Prevalence of and factors associated with MDR Neisseria gonorrhoeae in England and Wales between 2004 and 2015: analysis of annual cross-sectional surveillance surveys

Prevalence of and factors associated with MDR Neisseria gonorrhoeae in England and Wales between... Abstract Objectives To describe trends in prevalence, susceptibility profile and risk factors for MDR Neisseria gonorrhoeae (MDR-NG) in England and Wales. Methods Isolates from 16 242 gonorrhoea episodes at sexual health clinics within the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) underwent antimicrobial susceptibility testing. MDR-NG was defined as resistance to ceftriaxone, cefixime or azithromycin, plus at least two of penicillin, ciprofloxacin and spectinomycin. Trends in resistance are presented for 2004–15; prevalence and logistic regression analyses for MDR-NG cover the period of the most recent treatment guideline (ceftriaxone plus azithromycin), 2011–15. Results Between 2004 and 2015, the proportion of N. gonorrhoeae isolates fully susceptible to all antimicrobial classes fell from 80% to 46%, with the proportion resistant to multiple (two or more) classes increasing from 7.3% to 17.5%. In 2011–15, 3.5% of isolates were MDR-NG, most of which were resistant to cefixime (100% in 2011, decreasing to 36.9% in 2015) and/or azithromycin (4.2% in 2011, increasing to 84.3% in 2015). After excluding azithromycin-resistant isolates, modal azithromycin MICs were higher in MDR versus non-MDR isolates (0.5 versus 0.125 mg/L), with similar results for ceftriaxone (modal MICs 0.03 versus ≤0.002 mg/L). After adjustment for confounders, MDR-NG was more common among isolates from heterosexual men, although absolute differences in prevalence were small [4.6% versus 3.3% (MSM) and 2.5% (women)]. Conclusions N. gonorrhoeae is becoming less susceptible to available antimicrobials. Since 2011, a minority of isolates were MDR-NG; however, MICs of azithromycin or ceftriaxone (first-line therapies) for many of these were elevated. These findings highlight the importance of continued antimicrobial stewardship for gonorrhoea. Introduction Gonorrhoea, caused by the bacterium Neisseria gonorrhoeae, is the second most commonly diagnosed bacterial sexually transmitted infection (STI) in England.1 Although estimated prevalence in community settings in Britain is low (<0.1%),2 recent years have seen worrying increases in diagnoses among MSM.1,3 The history of rapid development of resistance to antimicrobials used for treatment has made antimicrobial-resistant (AMR) N. gonorrhoeae a major global health concern and a priority area for Public Health England (PHE).4–9 Extended-spectrum cephalosporins (ESCs) are the most recent class of antimicrobial introduced to treat gonorrhoea and represent a ‘last-line’ treatment option, with no new antimicrobials available and few in development.4,5,9,10 Since 2011, recommended first-line treatment in the UK has been dual therapy with 500 mg of intramuscularly injectable ceftriaxone (an ESC) plus 1 g of oral azithromycin, in an attempt to prevent sustained resistance to ESCs becoming established,10,11 an approach which has been implemented in many other regions globally.12 Although resistance to ceftriaxone is rare, recent increases in azithromycin resistance have been described, including high-level resistance.13,14 There is also evidence of N. gonorrhoeae becoming gradually less susceptible to ceftriaxone,15 and the first reported global case of dual treatment failure was also detected in the UK.16 Many have now highlighted that MDR N. gonorrhoeae (MDR-NG) poses a serious threat and untreatable gonorrhoea is an increasingly plausible prospect.5,7,9,10 It is critical to understand the epidemiology of AMR N. gonorrhoeae to inform treatment guidelines and prevention and control measures, in addition to wider gonorrhoea prevention efforts.4,7,17 The Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) was established in 2000 to monitor trends and provide information on determinants of AMR N. gonorrhoeae in England and Wales18 and combines susceptibility data with demographic, behavioural and clinical information from those diagnosed with gonorrhoea at selected specialist sexual health services. GRASP has provided detailed insight into patterns of antimicrobial resistance in N. gonorrhoeae and informed changes to treatment guidelines.10,19 To date, GRASP data on trends and risk factors for individual antimicrobials have been reported, 13,15,20,21 but detailed analyses of MDR-NG have not. This project seeks to fill this knowledge gap by investigating the prevalence, resistance profile and risk factors for MDR-NG in England and Wales in order to understand implications for the future treatment of gonorrhoea and contribute to the scant epidemiological literature on MDR-NG.7,22–27 Methods Ethics and governance PHE has permission to handle data obtained by GRASP under section 251 of the UK National Health Service Act of 2006, which was renewed annually by the Ethics and Confidentiality Committee of the National Information Governance Board until 2013. Since then, the power of approval of public health surveillance activity has been granted directly to PHE. Data sources Detailed descriptions of GRASP methodology have been published previously.13 Briefly, isolates from individuals with gonorrhoea attending 27 specialist sexual health clinics in England and Wales during a three-month period each summer between 2004 and 2015 were cultured and submitted to PHE for susceptibility testing. An agar dilution method was used to determine MICs of ceftriaxone, cefixime, spectinomycin, azithromycin, penicillin and ciprofloxacin. Susceptibility data were matched to demographic, clinical and behavioural data submitted by the clinics. All patients diagnosed with gonorrhoea during this period were eligible for inclusion; however, approximately half of episodes did not have susceptibility data due to culture not being attempted or culture not being successful.28 Azithromycin MIC data The diagnostic susceptibility test (DST) medium used for susceptibility testing for GRASP isolates was changed in 2015, whereupon MICs of azithromycin, and subsequently the proportion of resistant isolates, increased.13 A validation study compared the MICs determined by the new and old DST agars and found MICs of azithromycin were higher by approximately one dilution using the new DST medium. The new DST medium provided better pH and physiological conditions for growth of fastidious strains of N. gonorrhoeae which subsequently resulted in more reliable azithromycin MIC determination; this was also confirmed by local quality assurance data.13 Azithromycin MIC data for 2013 and 2014 (the years in which the problems with growth on the old DST medium were seen) were therefore adjusted upwards by a factor of one dilution to enable more accurate description of trends over time. Definition of MDR-NG Defining MDR-NG is challenging due to differences in first-line treatments over time and internationally. We therefore present analyses of: (i) patterns of AMR N. gonorrhoeae over time, including resistance or decreased susceptibility to multiple classes of antimicrobials, to facilitate international and longer-term comparisons; and (ii) MDR-NG defined as relevant to current clinical practice in the UK. For the latter, we adapted the working definition proposed by Tapsall et al.7 (2009): resistance or decreased susceptibility to one or more antimicrobial in widespread use to treat gonorrhoea (category 1) and resistance to two or more antimicrobials in less frequent use/little use but proposed for more frequent use (category 2). The original Tapsall et al.7 definition included spectinomycin in category 1 and azithromycin in category 2; we updated this based on currently recommended therapies in the UK (Table 1). Although cefixime has not been recommended for treatment of N. gonorrhoeae since 2011, we retained it in category 1 as it is an ESC. Table 1. Category of antibiotic and MIC thresholds used to define resistance or decreased susceptibility in GRASP   MIC breakpoint for resistance (R) or decreased susceptibility (DS)  Category 1 antibiotics   ceftriaxoneDS  >0.06 mg/L   cefiximeDS  >0.06 mg/L   azithromycinR  >0.5 mg/L  Category 2 antibiotics   ciprofloxacinR  >0.5 mg/L   penicillinR  >0.5 mg/L or β-lactamase positive   spectinomycinR  >64 mg/L    MIC breakpoint for resistance (R) or decreased susceptibility (DS)  Category 1 antibiotics   ceftriaxoneDS  >0.06 mg/L   cefiximeDS  >0.06 mg/L   azithromycinR  >0.5 mg/L  Category 2 antibiotics   ciprofloxacinR  >0.5 mg/L   penicillinR  >0.5 mg/L or β-lactamase positive   spectinomycinR  >64 mg/L  GRASP standard breakpoints.13 Decreased susceptibility, rather than ‘resistance’, is used in GRASP for ESCs as treatment failures have been observed across a range of MIC values in some patients but not others. Descriptive and statistical analyses Descriptive analyses were used to examine trends in AMR N. gonorrhoeae for 2004–15. Analysis of MDR-NG was restricted to 2011 onwards, to reflect prevalence and risk factors relevant to current treatment guidelines. Modal ceftriaxone and azithromycin MICs were compared between MDR and non-MDR isolates to assess whether there was a drift towards resistance to first-line therapies in MDR-NG among those not yet resistant to these antimicrobials. As resistance to ceftriaxone or azithromycin is included in the definition of MDR-NG, these sub-analyses excluded all isolates which already had decreased susceptibility to ceftriaxone (for comparison of ceftriaxone MICs) or resistance to azithromycin (for comparison of azithromycin MICs). For the risk factor analysis, logistic regression was used to generate ORs initially adjusted for year, age (as a quadratic term, to account for the non-linear relationship) and gender/sexual orientation (groupings: MSM, heterosexual men, all women). Associations with the following variables