Article Text

PDF

Original article
Drifting towards ceftriaxone treatment failure in gonorrhoea: risk factor analysis of data from the Gonococcal Resistance to Antimicrobials Surveillance Programme in England and Wales
  1. K Town1,
  2. C Obi1,
  3. N Quaye2,
  4. S Chisholm2,
  5. G Hughes1
  6. on behalf of the GRASP Collaborative Group
    1. 1HIV/STI Department, National Infection Service, Public Health England, London, UK
    2. 2Sexually Transmitted Bacteria Reference Unit, National Infection Service, Public Health England, London, UK
    1. Correspondence to K Town, HIV/STI Department, National Infection Service, Public Health England, PHE Colindale, 61 Colindale Avenue, London NW9 5EQ, UK; Katy.town{at}phe.gov.uk

    Abstract

    Objectives Treatment of Neisseria gonorrhoeae is threatened by the emergence of antimicrobial resistance. We analysed data from the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) in England and Wales to identify groups most at risk of reduced susceptibility to the currently recommended first-line therapy, ceftriaxone.

    Methods Data from GRASP between 2007 and 2013 on ceftriaxone susceptibility and strain types were analysed. Risk factors associated with isolates exhibiting a ceftriaxone minimum inhibitory concentration (MIC) of ≥0.015 mg/L (CTR ≥0.015 mg/L) were identified using logistic regression.

    Results One third of isolates from men who have sex with men (MSM) (1279/4203) and 9.9% from heterosexuals (458/4626) exhibited CTR ≥0.015 mg/L. Between 2007 and 2013, the modal MIC for isolates remained at 0.004 mg/L for MSM but increased from 0.002 to 0.004 mg/L for heterosexuals. Among MSM, CTR ≥0.015 mg/L was associated with Asian ethnicity (crude OR: 1.42; 95% CI 1.07 to 1.88) and previous gonorrhoea (1.34; 1.16 to 1.54). Among heterosexuals, CTR ≥0.015 mg/L was associated with older age (35+ years: 4.31; 3.34 to 5.55), ≥6 sexual partners (1.58; 1.01 to 2.44) and sex abroad (2.23; 1.71 to 2.91). CTR ≥0.015 mg/L was less likely in isolates from heterosexuals of black Caribbean or African ethnicity (0.29; 0.20 to 0.41, 0.66; 0.43 to 0.99), with a concurrent chlamydial infection (0.25; 0.19 to 0.34) or women (0.57; 0.46 to 0.71). Over 600 isolates (CTR ≥0.015 mg/L) were typed; the majority were in Genogroup 1407, containing sequence type 1407.

    Conclusions The emergence and spread of gonorrhoea with reduced susceptibility to ceftriaxone seems a realistic prospect, most likely in those involved in ‘rapid-transmission’ or bridging sexual networks.

    • NEISSERIA GONORRHOEA
    • EPIDEMIOLOGY (GENERAL)
    • PUBLIC HEALTH
    • ANTIBIOTIC RESISTANCE
    • GENITOURINARY MEDICINE

    Statistics from Altmetric.com

    Introduction

    Ceftriaxone is currently the first-line antimicrobial therapy used to treat infection with Neisseria gonorrhoeae in many countries across the world. The dosage regimen varies from 250 to 1 g/L intramuscular injections and is frequently prescribed alongside other antimicrobials, such as azithromycin, as part of dual therapy.1 ,2 N. gonorrhoeae has developed antimicrobial resistance (AMR) to all agents formerly used to treat infection. For all previously used single agents, AMR prevalence has breached the WHO recommended threshold of 5%.3

    Ceftriaxone treatment failures have already been reported, mainly from pharyngeal infections,4–6 and while the use of a dual therapy aims to delay the spread of resistance,7 it seems inevitable that gonococcal AMR to ceftriaxone will become more prevalent. Limited treatment options remain if ceftriaxone becomes unusable and there are few new antimicrobials in development.8

    The Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) in England and Wales has identified only 17 isolates exhibiting ceftriaxone resistance (minimum inhibitory concentration (MIC) ≥0.125 mg/L), in its 13-year history, and only 3 in 2013.9 However, it is prudent to be vigilant to a drift in the ceftriaxone susceptibility profile of the gonococcal population, to ensure guidelines on patient treatment and care remain fit for purpose. We present a unique analysis of GRASP data using a lower MIC cut-off to identify population groups associated with a drift towards higher ceftriaxone MICs in England and Wales, and among whom ceftriaxone-resistant gonorrhoea may be likely to emerge and spread.

