 (7.9%)	23 (36.5%)	5 (7.9%)	29 (46.0%)
Residence: outside London	194	18 (9.3%)	50 (25.8%)	14 (7.2%)	92 (47.4%)
Residence: London	56	10 (17.9%)	23 (41.1%)	3 (5.4%)	27 (48.2%)
HIV status: negative	214	22 (10.3%)	62 (29.0%)	16 (7.5%)	102 (47.7%)
HIV status: positive	1	1 (100.0%)	0 (0.0%)	0 (0.0%)	1 (100.0%)
HIV status: not reported	35	5 (14.3%)	11 (31.4%)	1 (2.9%)	16 (45.7%)
Symptoms: no discharge and/or dysuria	125	13 (10.4%)	38 (30.4%)	9 (7.2%)	57 (45.6%)
Symptoms: yes (discharge and/or dysuria)	125	15 (12.0%)	35 (28.0%)	8 (6.4%)	62 (49.6%)
Previously diagnosed with gonorrhoea: no	139	15 (10.8%)	33 (23.7%)	10 (7.2%)	64 (46.0%)
Previously diagnosed with gonorrhoea: yes	31	6 (19.4%)	14 (45.2%)	2 (6.5%)	19 (61.3%)
Previously diagnosed with gonorrhoea: not reported	80	7 (8.8%)	26 (32.5%)	5 (6.3%)	36 (45.0%)
Total sexual partners (past 3 months): 0 to 1	149	18 (12.1%)	46 (30.9%)	9 (6.0%)	71 (47.7%)
Total sexual partners (past 3 months): 2 to 5	61	3 (4.9%)	14 (23.0%)	4 (6.6%)	28 (45.9%)
Total sexual partners (past 3 months): 6 to 10	5	1 (20.0%)	2 (40.0%)	0 (0.0%)	3 (60.0%)
Total sexual partners (past 3 months): 11 and over	1	0 (0.0%)	0 (0.0%)	0 (0.0%)	1 (100.0%)
Total sexual partners (past 3 months): not reported	34	6 (17.6%)	11 (32.4%)	4 (11.8%)	16 (47.1%)
Sex abroad (past 3 months): no	204	22 (10.8%)	59 (28.9%)	13 (6.4%)	101 (49.5%)
Sex abroad (past 3 months): yes	12	0 (0.0%)	3 (25.0%)	0 (0.0%)	2 (16.7%)
Sex abroad (past 3 months): not reported	34	6 (17.6%)	11 (32.4%)	4 (11.8%)	16 (47.1%)

Note for Table 8:

Note 1: no isolates were resistant to ceftriaxone or spectinomycin in the 2022 sentinel surveillance collection. Data not included for cefixime due to small numbers (n=2). Percentages are row % however, as individuals can have isolates resistant to more than one antimicrobial, they will not equal 100%.

Appendix 4. Ethnic categories

The ethnic categories used in this report are as specified by the Office for National Statistics (ONS). Data is presented by disaggregated ethnic groups among people of black ethnicity to highlight the variability in rates among the ethnic group experiencing the highest rates of the most commonly diagnosed STIs. People of Asian, mixed, other and white ethnicity are presented as aggregated ethnic groups for comparison (13). The ethnicities included in each of the aggregated ethnic groups are presented below.

List of ethnicities by ethnic category

White:

• British
• Irish
• any other white background

Mixed:

• white and black Caribbean
• white and black African
• white and Asian
• any other mixed background

Asian or Asian British:

• Indian
• Pakistani
• Bangladeshi
• Chinese
• any other Asian background

Black or black British:

• Caribbean
• African
• any other black background

Other ethnic groups:

• any other ethnic group

References

1. Fifer H, Saunders J, Soni S, Sadiq ST, and FitzGerald M. ‘2018 UK national guideline for the management of infection with Neisseria gonorrhoeae’. International Journal of STD and AIDS 2020; volume 31: pages 4 to 15 (accessed 27 September 2023)

2. UKHSA. ‘Sexually transmitted infections and screening for chlamydia in England: 2021 report’ (accessed 27 September 2023)

3. UKHSA. ‘GUMCAD STI Surveillance System’ (accessed 27 September 2023)

4. Mohammed H, Blomquist P, Ogaz D, Duffell S and others. ‘100 years of STIs in the UK: a review of national surveillance data’. Sexually Transmitted Infections. 2018; volume 94: pages 553 to 558 (accessed 27 September 2023)

5. UKHSA. ‘Gonococcal resistance to antimicrobials surveillance programme (GRASP) protocol’ (accessed 27 September 2023)

6. UKHSA. ‘Notifiable diseases and causative organisms: how to report’ (accessed 25 October 2022)

7. European Committee on Antimicrobial Susceptibility Testing (EUCAST). ‘Clinical breakpoints - breakpoints and guidance’ (accessed 27 September 2023)