were examined: ethnicity, residential neighbourhood-level index of multiple deprivation (IMD), number of recent sexual partners (past 3 months), recent sex abroad (past 3 months), previous gonorrhoea infection, symptomatic infection, clinician-coded site of infection, concurrent STIs and HIV status. Multivariable logistic regression analyses were used to determine independent associations, using a forwards model-building approach, with variables retained in the final model based on a P value of ≤0.10. Exploratory analysis showed evidence of within-clinic (but not within-patient) clustering of MDR-NG, i.e. there was greater similarity in MDR-NG between isolates collected within the same clinic than at different clinics. To avoid this resulting in underestimated standard errors, clustering was accounted for in the risk factor analysis using generalized estimating equations under the assumption of an exchangeable correlation matrix.29 Results Sample characteristics Between 2004 and 2015, 16 242 isolates from 15 781 patients underwent susceptibility testing, with 47.4% of isolates from MSM, 28.2% from heterosexual men and 20.6% from women (Table S1, available as Supplementary data at JAC Online). Patterns of antimicrobial resistance in GRASP 2004–15 Resistance to azithromycin was generally low until 2012 (<5%), then increased to 9.8% in 2015 (Figure 1). Decreased susceptibility to ceftriaxone was rare (0.1%), whereas levels of decreased susceptibility to cefixime increased rapidly between 2008 and 2010 (from 3% to 17%), then decreased to 1.1% in 2015 (Figure 1). Resistance to penicillin and ciprofloxacin was widespread (>10%) throughout the study period. Figure 1. View largeDownload slide Percentage of N. gonorrhoeae isolates with antimicrobial resistance/decreased susceptibility, by year, England and Wales, GRASP 2004–15 (n = 16 242). Note: azithromycin data for 2013–14 adjusted to account for poor growth on the DST medium leading to underestimation of azithromycin MIC in those years (see the Methods section for further details). This figure appears in colour in the online version of JAC and in black and white in the print version of JAC. Figure 1. View largeDownload slide Percentage of N. gonorrhoeae isolates with antimicrobial resistance/decreased susceptibility, by year, England and Wales, GRASP 2004–15 (n = 16 242). Note: azithromycin data for 2013–14 adjusted to account for poor growth on the DST medium leading to underestimation of azithromycin MIC in those years (see the Methods section for further details). This figure appears in colour in the online version of JAC and in black and white in the print version of JAC. Between 2004 and 2015, the proportion of N. gonorrhoeae isolates fully susceptible to all classes of antimicrobials fell from 80% to 46%, with the proportion resistant to multiple (two or more) classes increasing from 7.3% to 17.5% (Figure 2). Resistance to three classes increased between 2008 and 2010 then declined, mirroring trends in cefixime resistance (Figures 1 and 2). A small number of isolates were resistant to all four classes tested (n = 49; 0.3% overall). Figure 2. View largeDownload slide Percentage of N. gonorrhoeae isolates resistant to 0, 1, 2, 3 or 4 classes of antimicrobials, by year, England and Wales, GRASP 2004–15 (n = 16 242). Classes of antimicrobials: (i) ESC (cefixime and ceftriaxone); (ii) macrolide (azithromycin); (iii) fluoroquinolone (ciprofloxacin); (iv) penicillin; and (v) aminoglycoside (spectinomycin). a2013–14 estimates calculated using adjusted azithromycin data. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC. Figure 2. View largeDownload slide Percentage of N. gonorrhoeae isolates resistant to 0, 1, 2, 3 or 4 classes of antimicrobials, by year, England and Wales, GRASP 2004–15 (n = 16 242). Classes of antimicrobials: (i) ESC (cefixime and ceftriaxone); (ii) macrolide (azithromycin); (iii) fluoroquinolone (ciprofloxacin); (iv) penicillin; and (v) aminoglycoside (spectinomycin). a2013–14 estimates calculated using adjusted azithromycin data. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC. Despite high levels of susceptibility to prevailing first-line therapies immediately following revisions to treatment guidelines in 2005 (from ciprofloxacin to cefixime)30 and 2011 (from cefixime to ceftriaxone and azithromycin dual therapy),11 the proportion of isolates fully susceptible to first-line therapies declined in the following years, from 99.9% in 2005 to 82.9% in 2010 and from 99.5% in 2011 to 90.2% in 2015 (Figure 3). Figure 3. View largeDownload slide Percentage of isolates fully susceptible to recommended first-line therapya, England and Wales, GRASP 2004–15 (n = 16 242). aRecommended first-line therapies: ciprofloxacin (2004), cefixime (2005–10) and ceftriaxone and azithromycin (2011–15). bAzithromycin data for 2013–14 adjusted to account for poor growth on the DST medium leading to underestimation of azithromycin MIC in those years (see the Methods section for further details). Figure 3. View largeDownload slide Percentage of isolates fully susceptible to recommended first-line therapya, England and Wales, GRASP 2004–15 (n = 16 242). aRecommended first-line therapies: ciprofloxacin (2004), cefixime (2005–10) and ceftriaxone and azithromycin (2011–15). bAzithromycin data for 2013–14 adjusted to account for poor growth on the DST medium leading to underestimation of azithromycin MIC in those years (see the Methods section for further details). Prevalence and profile of MDR-NG Between 2011 and 2015, 3.5% (n = 266) of isolates were MDR-NG, with small increases in prevalence between 2011 and 2013 (from 3.7% to 4.5%) followed by a subsequent decrease to 2.2% in 2015 (χ2 test P = 0.004). The profile of resistance to category 1 antimicrobials among MDR-NG isolates changed over time: 100% were resistant to cefixime in 2011, reducing to 36.9% in 2015, with increases in the proportion resistant to azithromycin over this time frame from 4.2% to 84.3% (P < 0.01) (Figure 4). All MDR-NG isolates were resistant to both ciprofloxacin and penicillin, but not spectinomycin, in category 2. Over time, the proportion of MDR-NG resistant to four antimicrobials (cefixime, azithromycin, penicillin and ciprofloxacin) increased from 4.2% in 2011 to 21.1% in 2015. One isolate had resistance/decreased susceptibility to five antimicrobials: ceftriaxone (MIC 0.125 mg/L), cefixime (MIC 0.25 mg/L), azithromycin (MIC 1.0 mg/L), ciprofloxacin (MIC ≥16 mg/L) and penicillin (MIC 1 mg/L). Figure 4. View largeDownload slide Resistance/decreased susceptibility to category 1a antimicrobials among MDR-NG isolates over time, England and Wales, GRASP 2011–15 (n = 266). aCategory 1 antimicrobials: ceftriaxone, cefixime and azithromycin; category 2 antimicrobials: ciprofloxacin, penicillin and spectinomycin. See the Methods section for further details. All MDR-NG isolates were resistant to ciprofloxacin and penicillin in category 2. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC. Figure 4. View largeDownload slide Resistance/decreased susceptibility to category 1a antimicrobials among MDR-NG isolates over time, England and Wales, GRASP 2011–15 (n = 266). aCategory 1 antimicrobials: ceftriaxone, cefixime and azithromycin; category 2 antimicrobials: ciprofloxacin, penicillin and spectinomycin. See the Methods section for further details. All MDR-NG isolates were resistant to ciprofloxacin and penicillin in category 2. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC. In a sub-analysis excluding all isolates with resistance to azithromycin, the MICs of azithromycin for MDR isolates were elevated (modal MIC 0.5 mg/L) compared with those for non-MDR isolates (modal MIC 0.125 mg/L) (Figure 5a). Similarly, after excluding isolates with decreased susceptibility to ceftriaxone, modal ceftriaxone MICs for MDR isolates were higher (0.03 mg/L) than those for non-MDR isolates (≤0.002 mg/L) (Figure 5b). The elevated ceftriaxone MICs among MDR isolates were observed in a further sub-analysis stratified by year [grouped as 2011–13 (n = 176 MDR isolates) and 2014–15 (n = 87 MDR isolates)]; ceftriaxone modal MIC of 0.03 mg/L among MDR isolates versus 0.004 mg/L among non-MDR isolates in both time periods. Figure 5. View largeDownload slide Distribution of MICs of (a) azithromycin and (b) ceftriaxone among MDR-NG and non-MDR-NG isolates not meeting the resistance/decreased susceptibility thresholds for azithromycin and ceftriaxone, respectively, England and Wales, 2011–15. Figure 5. View largeDownload slide Distribution of MICs of (a) azithromycin and (b) ceftriaxone among MDR-NG and non-MDR-NG isolates not meeting the resistance/decreased susceptibility thresholds for azithromycin and ceftriaxone, respectively, England and Wales, 2011–15. Risk factors for MDR-NG MDR-NG was more common among heterosexual men than MSM or women (4.6% versus 3.3% and 2.5%, respectively); these differences remained significant after adjustment for other factors (Table 2). Multivariable analysis also found MDR-NG to be more common among isolates from older patients [adjusted OR (AOR) for those aged ≥45 years: 1.89 (95% CI: 1.25–2.86), compared with those aged ≤24 years] and those reporting recent sex abroad [AOR 1.38 (95% CI: 1.02–1.87)] and less common among isolates from patients who were of black Caribbean ethnicity [AOR 0.26 (95% CI: 0.47–0.87)], were HIV positive [AOR 0.64 (95% CI: 0.47–0.87)] or had a concurrent STI [AOR 0.77 (95% CI: 0.61–0.97)]. Neighbourhood deprivation (IMD) data were not available in GRASP for 2011 and so IMD was not included in the multivariable model; however, a separate multivariable model run on 2012–15 data found no association between MDR-NG and IMD after adjustment for other factors. Table 2. Risk factors for MDR-NG among N. gonorrhoeae isolates, England and Wales, GRASP 2011–15   Total N  n  %  Adjusted for age, year and gender/ sexual orientation   Multivariable model (n = 4027)   AOR1  (95% CI)  