    Methods

    Data sources

    Isolates submitted to GRASP between 2007 and 2013 were tested for susceptibility to ceftriaxone and the MIC recorded, as per the standard GRASP protocol described elsewhere.10 ,11 In brief, each year between July and September, consecutive gonorrhoea diagnoses that were cultured in 27 participating specialist sexually transmitted infection (STI) clinics (known as genitourinary medicine, GUM, clinics) in England and Wales were sent to Public Health England's Sexually Transmitted Bacteria Reference Unit (STBRU) and tested by an agar dilution method for antimicrobial susceptibility to seven antimicrobials, including ceftriaxone. These laboratory data were matched to patient clinical, demographic and behavioural data from the clinic. Public Health England has permission to handle data obtained by GRASP under section 251 of the UK National Health Service Act of 2006 (previously section 60 of the Health and Social Care Act of 2001), which was renewed annually by the ethics and confidentiality committee of the National Information Governance Board (now the HRA Confidentiality Advisory Group).

    Descriptive analyses of ceftriaxone MIC

    To describe the drift in N. gonorrhoeae susceptibility to ceftriaxone following the change in treatment guidelines (2011),1 MIC ranges were presented graphically for each year between 2007 and 2013 by gender and sexual orientation (men who have sex with men (MSM), heterosexual men and heterosexual women).

    Risk factor analysis

    To identify risk factors associated with higher ceftriaxone MICs, logistic univariate and multivariable models were developed using GRASP data from 2007 to 2013. The outcome of interest was infection with an N. gonorrhoeae strain with a ceftriaxone MIC of ≥0.015 mg/L. This cut-off was used because it is the mid-point MIC dilution used in GRASP (range 0.002–1 mg/L) and provided a robust sample size for regression analyses. The explanatory variables included were age, ethnicity, number of sexual partners in the 3 months prior to diagnosis, sex abroad in the 3 months prior to diagnosis, symptoms present, isolation site, previous infection with gonorrhoea, concurrent chlamydial infection, HIV status, year of diagnosis and gender (heterosexual model only). Any associations that were significant in univariate models at p<0.05 were included and retained in the multivariable model if they remained significant. All analyses were conducted in STATA V.13. Separate models were created for heterosexual patients (men and women grouped) and male patients who self-identified as homosexual or bisexual (MSM), due to differing prevalence and distribution of antimicrobial susceptibility in these groups. The GRASP data set contained few female patients that identified as homosexual (<1%), so no separate analysis was performed for this group.

    Strain typing

    GRASP has routinely typed isolates with cefixime MIC ≥0.125 mg/L using N. gonorrhoeae-Multi Antigen Sequence Typing (NG-MAST).12 ,13 Nearly all isolates with cefixime MIC ≥0.125 mg/L from MSM and heterosexual patients between 2007 and 2013 have ceftriaxone MICs ≥0.015 mg/L (98.8%; 621/628). We present here a descriptive analysis of the sequence types of these 621 isolates from MSM and heterosexuals (men and women grouped) with a ceftriaxone MIC ≥0.015 mg/L. Strains were differentiated on the basis of sequence variation in fragments of two genes: porin PorB (porB) and subunit B of the transferrin-binding protein (tbpB). Sequence types (STs) were aligned in BioNumerics V.6.1 to examine relatedness. Different STs which were >99% similar in the two genes sequenced were grouped into Genogroups to demonstrate closely related strains. A Genogroup was named according to its most predominant ST; thus, Genogroup 1407 includes ST1407 (por allele 908; tbpB allele 110) and all other STs which were >99% similar to ST1407.

    Results

    Ceftriaxone MIC 2007–2013

    Between 2007 and 2013, there were 8829 isolates from patients with known sexual orientation and gender tested for ceftriaxone susceptibility. Nearly half were from MSM (4203; 47.6%), a third were from heterosexual men (2732; 30.9%) and a fifth were from heterosexual women (1894; 21.4%). In total, 19.7% (1737/8829) isolates were identified as exhibiting a ceftriaxone MIC of ≥0.015 mg/L and this increased from 14.4% to 22.5% between 2007 and 2013. Almost one third of isolates from MSM had a ceftriaxone MIC ≥0.015 mg/L (30.4%; 1279/4203), a greater proportion than for heterosexuals (9.9%; 458/4626). During this period, ceftriaxone MICs for isolates from MSM ranged from 0.002 to 0.125 mg/L, and isolates from heterosexuals ranged from 0.002 to 0.25 mg/L (figure 1). The modal ceftriaxone MIC for isolates from MSM was 0.002 mg/L in 2007 and 0.004 mg/L for all subsequent years, except for 2010 when the modal MIC rose to 0.03 mg/L and for 2011 when the modal MIC was 0.002 mg/L. For isolates from heterosexuals, the modal ceftriaxone MIC remained at 0.002 mg/L from 2007 to 2011, increasing to 0.004 mg/L in 2012 and 2013.