8. UKHSA. ‘Surveillance of antimicrobials resistance in Neisseria gonorrhoeae, 2016’ (accessed 27 September 2023)

9. Day Michaela, Pitt Rachel, Mody Nisha, Saunders John, Rai Rupa, Nori Achyuta and others. ‘Detection of 10 cases of ceftriaxone-resistant Neisseria gonorrhoeae in the United Kingdom, December 2021 to June 2022’ Eurosurveillance. 2022; volume 27 (accessed 27 September 2023)

10. Pitt R, Merrick R, Donaldson H, Rayment M, Day M, Cole M, and others. ‘P91 Increasing tetracycline resistance in Neisseria gonorrhoeae in England: investigating possible clinic-epidemiological associations’. Sexually Transmitted Infections 2022; volume 98: pages A65- to A66 (accessed 27 September 2023)

11. Unemo M, Lahra MM, Escher M, Eremin S, Cole MJ, Galarza P, and others. ‘WHO global antimicrobial resistance surveillance for Neisseria gonorrhoeae 2017 to 18: a retrospective observational study’. Lancet Microbe 2021; volume 2: pages 627 to 636 (accessed 27 September 2023)

12. Merrick R, Cole M, Pitt R, Enayat Q, Ivanov Z, Day M, and others. ‘Antimicrobial-resistant gonorrhoea: the national public health response, England, 2013 to 2020’. Eurosurveillance 2022; volume 27 (accessed 27 September 2023)

13. ONS. ‘2001 to 2011 Census in England and Wales questionnaire comparability’. December 2012, ONS (accessed 27 September 2023)

Acknowledgements 

GRASP would like to thank the collaborating centres and the advisory group for their continued support, SHSs for the prompt submission of clinical data and laboratories for sending isolates to the national STI reference laboratory at the UKHSA, Colindale.  

Advisory group 

• DM Livermore
• C Ison
• E Jungmann
• H Donaldson
• H Fifer
• H Mohammed
• J Ross
• J Shepherd
• K Sinka
• K Templeton
• M Cole
• M Rayment
• R Browne
• R Pitt
• T Sadiq 

Collaborating centres 

• Birmingham (H Ahmed, R Chaudhry, M Smith-Banks, S Jog, J Phattey, S Brown, J Ross)
• Bristol (S Brazier, M Williams, J Gabb, A Wolujewicz)
• Brighton (C McKeon, K Parker, C Reynolds, S Curtis, G Dean, S Soni)
• Cambridgeshire (C Krause, E Hodges, H Donson, M Grayson, S Ellam, H Vyse-White, G Peters, J Brady)
• Cardiff (J Richards, L Davies, R Howe, M Wootton, R Drayton)
• Falcon Road (E Bird, C Wilson, L Birycki, L Aitken, P Wezka, K Stegmann, M Grayson, S Ellam, H Vyse-White, G Peters, J Brady)
• Gloucester (J Lewis, A Read, J Boyes, A Godwin, A DeBurgh-Thomas)
• Homerton (P Horne, P Zachary, S Zetie, J Ofori-Boateng, F Abbs N Marshall, N North, D Ball, T Karadag)
• King’s (A Ratnappuli, N Kaur, N Pitto, T Kamvumbi, C McDonald, M Brady, G MacMillan, K Stocker, M Brown)
• Leeds (S Birdi, F Windebank, A Evans, K Sibson, N Foster)
• Liverpool (A Elmer, G McCarthy, E Clarke, H Carney, J Anson)
• London Charing Cross, Chelsea and Westminster (S Goonesekera, S Shah, A Bari, H Donaldson, A Colcutt, B Cookhorn, K Bide, N Chapman, F Ahmed A McOwan, I Mavropoulos, N Jeyapalan, J Greenham, I Clapp, S OConnor, R Pite, G Whitlock, S Goh, V Beesley, G McDonald, R Wilson, T Carvalho, C Scott)
• Luton (K Zyla, S Mottershaw, R Wood, J Turner, D Karim, R Mulla)
• Manchester (H Heapy, S Flaherty, E Sandham, A Sukthankar, L Devine, Z Jeffrey, J Birtles, A Qamruddin)
• Newcastle (M Knops, A Oliver, C Cullerton, A Geering, S Mattu, D Weiland)
• Newport (C Knapper, J Bendle, C Barret, N Berry)
• Northampton (M Kelly, L Riddell, T Streeter, E Chiriseri, M Ntoumpanaki)
• Nottingham (M Pammi, J Deery, B Mistry, J Bowskill)
• Sheffield (C Megson, A Carr, R Matcham, H Parsons, C Turnock, C Dewsnap)
• St Mary’s (O Dosekun, S Goonesekera, S Shah, A Bari, H Donaldson)
• Central and North West London (L Matthews, M Nur, M Mansoor, E Jungmann, R Browne, M Grayson, S Ellam, H Vyse-White, G Peters, J Brady)
• Wolverhampton (S Lovegrove, J Hudson, D Dobie, K Whitehouse, R McCathie)
• Woolwich (D Ward, S Kegg, S Allen, P Merrett, M Dall’Antonia)