AOR2  (95% CI)  All  7562  266  3.5          Year        P = 0.04  P < 0.001   2011  1288  48  3.7  ref    ref     2012  1375  57  4.1  1.16  (0.76–1.66)  1.16  (0.72–1.88)   2013  1636  74  4.5  1.26  (0.77–2.08)  3.86  (2.51–5.94)   2014  1564  49  3.1  0.84  (0.62–1.14)  3.61  (2.43–5.37)   2015  1699  38  2.2  0.64  (0.36–1.11)  0.60  (0.35–1.03)  Gender/sexual orientation        P = 0.02  P = 0.05   heterosexual men  1571  72  4.6  ref    ref     MSM  4683  156  3.3  0.67  (0.45–1.01)  0.76  (0.57–0.99)   women  1123  28  2.5  0.62  (0.42–0.90)  0.66  (0.44–0.99)  Age group (years)        P = 0.13  P = 0.01   ≤24  2337  64  2.7  ref    ref     25–44  4507  173  3.8  1.42  (0.98–2.03)  1.35  (1.01–1.81)   ≥45  714  29  4.1  1.49  (0.96–2.29)  1.89  (1.25–2.86)  Ethnicity        P = 0.01  P = 0.004   white  5187  197  3.8  ref    ref     black Caribbean  580  12  2.1  0.42  (0.21–0.81)  0.26  (0.47–0.87)   black African  281  7  2.5  0.55  (0.25–1.19)  0.87  (0.43–1.76)   black other  180  5  2.8  0.63  (0.24–1.66)  0.27  (0.04–1.78)   Asian (including Chinese)  360  15  4.2  1.04  (0.53–2.06)  1.58  (0.79–3.14)   mixed ethnic group  500  13  2.6  0.63  (0.30–1.32)  0.75  (0.35–1.62)   other ethnic group  181  5  2.8  0.64  (0.25–1.63)  1.00  (1.02–1.87)  Patient’s area-level deprivation (IMD) quintilea        P = 0.09       1 or 2 (least deprived)  698  34  4.9  ref         3  835  26  3.1  0.63  (0.42–0.93)       4  1974  70  3.5  0.71  (0.49–1.04)       5 (most deprived)  2341  73  3.1  0.59  (0.37–0.96)      Number of sexual partners (past 3 months)        P > 0.99       0–1  1974  71  3.6  ref         2–5  3021  112  3.7  0.99  (0.72–1.38)       ≥6  845  30  3.6  1.00  (0.60–1.69)      Sex while abroad (past 3 months)        P = 0.03  P = 0.04   no  5170  175  3.4  ref    ref     yes  670  38  5.7  1.55  (1.04–2.30)  1.38  (1.02–1.87)  Previous gonorrhoea infection        P = 0.69       no  4440  159  3.6  ref         yes  2325  77  3.3  0.95  (0.72–1.25)      Symptoms of gonorrhoeab        P = 0.68       no  1810  59  3.3  ref         yes  4241  162  3.8  1.07  (0.78–1.46)      Clinician-coded site of infectionc                 genital        P = 0.87        no  1848  69  3.7  ref          yes  4644  167  3.6  0.88  (0.62–1.25)       rectal        P = 0.49        no  4027  155  3.8  ref          yes  2480  81  3.3  0.90  (0.68–1.20)       throat        P = 0.06        no  4517  154  3.4  ref          yes  1990  82  4.1  1.43  (0.98–2.09)       other        P = 0.67        no  6338  229  3.6  ref          yes  169  7  4.1  1.31  (0.73–2.34)       multiple sites of infection        P = 0.76        no  4353  160  3.7  ref          yes  2154  76  3.5  1.06  (0.72–1.57)      Concurrent STI (excluding HIV)        P = 0.01  P = 0.03   no  5639  219  3.9  ref    ref     yes  1923  47  2.4  0.66  (0.48–0.90)  0.77  (0.61–0.97)  HIV status        P = 0.002  P = 0.005   negative  3592  141  3.9  ref    ref     positive  1264  31  2.5  0.52  (0.34–0.78)  0.64  (0.47–0.87)    Total N  n  %  Adjusted for age, year and gender/ sexual orientation   Multivariable model (n = 4027)   AOR1  (95% CI)  AOR2  (95% CI)  All  7562  266  3.5          Year        P = 0.04  P < 0.001   2011  1288  48  3.7  ref    ref     2012  1375  57  4.1  1.16  (0.76–1.66)  1.16  (0.72–1.88)   2013  1636  74  4.5  1.26  (0.77–2.08)  3.86  (2.51–5.94)   2014  1564  49  3.1  0.84  (0.62–1.14)  3.61  (2.43–5.37)   2015  1699  38  2.2  0.64  (0.36–1.11)  0.60  (0.35–1.03)  Gender/sexual orientation        P = 0.02  P = 0.05   heterosexual men  1571  72  4.6  ref    ref     MSM  4683  156  3.3  0.67  (0.45–1.01)  0.76  (0.57–0.99)   women  1123  28  2.5  0.62  (0.42–0.90)  0.66  (0.44–0.99)  Age group (years)        P = 0.13  P = 0.01   ≤24  2337  64  2.7  ref    ref     25–44  4507  173  3.8  1.42  (0.98–2.03)  1.35  (1.01–1.81)   ≥45  714  29  4.1  1.49  (0.96–2.29)  1.89  (1.25–2.86)  Ethnicity        P = 0.01  P = 0.004   white  5187  197  3.8  ref    ref     black Caribbean  580  12  2.1  0.42  (0.21–0.81)  0.26  (0.47–0.87)   black African  281  7  2.5  0.55  (0.25–1.19)  0.87  (0.43–1.76)   black other  180  5  2.8  0.63  (0.24–1.66)  0.27  (0.04–1.78)   Asian (including Chinese)  360  15  4.2  1.04  (0.53–2.06)  1.58  (0.79–3.14)   mixed ethnic group  500  13  2.6  0.63  (0.30–1.32)  0.75  (0.35–1.62)   other ethnic group  181  5  2.8  0.64  (0.25–1.63)  1.00  (1.02–1.87)  Patient’s area-level deprivation (IMD) quintilea        P = 0.09       1 or 2 (least deprived)  698  34  4.9  ref         3  835  26  3.1  0.63  (0.42–0.93)       4  1974  70  3.5  0.71  (0.49–1.04)       5 (most deprived)  2341  73  3.1  0.59  (0.37–0.96)      Number of sexual partners (past 3 months)        P > 0.99       0–1  1974  71  3.6  ref         2–5  3021  112  3.7  0.99  (0.72–1.38)       ≥6  845  30  3.6  1.00  (0.60–1.69)      Sex while abroad (past 3 months)        P = 0.03  P = 0.04   no  5170  175  3.4  ref    ref     yes  670  38  5.7  1.55  (1.04–2.30)  1.38  (1.02–1.87)  Previous gonorrhoea infection        P = 0.69       no  4440  159  3.6  ref         yes  2325  77  3.3  0.95  (0.72–1.25)      Symptoms of gonorrhoeab        P = 0.68       no  1810  59  3.3  ref         yes  4241  162  3.8  1.07  (0.78–1.46)      Clinician-coded site of infectionc                 genital        P = 0.87        no  1848  69  3.7  ref          yes  4644  167  3.6  0.88  (0.62–1.25)       rectal        P = 0.49        no  4027  155  3.8  ref          yes  2480  81  3.3  0.90  (0.68–1.20)       throat        P = 0.06        no  4517  154  3.4  ref          yes  1990  82  4.1  1.43  (0.98–2.09)       other        P = 0.67        no  6338  229  3.6  ref          yes  169  7  4.1  1.31  (0.73–2.34)       multiple sites of infection        P = 0.76        no  4353  160  3.7  ref          yes  2154  76  3.5  1.06  (0.72–1.57)      Concurrent STI (excluding HIV)        P = 0.01  P = 0.03   no  5639  219  3.9  ref    ref     yes  1923  47  2.4  0.66  (0.48–0.90)  0.77  (0.61–0.97)  HIV status        P = 0.002  P = 0.005   negative  3592  141  3.9  ref    ref     positive  1264  31  2.5  0.52  (0.34–0.78)  0.64  (0.47–0.87)  AOR1 = AOR, adjusted for year, age (quadratic) and gender/sexual orientation. AOR2 = multivariable model, adjusted for other variables shown. Age adjusted for as a quadratic variable, but AORs and P value presented for age group for ease of interpretation. a IMD was not available for 2011 in GRASP. b Discharge/painful urination (dysuria). c Sites not mutually exclusive. Where patient had multiple infection sites, this site may not correspond to the site that underwent susceptibility testing as only one isolate per patient was included in GRASP. Isolates were prioritized as follows: (i) male rectal; (ii) male urethral; (iii) female cervical; and (iv) any other site. Discussion Our data demonstrate increases in antimicrobial resistance of N. gonorrhoeae over the past decade in England and Wales, with the proportion of N. gonorrhoeae isolates fully susceptible to all classes of antimicrobials falling from 80% in 2004 to 46% in 2015 and the proportion resistant to two or more classes increasing from 7.3% to 17.5% over this period. Despite high levels of susceptibility to recommended treatments immediately following changes to treatment guidelines in 2005 and 2011, the proportion fully susceptible to these decreased in a matter of years. In 2011–15, 3.5% of isolates were classed as MDR-NG, meaning they were resistant to either azithromycin or an ESC, as well as to penicillin and ciprofloxacin. In 2011, MDR-NG isolates were predominantly resistant to cefixime; however, by 2015 the majority were resistant to azithromycin, with around one in five resistant to both. We also found evidence of drift towards azithromycin resistance among MDR-NG isolates that were not resistant to azithromycin and similar drift towards ceftriaxone resistance. The fact that these elevated ceftriaxone MICs in the MDR isolates were observed in 2014–15 as well as 2011–13 suggests this finding is unlikely to be solely due to the cefixime-resistant ST1407 strains that also have elevated ceftriaxone MICs and were prevalent during 2011–13.25 Although the risk factor analysis found MDR-NG was more common among isolates from some groups, including heterosexual men and older patients, absolute differences in prevalence were small, providing little basis for targeted treatment strategies. These findings highlight the importance of continued surveillance and prevention efforts, given the severely limited treatment options available to those with MDR-NG. Advantages of using the GRASP surveillance data include the large sample size, the ability to look at trends over time and the ability to combine MIC data with demographic, clinical and behavioural information. GRASP is reasonably representative of gonorrhoea cases across England, although MSM are somewhat over-represented.31 It is likely that risk characteristics of MSM and heterosexual sexual networks differ, but small numbers of MDR-NG prohibited stratification of risk factor analysis by gender/sexual orientation. Another limitation is the potential for missing data to bias results of the risk factor analysis; for example, completion of behavioural data varied by clinic resulting in more missing data for MSM. Azithromycin MIC data from 2013–14 were adjusted to account for poor organism growth using DST media which underestimated MICs. This adjustment enabled comparisons of antimicrobial resistance over time, but is a crude correction and some misclassification is likely. In line with low levels of resistance to ceftriaxone generally,13 few MDR-NG cases had decreased susceptibility to ceftriaxone. However, MICs of ceftriaxone have been drifting towards resistance in recent years,15 leaving no room for complacency about the long-term effectiveness of current dual therapy. Our analysis found that the ceftriaxone MICs for MDR-NG isolates were higher than for non-MDR isolates, after excluding those with decreased susceptibility to ceftriaxone, demonstrating how easily MDR-NG with resistance to ceftriaxone could emerge and lead to infections that would be difficult to treat. Although all isolates were susceptible to spectinomycin, this is not considered a viable first-line treatment as resistance has historically developed rapidly when it has been used, it is not effective in treating pharyngeal gonorrhoea and it is currently unavailable in many countries.5 It should be borne in mind that 96.5% of isolates were not MDR, which is promising in light of efforts to develop point-of-care antimicrobial resistance testing to guide treatment choices.32 If successful, such tests could identify infections for which previously used therapies would be effective, reducing ceftriaxone use and the selection pressure for resistance. Despite commentaries on the emerging threat of MDR-NG,5,6,33 the international literature on prevalence and risk factors is scant, perhaps due to lack of consensus on an MDR definition, preventing comparison of prevalence and risk factors.22,23,26 In general, the risk factors for MDR-NG identified here are consistent with those associated with resistance to some individual antimicrobials in previous studies, including being a heterosexual man (ciprofloxacin, azithromycin, cefixime),34 the inverse relationships with black Caribbean ethnicity (ciprofloxacin, cefixime),20,21 and concurrent STI infection (ciprofloxacin, cefixime).20,21 However, previous analyses of GRASP data have found a positive association between HIV and N. gonorrhoeae that was resistant to cefixime, ciprofloxacin or penicillin,20,21 in contrast with the inverse relationship with MDR-NG found here. Continued monitoring of the epidemiology of MDR-NG alongside resistance to individual antibiotics is therefore needed. These data emphasize the loss of susceptibility of N. gonorrhoeae to sequential antimicrobial classes used for treatment and provide the first prevalence estimates of MDR-NG in England and Wales. Although prevalence of MDR-NG was relatively low, many of these isolates were resistant to azithromycin and had ceftriaxone MICs that were higher than those for non-MDR isolates. In the context of limited new treatment options, the emergence of ceftriaxone resistance in MDR-NG could herald the prospect of untreatable N. gonorrhoeae. MDR-NG was generally homogeneously distributed by demographic and behavioural characteristics, with no groups identified as being at especially high risk, highlighting the need for continued culture and susceptibility testing and test of cure among all patients with gonorrhoea. Our findings underline the essential role of timely surveillance to identify and respond to clinically significant changes in AMR N. gonorrhoeae in the coming years. Acknowledgements We would like to thank all GRASP collaborators including the following: members of the reference laboratory at PHE (A. Kundu and S. Chisholm), the collaborating centres and the Steering Group for their continued support, GUM clinic staff for the prompt submission of clinical data and laboratories for sending isolates to the reference laboratory at PHE, Colindale. Steering Group D. M. Livermore, C. Bignell, H. Donaldson, B. Macrae, K. Templeton, J. Shepherd, P. French, M. Portman, A. P. Johnson, J. Paul, A. Robinson, J. Ross, J. Wade, C. Ison, G. Hughes, K. Town, N. Woodford, R. Mulla, T. Sadiq, H. Fifer, A. Andreasen and M. Cole. Collaborating centres Birmingham (M. David and J. Ross), Bristol (O. M. Williams and P. Horner), Brighton (M. Cubbon and G. Dean), Cambridge (N. Brown and C. Carne), Cardiff (R. Howe and J. Nicholls), Gloucester (P. Moore and A. DeBurgh-Thomas), Homerton (A. Jepson and M. Nathan), Kings (J. Wade, C. McDonald and M. Brady), Leeds (M. Denton and J. Clarke), Liverpool (J. Anson and M. Bradley), London Charing Cross, Chelsea and Westminster (K. McLean, A. McOwan, G. Paul and H. Donaldson), Luton (R. Mulla and T. Balachandran), Manchester (A. Qamruddin and A. Sukthankar), Newcastle (M. Valappil and K. N. Sankar), Newport (S. Majumdar and H. Birley), Northampton (M. Minassian and L. Riddell), Nottingham (V. Weston, C. Bignell and M. Pammi), Reading (G. Wildman and S. Iyer), Sheffield (L. Prtak, C. Bowman and C. Dewnsap), St George’s (P. Riley and P. Hay), St Mary’s (D. Wilkinson), University College Hospital (B. Macrae, M. Portman and E. Jungmann), Wolverhampton (D. Dobie and A. Tariq) and Woolwich (M. Dall’Antonia and J. Russell). Funding GRASP has been funded totally (2000–04) and partly (2005–10) by the Department of Health (England) and by Public Health England. S. C. was funded to undertake independent research supported by the National Institute for Health Research (NIHR Research Methods Programme, Fellowships and Internships, NIHR-RMFI-2014-05-28). Transparency declarations H. F. is a member of the Scientific Advisory Board for Discuva Ltd. All other authors: none to declare. Disclaimer The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. Supplementary data Table S1 is available as Supplementary data at JAC Online. References 1 PHE. Sexually Transmitted Infections and Chlamydia Screening in England, 2016. Health Protection Report, Volume 11 Number 20. 2017. https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/617025/Health_Protection_Report_STIs_NCSP_2017.pdf. 2 Sonnenberg P, Clifton S, Beddows S et al.   Prevalence, risk factors, and uptake of interventions for sexually transmitted infections in Britain: findings from the National Surveys of Sexual Attitudes and Lifestyles (Natsal). Lancet  2013; 382: 1795– 806. Google Scholar CrossRef Search ADS PubMed  3 Mohammed H, Mitchell H, Sile B et al.   Increase in sexually transmitted infections among men who have sex with men, England, 2014. Emerg Infect Dis  2016; 22: 88– 91. Google Scholar CrossRef Search ADS PubMed  4 WHO. Emergence of Multi-Drug Resistant Neisseria Gonorrhoeae—Threat of Global Rise in Untreatable Sexually Transmitted Infections, Fact Sheet . Geneva, Switzerland: WHO, 2011. http://www.who.int/reproductivehealth/publications/rtis/who_rhr_11_14/en/. 5 Unemo M, Nicholas RA. Emergence of multidrug-resistant, extensively drug-resistant and untreatable gonorrhea. Future Microbiol  2012; 7: 1401– 22. Google Scholar CrossRef Search ADS PubMed  6 Ndowa F, Lusti-Narasimhan M, Unemo M. The serious threat of multidrug-resistant and untreatable gonorrhoea: the pressing need for global action to control the spread of antimicrobial resistance, and mitigate the impact on sexual and reproductive health. Sex Transm Infect  2012; 88: 317– 8. Google Scholar CrossRef Search ADS PubMed  7 Tapsall JW, Ndowa F, Lewis DA et al.   Meeting the public health challenge of multidrug- and extensively drug-resistant Neisseria gonorrhoeae. Expert Rev Anti Infect Ther  2009; 7: 821– 34. Google Scholar CrossRef Search ADS PubMed  8 Department of Health. UK Five Year Antimicrobial Resistance Strategy 2013 to 2018 . London, UK: Department of Health, 2013. 9 Alirol E, Wi TE, Bala M et al.   Multidrug-resistant gonorrhea: a research and development roadmap to discover new medicines. PLoS Med  2017; 14: e1002366. Google Scholar CrossRef Search ADS PubMed  10 Ison CA, Deal C, Unemo M. Current and future treatment options for gonorrhoea. Sex Transm Infect  2013; 89 Suppl 4: iv52– 6. Google Scholar CrossRef Search ADS PubMed  11 Bignell C, FitzGerald M. UK national guideline for the management of gonorrhoea in adults, 2011. Int J STD AIDS  2011; 22: 541– 7. Google Scholar CrossRef Search ADS PubMed  12 Unemo M. Current and future antimicrobial treatment of gonorrhoea—the rapidly evolving Neisseria gonorrhoeae continues to challenge. BMC Infect Dis  2015; 15: 364. Google Scholar CrossRef Search ADS PubMed  13 PHE. Surveillance of antimicrobial resistance in Neisseria gonorrhoeae: Key findings from the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP)—Data up to October 2016 . London, UK: PHE, 2016. 14 PHE. Health Protection Report: Weekly Report, Volume 10 Number 15. 2016. https://www.gov.uk/government/publications/health-protection-report-volume-10-2016/hpr-volume-10-issue-15-news-15-april. 15 Town K, Obi C, Quaye N et al.   Drifting towards ceftriaxone treatment failure in gonorrhoea: risk factor analysis of data from the Gonococcal Resistance to Antimicrobials Surveillance Programme in England and Wales. Sex Transm Infect  2017; 93: 39– 45. Google Scholar CrossRef Search ADS PubMed  16 Fifer H, Natarajan U, Unemo M. Failure of dual antimicrobial therapy in treatment of gonorrhea. N Engl J Med  2016; 374: 2504– 6. Google Scholar CrossRef Search ADS PubMed  17 Health Protection Agency. Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) Action Plan for England and Wales: Informing the Public Health Response . London, UK: Health Protection Agency, 2013. 18 Paine TC, Fenton KA, Herring A et al.   GRASP: a new national sentinel surveillance initiative for monitoring gonococcal antimicrobial resistance in England and Wales. Sex Transm Infect  2001; 77: 398– 401. Google Scholar CrossRef Search ADS PubMed  19 WHO. Baseline report on global sexually transmitted infection surveillance 2012 . Geneva, Switzerland: WHO, 2013. http://www.who.int/reproductivehealth/publications/rtis/9789241505895/en/. 20 Ison CA, Town K, Obi C et al.   Decreased susceptibility to cephalosporins among gonococci: data from the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) in England and Wales, 2007–2011. Lancet Infect Dis  2013; 13: 762– 8. Google Scholar CrossRef Search ADS PubMed  21 PHE. Surveillance of antimicrobial resistance in Neisseria gonorrhoeae: Key findings from the Gonococcal resistance to antimicrobials surveillance programme (GRASP) and related surveillance data 2014 . London, UK: PHE, 2015. 22 Carannante A, Renna G, Dal Conte I et al.   Changing antimicrobial resistance profiles among Neisseria gonorrhoeae isolates in Italy, 2003 to 2012. Antimicrob Agents Chemother  2014; 58: 5871– 6. Google Scholar CrossRef Search ADS PubMed  23 Endimiani A, Guilarte YN, Tinguely R et al.   Characterization of Neisseria gonorrhoeae isolates detected in Switzerland (1998–2012): emergence of multidrug-resistant clones less susceptible to cephalosporins. BMC Infect Dis  2014; 14: 106. Google Scholar CrossRef Search ADS PubMed  24 Mlynarczyk-Bonikowska B, Serwin AB, Golparian D et al.   Antimicrobial susceptibility/resistance and genetic characteristics of Neisseria gonorrhoeae isolates from Poland, 2010-2012. BMC Infect Dis  2014; 14: 65. Google Scholar CrossRef Search ADS PubMed  25 Chisholm SA, Unemo M, Quaye N et al.   Molecular epidemiological typing within the European Gonococcal Antimicrobial Resistance Surveillance Programme reveals predominance of a multidrug-resistant clone. Euro Surveill  2013; 18: pii=20358. 26 Vries HJC, Helm JJ, Schim van der Loeff MF et al.   Multidrug-resistant Neisseria gonorrhoeae with reduced cefotaxime susceptibility is increasingly common in men who have sex with men, Amsterdam, the Netherlands. Euro Surveill  2009; 14: pii=19330. 27 Kirkcaldy RD, Harvey A, Papp JR et al.   Neisseria gonorrhoeae antimicrobial susceptibility surveillance—the Gonococcal Isolate Surveillance Project, 27 sites, United States, 2014. MMWR Surveill Summ  2016; 65: 1– 19. Google Scholar CrossRef Search ADS PubMed  28 Mohammed H, Ison CA, Obi C et al.   Frequency and correlates of culture-positive infection with Neisseria gonorrhoeae in England: a review of sentinel surveillance data. Sex Transm Infect  2015; 91: 287– 93. Google Scholar CrossRef Search ADS PubMed  29 Hanley JA. Statistical analysis of correlated data using generalized estimating equations: an orientation. Am J Epidemiol  2003; 157: 364– 75. Google Scholar CrossRef Search ADS PubMed  30 Bignell C. National Guideline on the Diagnosis and Treatment of Gonorrhoea in Adults 2005. https://www.bashh.org/documents/116/116.pdf. 31 Hughes G, Nichols T, Ison CA. Estimating the prevalence of gonococcal resistance to antimicrobials in England and Wales. Sex Transm Infect  2011; 87: 526– 31. Google Scholar CrossRef Search ADS PubMed  32 Pond MJ, Hall CL, Miari VF et al.   Accurate detection of Neisseria gonorrhoeae ciprofloxacin susceptibility directly from genital and extragenital clinical samples: towards genotype-guided antimicrobial therapy. J Antimicrob Chemother  2016; 71: 897– 902. Google Scholar CrossRef Search ADS PubMed  33 Unemo M, Golparian D, Shafer WM. Challenges with gonorrhea in the era of multi-drug and extensively drug resistance—are we on the right track? Expert Rev Anti Infect Ther  2014; 12: 653– 6. Google Scholar CrossRef Search ADS PubMed  34 Cole MJ, Spiteri G, Town K et al.   Risk factors for antimicrobial-resistant Neisseria gonorrhoeae in Europe. Sex Transm Dis  2014; 41: 723– 9. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Antimicrobial Chemotherapy Oxford University Press

Prevalence of and factors associated with MDR Neisseria gonorrhoeae in England and Wales between 2004 and 2015: analysis of annual cross-sectional surveillance surveys

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Oxford University Press
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0305-7453
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1460-2091
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10.1093/jac/dkx520
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Abstract

Abstract Objectives To describe trends in prevalence, susceptibility profile and risk factors for MDR Neisseria gonorrhoeae (MDR-NG) in England and Wales. Methods Isolates from 16 242 gonorrhoea episodes at sexual health clinics within the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) underwent antimicrobial susceptibility testing. MDR-NG was defined as resistance to ceftriaxone, cefixime or azithromycin, plus at least two of penicillin, ciprofloxacin and spectinomycin. Trends in resistance are presented for 2004–15; prevalence and logistic regression analyses for MDR-NG cover the period of the most recent treatment guideline (ceftriaxone plus azithromycin), 2011–15. Results Between 2004 and 2015, the proportion of N. gonorrhoeae isolates fully susceptible to all antimicrobial classes fell from 80% to 46%, with the proportion resistant to multiple (two or more) classes increasing from 7.3% to 17.5%. In 2011–15, 3.5% of isolates were MDR-NG, most of which were resistant to cefixime (100% in 2011, decreasing to 36.9% in 2015) and/or azithromycin (4.2% in 2011, increasing to 84.3% in 2015). After excluding azithromycin-resistant isolates, modal azithromycin MICs were higher in MDR versus non-MDR isolates (0.5 versus 0.125 mg/L), with similar results for ceftriaxone (modal MICs 0.03 versus ≤0.002 mg/L). After adjustment for confounders, MDR-NG was more common among isolates from heterosexual men, although absolute differences in prevalence were small [4.6% versus 3.3% (MSM) and 2.5% (women)]. Conclusions N. gonorrhoeae is becoming less susceptible to available antimicrobials. Since 2011, a minority of isolates were MDR-NG; however, MICs of azithromycin or ceftriaxone (first-line therapies) for many of these were elevated. These findings highlight the importance of continued antimicrobial stewardship for gonorrhoea. Introduction Gonorrhoea, caused by the bacterium Neisseria gonorrhoeae, is the second most commonly diagnosed bacterial sexually transmitted infection (STI) in England.1 Although estimated prevalence in community settings in Britain is low (<0.1%),2 recent years have seen worrying increases in diagnoses among MSM.1,3 The history of rapid development of resistance to antimicrobials used for treatment has made antimicrobial-resistant (AMR) N. gonorrhoeae a major global health concern and a priority area for Public Health England (PHE).4–9 Extended-spectrum cephalosporins (ESCs) are the most recent class of antimicrobial introduced to treat gonorrhoea and represent a ‘last-line’ treatment option, with no new antimicrobials available and few in development.4,5,9,10 Since 2011, recommended first-line treatment in the UK has been dual therapy with 500 mg of intramuscularly injectable ceftriaxone (an ESC) plus 1 g of oral azithromycin, in an attempt to prevent sustained resistance to ESCs becoming established,10,11 an approach which has been implemented in many other regions globally.12 Although resistance to ceftriaxone is rare, recent increases in azithromycin resistance have been described, including high-level resistance.13,14 There is also evidence of N. gonorrhoeae becoming gradually less susceptible to ceftriaxone,15 and the first reported global case of dual treatment failure was also detected in the UK.16 Many have now highlighted that MDR N. gonorrhoeae (MDR-NG) poses a serious threat and untreatable gonorrhoea is an increasingly plausible prospect.5,7,9,10 It is critical to understand the epidemiology of AMR N. gonorrhoeae to inform treatment guidelines and prevention and control measures, in addition to wider gonorrhoea prevention efforts.4,7,17 The Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) was established in 2000 to monitor trends and provide information on determinants of AMR N. gonorrhoeae in England and Wales18 and combines susceptibility data with demographic, behavioural and clinical information from those diagnosed with gonorrhoea at selected specialist sexual health services. GRASP has provided detailed insight into patterns of antimicrobial resistance in N. gonorrhoeae and informed changes to treatment guidelines.10,19 To date, GRASP data on trends and risk factors for individual antimicrobials have been reported, 13,15,20,21 but detailed analyses of MDR-NG have not. This project seeks to fill this knowledge gap by investigating the prevalence, resistance profile and risk factors for MDR-NG in England and Wales in order to understand implications for the future treatment of gonorrhoea and contribute to the scant epidemiological literature on MDR-NG.7,22–27 Methods Ethics and governance PHE has permission to handle data obtained by GRASP under section 251 of the UK National Health Service Act of 2006, which was renewed annually by the Ethics and Confidentiality Committee of the National Information Governance Board until 2013. Since then, the power of approval of public health surveillance activity has been granted directly to PHE. Data sources Detailed descriptions of GRASP methodology have been published previously.13 Briefly, isolates from individuals with gonorrhoea attending 27 specialist sexual health clinics in England and Wales during a three-month period each summer between 2004 and 2015 were cultured and submitted to PHE for susceptibility testing. An agar dilution method was used to determine MICs of ceftriaxone, cefixime, spectinomycin, azithromycin, penicillin and ciprofloxacin. Susceptibility data were matched to demographic, clinical and behavioural data submitted by the clinics. All patients diagnosed with gonorrhoea during this period were eligible for inclusion; however, approximately half of episodes did not have susceptibility data due to culture not being attempted or culture not being successful.28 Azithromycin MIC data The diagnostic susceptibility test (DST) medium used for susceptibility testing for GRASP isolates was changed in 2015, whereupon MICs of azithromycin, and subsequently the proportion of resistant isolates, increased.13 A validation study compared the MICs determined by the new and old DST agars and found MICs of azithromycin were higher by approximately one dilution using the new DST medium. The new DST medium provided better pH and physiological conditions for growth of fastidious strains of N. gonorrhoeae which subsequently resulted in more reliable azithromycin MIC determination; this was also confirmed by local quality assurance data.13 Azithromycin MIC data for 2013 and 2014 (the years in which the problems with growth on the old DST medium were seen) were therefore adjusted upwards by a factor of one dilution to enable more accurate description of trends over time. Definition of MDR-NG Defining MDR-NG is challenging due to differences in first-line treatments over time and internationally. We therefore present analyses of: (i) patterns of AMR N. gonorrhoeae over time, including resistance or decreased susceptibility to multiple classes of antimicrobials, to facilitate international and longer-term comparisons; and (ii) MDR-NG defined as relevant to current clinical practice in the UK. For the latter, we adapted the working definition proposed by Tapsall et al.7 (2009): resistance or decreased susceptibility to one or more antimicrobial in widespread use to treat gonorrhoea (category 1) and resistance to two or more antimicrobials in less frequent use/little use but proposed for more frequent use (category 2). The original Tapsall et al.7 definition included spectinomycin in category 1 and azithromycin in category 2; we updated this based on currently recommended therapies in the UK (Table 1). Although cefixime has not been recommended for treatment of N. gonorrhoeae since 2011, we retained it in category 1 as it is an ESC. Table 1. Category of antibiotic and MIC thresholds used to define resistance or decreased susceptibility in GRASP   MIC breakpoint for resistance (R) or decreased susceptibility (DS)  Category 1 antibiotics   ceftriaxoneDS  >0.06 mg/L   cefiximeDS  >0.06 mg/L   azithromycinR  >0.5 mg/L  Category 2 antibiotics   ciprofloxacinR  >0.5 mg/L   penicillinR  >0.5 mg/L or β-lactamase positive   spectinomycinR  >64 mg/L    MIC breakpoint for resistance (R) or decreased susceptibility (DS)  Category 1 antibiotics   ceftriaxoneDS  >0.06 mg/L   cefiximeDS  >0.06 mg/L   azithromycinR  >0.5 mg/L  Category 2 antibiotics   ciprofloxacinR  >0.5 mg/L   penicillinR  >0.5 mg/L or β-lactamase positive   spectinomycinR  >64 mg/L  GRASP standard breakpoints.13 Decreased susceptibility, rather than ‘resistance’, is used in GRASP for ESCs as treatment failures have been observed across a range of MIC values in some patients but not others. Descriptive and statistical analyses Descriptive analyses were used to examine trends in AMR N. gonorrhoeae for 2004–15. Analysis of MDR-NG was restricted to 2011 onwards, to reflect prevalence and risk factors relevant to current treatment guidelines. Modal ceftriaxone and azithromycin MICs were compared between MDR and non-MDR isolates to assess whether there was a drift towards resistance to first-line therapies in MDR-NG among those not yet resistant to these antimicrobials. As resistance to ceftriaxone or azithromycin is included in the definition of MDR-NG, these sub-analyses excluded all isolates which already had decreased susceptibility to ceftriaxone (for comparison of ceftriaxone MICs) or resistance to azithromycin (for comparison of azithromycin MICs). For the risk factor analysis, logistic regression was used to generate ORs initially adjusted for year, age (as a quadratic term, to account for the non-linear relationship) and gender/sexual orientation (groupings: MSM, heterosexual men, all women). Associations with the following variables were examined: ethnicity, residential neighbourhood-level index of multiple deprivation (IMD), number of recent sexual partners (past 3 months), recent sex abroad (past 3 months), previous gonorrhoea infection, symptomatic infection, clinician-coded site of infection, concurrent STIs and HIV status. Multivariable logistic regression analyses were used to determine independent associations, using a forwards model-building approach, with variables retained in the final model based on a P value of ≤0.10. Exploratory analysis showed evidence of within-clinic (but not within-patient) clustering of MDR-NG, i.e. there was greater similarity in MDR-NG between isolates collected within the same clinic than at different clinics. To avoid this resulting in underestimated standard errors, clustering was accounted for in the risk factor analysis using generalized estimating equations under the assumption of an exchangeable correlation matrix.29 Results Sample characteristics Between 2004 and 2015, 16 242 isolates from 15 781 patients underwent susceptibility testing, with 47.4% of isolates from MSM, 28.2% from heterosexual men and 20.6% from women (Table S1, available as Supplementary data at JAC Online). Patterns of antimicrobial resistance in GRASP 2004–15 Resistance to azithromycin was generally low until 2012 (<5%), then increased to 9.8% in 2015 (Figure 1). Decreased susceptibility to ceftriaxone was rare (0.1%), whereas levels of decreased susceptibility to cefixime increased rapidly between 2008 and 2010 (from 3% to 17%), then decreased to 1.1% in 2015 (Figure 1). Resistance to penicillin and ciprofloxacin was widespread (>10%) throughout the study period. Figure 1. View largeDownload slide Percentage of N. gonorrhoeae isolates with antimicrobial resistance/decreased susceptibility, by year, England and Wales, GRASP 2004–15 (n = 16 242). Note: azithromycin data for 2013–14 adjusted to account for poor growth on the DST medium leading to underestimation of azithromycin MIC in those years (see the Methods section for further details). This figure appears in colour in the online version of JAC and in black and white in the print version of JAC. Figure 1. View largeDownload slide Percentage of N. gonorrhoeae isolates with antimicrobial resistance/decreased susceptibility, by year, England and Wales, GRASP 2004–15 (n = 16 242). Note: azithromycin data for 2013–14 adjusted to account for poor growth on the DST medium leading to underestimation of azithromycin MIC in those years (see the Methods section for further details). This figure appears in colour in the online version of JAC and in black and white in the print version of JAC. Between 2004 and 2015, the proportion of N. gonorrhoeae isolates fully susceptible to all classes of antimicrobials fell from 80% to 46%, with the proportion resistant to multiple (two or more) classes increasing from 7.3% to 17.5% (Figure 2). Resistance to three classes increased between 2008 and 2010 then declined, mirroring trends in cefixime resistance (Figures 1 and 2). A small number of isolates were resistant to all four classes tested (n = 49; 0.3% overall). Figure 2. View largeDownload slide Percentage of N. gonorrhoeae isolates resistant to 0, 1, 2, 3 or 4 classes of antimicrobials, by year, England and Wales, GRASP 2004–15 (n = 16 242). Classes of antimicrobials: (i) ESC (cefixime and ceftriaxone); (ii) macrolide (azithromycin); (iii) fluoroquinolone (ciprofloxacin); (iv) penicillin; and (v) aminoglycoside (spectinomycin). a2013–14 estimates calculated using adjusted azithromycin data. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC. Figure 2. View largeDownload slide Percentage of N. gonorrhoeae isolates resistant to 0, 1, 2, 3 or 4 classes of antimicrobials, by year, England and Wales, GRASP 2004–15 (n = 16 242). Classes of antimicrobials: (i) ESC (cefixime and ceftriaxone); (ii) macrolide (azithromycin); (iii) fluoroquinolone (ciprofloxacin); (iv) penicillin; and (v) aminoglycoside (spectinomycin). a2013–14 estimates calculated using adjusted azithromycin data. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC. Despite high levels of susceptibility to prevailing first-line therapies immediately following revisions to treatment guidelines in 2005 (from ciprofloxacin to cefixime)30 and 2011 (from cefixime to ceftriaxone and azithromycin dual therapy),11 the proportion of isolates fully susceptible to first-line therapies declined in the following years, from 99.9% in 2005 to 82.9% in 2010 and from 99.5% in 2011 to 90.2% in 2015 (Figure 3). Figure 3. View largeDownload slide Percentage of isolates fully susceptible to recommended first-line therapya, England and Wales, GRASP 2004–15 (n = 16 242). aRecommended first-line therapies: ciprofloxacin (2004), cefixime (2005–10) and ceftriaxone and azithromycin (2011–15). bAzithromycin data for 2013–14 adjusted to account for poor growth on the DST medium leading to underestimation of azithromycin MIC in those years (see the Methods section for further details). Figure 3. View largeDownload slide Percentage of isolates fully susceptible to recommended first-line therapya, England and Wales, GRASP 2004–15 (n = 16 242). aRecommended first-line therapies: ciprofloxacin (2004), cefixime (2005–10) and ceftriaxone and azithromycin (2011–15). bAzithromycin data for 2013–14 adjusted to account for poor growth on the DST medium leading to underestimation of azithromycin MIC in those years (see the Methods section for further details). Prevalence and profile of MDR-NG Between 2011 and 2015, 3.5% (n = 266) of isolates were MDR-NG, with small increases in prevalence between 2011 and 2013 (from 3.7% to 4.5%) followed by a subsequent decrease to 2.2% in 2015 (χ2 test P = 0.004). The profile of resistance to category 1 antimicrobials among MDR-NG isolates changed over time: 100% were resistant to cefixime in 2011, reducing to 36.9% in 2015, with increases in the proportion resistant to azithromycin over this time frame from 4.2% to 84.3% (P < 0.01) (Figure 4). All MDR-NG isolates were resistant to both ciprofloxacin and penicillin, but not spectinomycin, in category 2. Over time, the proportion of MDR-NG resistant to four antimicrobials (cefixime, azithromycin, penicillin and ciprofloxacin) increased from 4.2% in 2011 to 21.1% in 2015. One isolate had resistance/decreased susceptibility to five antimicrobials: ceftriaxone (MIC 0.125 mg/L), cefixime (MIC 0.25 mg/L), azithromycin (MIC 1.0 mg/L), ciprofloxacin (MIC ≥16 mg/L) and penicillin (MIC 1 mg/L). Figure 4. View largeDownload slide Resistance/decreased susceptibility to category 1a antimicrobials among MDR-NG isolates over time, England and Wales, GRASP 2011–15 (n = 266). aCategory 1 antimicrobials: ceftriaxone, cefixime and azithromycin; category 2 antimicrobials: ciprofloxacin, penicillin and spectinomycin. See the Methods section for further details. All MDR-NG isolates were resistant to ciprofloxacin and penicillin in category 2. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC. Figure 4. View largeDownload slide Resistance/decreased susceptibility to category 1a antimicrobials among MDR-NG isolates over time, England and Wales, GRASP 2011–15 (n = 266). aCategory 1 antimicrobials: ceftriaxone, cefixime and azithromycin; category 2 antimicrobials: ciprofloxacin, penicillin and spectinomycin. See the Methods section for further details. All MDR-NG isolates were resistant to ciprofloxacin and penicillin in category 2. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC. In a sub-analysis excluding all isolates with resistance to azithromycin, the MICs of azithromycin for MDR isolates were elevated (modal MIC 0.5 mg/L) compared with those for non-MDR isolates (modal MIC 0.125 mg/L) (Figure 5a). Similarly, after excluding isolates with decreased susceptibility to ceftriaxone, modal ceftriaxone MICs for MDR isolates were higher (0.03 mg/L) than those for non-MDR isolates (≤0.002 mg/L) (Figure 5b). The elevated ceftriaxone MICs among MDR isolates were observed in a further sub-analysis stratified by year [grouped as 2011–13 (n = 176 MDR isolates) and 2014–15 (n = 87 MDR isolates)]; ceftriaxone modal MIC of 0.03 mg/L among MDR isolates versus 0.004 mg/L among non-MDR isolates in both time periods. Figure 5. View largeDownload slide Distribution of MICs of (a) azithromycin and (b) ceftriaxone among MDR-NG and non-MDR-NG isolates not meeting the resistance/decreased susceptibility thresholds for azithromycin and ceftriaxone, respectively, England and Wales, 2011–15. Figure 5. View largeDownload slide Distribution of MICs of (a) azithromycin and (b) ceftriaxone among MDR-NG and non-MDR-NG isolates not meeting the resistance/decreased susceptibility thresholds for azithromycin and ceftriaxone, respectively, England and Wales, 2011–15. Risk factors for MDR-NG MDR-NG was more common among heterosexual men than MSM or women (4.6% versus 3.3% and 2.5%, respectively); these differences remained significant after adjustment for other factors (Table 2). Multivariable analysis also found MDR-NG to be more common among isolates from older patients [adjusted OR (AOR) for those aged ≥45 years: 1.89 (95% CI: 1.25–2.86), compared with those aged ≤24 years] and those reporting recent sex abroad [AOR 1.38 (95% CI: 1.02–1.87)] and less common among isolates from patients who were of black Caribbean ethnicity [AOR 0.26 (95% CI: 0.47–0.87)], were HIV positive [AOR 0.64 (95% CI: 0.47–0.87)] or had a concurrent STI [AOR 0.77 (95% CI: 0.61–0.97)]. Neighbourhood deprivation (IMD) data were not available in GRASP for 2011 and so IMD was not included in the multivariable model; however, a separate multivariable model run on 2012–15 data found no association between MDR-NG and IMD after adjustment for other factors. Table 2. Risk factors for MDR-NG among N. gonorrhoeae isolates, England and Wales, GRASP 2011–15   Total N  n  %  Adjusted for age, year and gender/ sexual orientation   Multivariable model (n = 4027)   AOR1  (95% CI)  AOR2  (95% CI)  All  7562  266  3.5          Year        P = 0.04  P < 0.001   2011  1288  48  3.7  ref    ref     2012  1375  57  4.1  1.16  (0.76–1.66)  1.16  (0.72–1.88)   2013  1636  74  4.5  1.26  (0.77–2.08)  3.86  (2.51–5.94)   2014  1564  49  3.1  0.84  (0.62–1.14)  3.61  (2.43–5.37)   2015  1699  38  2.2  0.64  (0.36–1.11)  0.60  (0.35–1.03)  Gender/sexual orientation        P = 0.02  P = 0.05   heterosexual men  1571  72  4.6  ref    ref     MSM  4683  156  3.3  0.67  (0.45–1.01)  0.76  (0.57–0.99)   women  1123  28  2.5  0.62  (0.42–0.90)  0.66  (0.44–0.99)  Age group (years)        P = 0.13  P = 0.01   ≤24  2337  64  2.7  ref    ref     25–44  4507  173  3.8  1.42  (0.98–2.03)  1.35  (1.01–1.81)   ≥45  714  29  4.1  1.49  (0.96–2.29)  1.89  (1.25–2.86)  Ethnicity        P = 0.01  P = 0.004   white  5187  197  3.8  ref    ref     black Caribbean  580  12  2.1  0.42  (0.21–0.81)  0.26  (0.47–0.87)   black African  281  7  2.5  0.55  (0.25–1.19)  0.87  (0.43–1.76)   black other  180  5  2.8  0.63  (0.24–1.66)  0.27  (0.04–1.78)   Asian (including Chinese)  360  15  4.2  1.04  (0.53–2.06)  1.58  (0.79–3.14)   mixed ethnic group  500  13  2.6  0.63  (0.30–1.32)  0.75  (0.35–1.62)   other ethnic group  181  5  2.8  0.64  (0.25–1.63)  1.00  (1.02–1.87)  Patient’s area-level deprivation (IMD) quintilea        P = 0.09       1 or 2 (least deprived)  698  34  4.9  ref         3  835  26  3.1  0.63  (0.42–0.93)       4  1974  70  3.5  0.71  (0.49–1.04)       5 (most deprived)  2341  73  3.1  0.59  (0.37–0.96)      Number of sexual partners (past 3 months)        P > 0.99       0–1  1974  71  3.6  ref         2–5  3021  112  3.7  0.99  (0.72–1.38)       ≥6  845  30  3.6  1.00  (0.60–1.69)      Sex while abroad (past 3 months)        P = 0.03  P = 0.04   no  5170  175  3.4  ref    ref     yes  670  38  5.7  1.55  (1.04–2.30)  1.38  (1.02–1.87)  Previous gonorrhoea infection        P = 0.69       no  4440  159  3.6  ref         yes  2325  77  3.3  0.95  (0.72–1.25)      Symptoms of gonorrhoeab        P = 0.68       no  1810  59  3.3  ref         yes  4241  162  3.8  1.07  (0.78–1.46)      Clinician-coded site of infectionc                 genital        P = 0.87        no  1848  69  3.7  ref          yes  4644  167  3.6  0.88  (0.62–1.25)       rectal        P = 0.49        no  4027  155  3.8  ref          yes  2480  81  3.3  0.90  (0.68–1.20)       throat        P = 0.06        no  4517  154  3.4  ref          yes  1990  82  4.1  1.43  (0.98–2.09)       other        P = 0.67        no  6338  229  3.6  ref          yes  169  7  4.1  1.31  (0.73–2.34)       multiple sites of infection        P = 0.76        no  4353  160  3.7  ref          yes  2154  76  3.5  1.06  (0.72–1.57)      Concurrent STI (excluding HIV)        P = 0.01  P = 0.03   no  5639  219  3.9  ref    ref     yes  1923  47  2.4  0.66  (0.48–0.90)  0.77  (0.61–0.97)  HIV status        P = 0.002  P = 0.005   negative  3592  141  3.9  ref    ref     positive  1264  31  2.5  0.52  (0.34–0.78)  0.64  (0.47–0.87)    Total N  n  %  Adjusted for age, year and gender/ sexual orientation   Multivariable model (n = 4027)   AOR1  (95% CI)  AOR2  (95% CI)  All  7562  266  3.5          Year        P = 0.04  P < 0.001   2011  1288  48  3.7  ref    ref     2012  1375  57  4.1  1.16  (0.76–1.66)  1.16  (0.72–1.88)   2013  1636  74  4.5  1.26  (0.77–2.08)  3.86  (2.51–5.94)   2014  1564  49  3.1  0.84  (0.62–1.14)  3.61  (2.43–5.37)   2015  1699  38  2.2  0.64  (0.36–1.11)  0.60  (0.35–1.03)  Gender/sexual orientation        P = 0.02  P = 0.05   heterosexual men  1571  72  4.6  ref    ref     MSM  4683  156  3.3  0.67  (0.45–1.01)  0.76  (0.57–0.99)   women  1123  28  2.5  0.62  (0.42–0.90)  0.66  (0.44–0.99)  Age group (years)        P = 0.13  P = 0.01   ≤24  2337  64  2.7  ref    ref     25–44  4507  173  3.8  1.42  (0.98–2.03)  1.35  (1.01–1.81)   ≥45  714  29  4.1  1.49  (0.96–2.29)  1.89  (1.25–2.86)  Ethnicity        P = 0.01  P = 0.004   white  5187  197  3.8  ref    ref     black Caribbean  580  12  2.1  0.42  (0.21–0.81)  0.26  (0.47–0.87)   black African  281  7  2.5  0.55  (0.25–1.19)  0.87  (0.43–1.76)   black other  180  5  2.8  0.63  (0.24–1.66)  0.27  (0.04–1.78)   Asian (including Chinese)  360  15  4.2  1.04  (0.53–2.06)  1.58  (0.79–3.14)   mixed ethnic group  500  13  2.6  0.63  (0.30–1.32)  0.75  (0.35–1.62)   other ethnic group  181  5  2.8  0.64  (0.25–1.63)  1.00  (1.02–1.87)  Patient’s area-level deprivation (IMD) quintilea        P = 0.09       1 or 2 (least deprived)  698  34  4.9  ref         3  835  26  3.1  0.63  (0.42–0.93)       4  1974  70  3.5  0.71  (0.49–1.04)       5 (most deprived)  2341  73  3.1  0.59  (0.37–0.96)      Number of sexual partners (past 3 months)        P > 0.99       0–1  1974  71  3.6  ref         2–5  3021  112  3.7  0.99  (0.72–1.38)       ≥6  845  30  3.6  1.00  (0.60–1.69)      Sex while abroad (past 3 months)        P = 0.03  P = 0.04   no  5170  175  3.4  ref    ref     yes  670  38  5.7  1.55  (1.04–2.30)  1.38  (1.02–1.87)  Previous gonorrhoea infection        P = 0.69       no  4440  159  3.6  ref         yes  2325  77  3.3  0.95  (0.72–1.25)      Symptoms of gonorrhoeab        P = 0.68       no  1810  59  3.3  ref         yes  4241  162  3.8  1.07  (0.78–1.46)      Clinician-coded site of infectionc                 genital        P = 0.87        no  1848  69  3.7  ref          yes  4644  167  3.6  0.88  (0.62–1.25)       rectal        P = 0.49        no  4027  155  3.8  ref          yes  2480  81  3.3  0.90  (0.68–1.20)       throat        P = 0.06        no  4517  154  3.4  ref          yes  1990  82  4.1  1.43  (0.98–2.09)       other        P = 0.67        no  6338  229  3.6  ref          yes  169  7  4.1  1.31  (0.73–2.34)       multiple sites of infection        P = 0.76        no  4353  160  3.7  ref          yes  2154  76  3.5  1.06  (0.72–1.57)      Concurrent STI (excluding HIV)        P = 0.01  P = 0.03   no  5639  219  3.9  ref    ref     yes  1923  47  2.4  0.66  (0.48–0.90)  0.77  (0.61–0.97)  HIV status        P = 0.002  P = 0.005   negative  3592  141  3.9  ref    ref     positive  1264  31  2.5  0.52  (0.34–0.78)  0.64  (0.47–0.87)  AOR1 = AOR, adjusted for year, age (quadratic) and gender/sexual orientation. AOR2 = multivariable model, adjusted for other variables shown. Age adjusted for as a quadratic variable, but AORs and P value presented for age group for ease of interpretation. a IMD was not available for 2011 in GRASP. b Discharge/painful urination (dysuria). c Sites not mutually exclusive. Where patient had multiple infection sites, this site may not correspond to the site that underwent susceptibility testing as only one isolate per patient was included in GRASP. Isolates were prioritized as follows: (i) male rectal; (ii) male urethral; (iii) female cervical; and (iv) any other site. Discussion Our data demonstrate increases in antimicrobial resistance of N. gonorrhoeae over the past decade in England and Wales, with the proportion of N. gonorrhoeae isolates fully susceptible to all classes of antimicrobials falling from 80% in 2004 to 46% in 2015 and the proportion resistant to two or more classes increasing from 7.3% to 17.5% over this period. Despite high levels of susceptibility to recommended treatments immediately following changes to treatment guidelines in 2005 and 2011, the proportion fully susceptible to these decreased in a matter of years. In 2011–15, 3.5% of isolates were classed as MDR-NG, meaning they were resistant to either azithromycin or an ESC, as well as to penicillin and ciprofloxacin. In 2011, MDR-NG isolates were predominantly resistant to cefixime; however, by 2015 the majority were resistant to azithromycin, with around one in five resistant to both. We also found evidence of drift towards azithromycin resistance among MDR-NG isolates that were not resistant to azithromycin and similar drift towards ceftriaxone resistance. The fact that these elevated ceftriaxone MICs in the MDR isolates were observed in 2014–15 as well as 2011–13 suggests this finding is unlikely to be solely due to the cefixime-resistant ST1407 strains that also have elevated ceftriaxone MICs and were prevalent during 2011–13.25 Although the risk factor analysis found MDR-NG was more common among isolates from some groups, including heterosexual men and older patients, absolute differences in prevalence were small, providing little basis for targeted treatment strategies. These findings highlight the importance of continued surveillance and prevention efforts, given the severely limited treatment options available to those with MDR-NG. Advantages of using the GRASP surveillance data include the large sample size, the ability to look at trends over time and the ability to combine MIC data with demographic, clinical and behavioural information. GRASP is reasonably representative of gonorrhoea cases across England, although MSM are somewhat over-represented.31 It is likely that risk characteristics of MSM and heterosexual sexual networks differ, but small numbers of MDR-NG prohibited stratification of risk factor analysis by gender/sexual orientation. Another limitation is the potential for missing data to bias results of the risk factor analysis; for example, completion of behavioural data varied by clinic resulting in more missing data for MSM. Azithromycin MIC data from 2013–14 were adjusted to account for poor organism growth using DST media which underestimated MICs. This adjustment enabled comparisons of antimicrobial resistance over time, but is a crude correction and some misclassification is likely. In line with low levels of resistance to ceftriaxone generally,13 few MDR-NG cases had decreased susceptibility to ceftriaxone. However, MICs of ceftriaxone have been drifting towards resistance in recent years,15 leaving no room for complacency about the long-term effectiveness of current dual therapy. Our analysis found that the ceftriaxone MICs for MDR-NG isolates were higher than for non-MDR isolates, after excluding those with decreased susceptibility to ceftriaxone, demonstrating how easily MDR-NG with resistance to ceftriaxone could emerge and lead to infections that would be difficult to treat. Although all isolates were susceptible to spectinomycin, this is not considered a viable first-line treatment as resistance has historically developed rapidly when it has been used, it is not effective in treating pharyngeal gonorrhoea and it is currently unavailable in many countries.5 It should be borne in mind that 96.5% of isolates were not MDR, which is promising in light of efforts to develop point-of-care antimicrobial resistance testing to guide treatment choices.32 If successful, such tests could identify infections for which previously used therapies would be effective, reducing ceftriaxone use and the selection pressure for resistance. Despite commentaries on the emerging threat of MDR-NG,5,6,33 the international literature on prevalence and risk factors is scant, perhaps due to lack of consensus on an MDR definition, preventing comparison of prevalence and risk factors.22,23,26 In general, the risk factors for MDR-NG identified here are consistent with those associated with resistance to some individual antimicrobials in previous studies, including being a heterosexual man (ciprofloxacin, azithromycin, cefixime),34 the inverse relationships with black Caribbean ethnicity (ciprofloxacin, cefixime),20,21 and concurrent STI infection (ciprofloxacin, cefixime).20,21 However, previous analyses of GRASP data have found a positive association between HIV and N. gonorrhoeae that was resistant to cefixime, ciprofloxacin or penicillin,20,21 in contrast with the inverse relationship with MDR-NG found here. Continued monitoring of the epidemiology of MDR-NG alongside resistance to individual antibiotics is therefore needed. These data emphasize the loss of susceptibility of N. gonorrhoeae to sequential antimicrobial classes used for treatment and provide the first prevalence estimates of MDR-NG in England and Wales. Although prevalence of MDR-NG was relatively low, many of these isolates were resistant to azithromycin and had ceftriaxone MICs that were higher than those for non-MDR isolates. In the context of limited new treatment options, the emergence of ceftriaxone resistance in MDR-NG could herald the prospect of untreatable N. gonorrhoeae. MDR-NG was generally homogeneously distributed by demographic and behavioural characteristics, with no groups identified as being at especially high risk, highlighting the need for continued culture and susceptibility testing and test of cure among all patients with gonorrhoea. Our findings underline the essential role of timely surveillance to identify and respond to clinically significant changes in AMR N. gonorrhoeae in the coming years. Acknowledgements We would like to thank all GRASP collaborators including the following: members of the reference laboratory at PHE (A. Kundu and S. Chisholm), the collaborating centres and the Steering Group for their continued support, GUM clinic staff for the prompt submission of clinical data and laboratories for sending isolates to the reference laboratory at PHE, Colindale. Steering Group D. M. Livermore, C. Bignell, H. Donaldson, B. Macrae, K. Templeton, J. Shepherd, P. French, M. Portman, A. P. Johnson, J. Paul, A. Robinson, J. Ross, J. Wade, C. Ison, G. Hughes, K. Town, N. Woodford, R. Mulla, T. Sadiq, H. Fifer, A. Andreasen and M. Cole. Collaborating centres Birmingham (M. David and J. Ross), Bristol (O. M. Williams and P. Horner), Brighton (M. Cubbon and G. Dean), Cambridge (N. Brown and C. Carne), Cardiff (R. Howe and J. Nicholls), Gloucester (P. Moore and A. DeBurgh-Thomas), Homerton (A. Jepson and M. Nathan), Kings (J. Wade, C. McDonald and M. Brady), Leeds (M. Denton and J. Clarke), Liverpool (J. Anson and M. Bradley), London Charing Cross, Chelsea and Westminster (K. McLean, A. McOwan, G. Paul and H. Donaldson), Luton (R. Mulla and T. Balachandran), Manchester (A. Qamruddin and A. Sukthankar), Newcastle (M. Valappil and K. N. Sankar), Newport (S. Majumdar and H. Birley), Northampton (M. Minassian and L. Riddell), Nottingham (V. Weston, C. Bignell and M. Pammi), Reading (G. Wildman and S. Iyer), Sheffield (L. Prtak, C. Bowman and C. Dewnsap), St George’s (P. Riley and P. Hay), St Mary’s (D. Wilkinson), University College Hospital (B. Macrae, M. Portman and E. Jungmann), Wolverhampton (D. Dobie and A. Tariq) and Woolwich (M. Dall’Antonia and J. Russell). Funding GRASP has been funded totally (2000–04) and partly (2005–10) by the Department of Health (England) and by Public Health England. S. C. was funded to undertake independent research supported by the National Institute for Health Research (NIHR Research Methods Programme, Fellowships and Internships, NIHR-RMFI-2014-05-28). Transparency declarations H. F. is a member of the Scientific Advisory Board for Discuva Ltd. All other authors: none to declare. Disclaimer The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. Supplementary data Table S1 is available as Supplementary data at JAC Online. References 1 PHE. Sexually Transmitted Infections and Chlamydia Screening in England, 2016. Health Protection Report, Volume 11 Number 20. 2017. https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/617025/Health_Protection_Report_STIs_NCSP_2017.pdf. 2 Sonnenberg P, Clifton S, Beddows S et al.   Prevalence, risk factors, and uptake of interventions for sexually transmitted infections in Britain: findings from the National Surveys of Sexual Attitudes and Lifestyles (Natsal). Lancet  2013; 382: 1795– 806. Google Scholar CrossRef Search ADS PubMed  3 Mohammed H, Mitchell H, Sile B et al.   Increase in sexually transmitted infections among men who have sex with men, England, 2014. Emerg Infect Dis  2016; 22: 88– 91. Google Scholar CrossRef Search ADS PubMed  4 WHO. Emergence of Multi-Drug Resistant Neisseria Gonorrhoeae—Threat of Global Rise in Untreatable Sexually Transmitted Infections, Fact Sheet . Geneva, Switzerland: WHO, 2011. http://www.who.int/reproductivehealth/publications/rtis/who_rhr_11_14/en/. 5 Unemo M, Nicholas RA. 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Challenges with gonorrhea in the era of multi-drug and extensively drug resistance—are we on the right track? Expert Rev Anti Infect Ther  2014; 12: 653– 6. Google Scholar CrossRef Search ADS PubMed  34 Cole MJ, Spiteri G, Town K et al.   Risk factors for antimicrobial-resistant Neisseria gonorrhoeae in Europe. Sex Transm Dis  2014; 41: 723– 9. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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Journal of Antimicrobial ChemotherapyOxford University Press

Published: Apr 1, 2018

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