    Figure 1

    Change in susceptibility to ceftriaxone between 2007 and 2013 for men who have sex with men (MSM) and heterosexuals (men and women grouped). MIC, minimum inhibitory concentration.

    Risk factors among MSM associated with ceftriaxone MIC ≥0.015 mg/L

    Results from the MSM univariate analysis found that MSM of Asian ethnicity compared with MSM of white ethnicity (crude odds ratio (cOR): 1.42, 95% confidence interval (CI) 1.07 to 1.88), with a history of previous gonorrhoea (cOR: 1.34, CI 1.16 to 1.54) or diagnosed in 2009 or 2010 relative to 2007 (cOR: 1.86, CI 1.39 to 2.49 and cOR: 1.98, CI 1.48 to 2.63) were significantly more likely to be infected with N. gonorrhoeae with a ceftriaxone MIC ≥0.015 mg/L (table 1). MSM with symptomatic gonococcal infection (cOR: 0.76, CI 0.65 to 0.89) or diagnosed in 2008 or 2012 compared with 2007 (cOR: 0.53, CI 0.37 to 0.76 and cOR: 0.75, CI 0.57 to 0.99) were less likely to be infected with N. gonorrhoeae with a ceftriaxone MIC ≥0.015 mg/L.

    Table 1

    Univariate and multivariable analyses of patient characteristics associated with Neisseria gonorrhoeae with a ceftriaxone MIC ≥0.015 mg/L among MSM, 2007–2013

    In the multivariable model, the associations with symptomatic infection and year of diagnosis remained: MSM with a symptomatic gonococcal infection or diagnosed in 2008 compared with 2007 were less likely to be infected with N. gonorrhoeae with a ceftriaxone MIC ≥0.015 mg/L (symptomatic infection adjusted OR (aOR): 0.77, CI 0.66 to 0.90; diagnosed in 2008, aOR: 0.55, CI 0.38 to 0.80). MSM diagnosed in 2009 or 2010 compared with 2007 were more likely to be infected with N. gonorrhoeae with a ceftriaxone MIC ≥0.015 mg/L (in 2009, aOR: 1.88, CI 1.40 to 2.52 and in 2010, aOR: 1.98, CI 1.48 to 2.64).

    Risk factors in heterosexual men and women associated with ceftriaxone MIC ≥0.015 mg/L

    Results from the univariate analysis found that heterosexuals older than 24 years (25–34 years: cOR: 2.17, CI 1.72 to 2.73 and 35+ years: cOR: 4.31, CI 3.34 to 5.55), with ≥6 sexual partners in 3 months prior to diagnosis (cOR: 1.58, CI 1.01 to 2.44), who had had sex abroad 3 months prior to diagnosis (cOR: 2.23, CI 1.71 to 2.91), who were HIV positive (cOR: 3.56, CI 1.70 to 7.46) or who were diagnosed in 2009, 2012 or 2013 compared with 2007 (cOR: 2.09, CI 1.44 to 3.05; cOR: 1.62, CI 1.07 to 2.44; cOR: 2.88, CI 1.97 to 4.20) or with a rectal or throat isolation site compared with a genital isolation site (cOR: 3.18, CI 1.85 to 5.48; cOR: 5.26, CI 3.01 to 9.17) were more likely to be infected with N. gonorrhoeae with a ceftriaxone MIC ≥0.015 mg/L (table 2). Heterosexuals of black Caribbean, black African or black other (classified by the patient as any other black background than black Caribbean or black African) ethnicity compared with those of white ethnicity, with previous gonorrhoea infection or with concurrent chlamydial infection were less likely to be infected with N. gonorrhoeae with a ceftriaxone MIC ≥0.015 mg/L (black Caribbean cOR: 0.29, CI 0.20 to 0.41; black African cOR: 0.66, CI 0.43 to 0.99; black other cOR: 0.21, CI 0.10 to 0.41; previous gonorrhoea infection cOR: 0.75, CI 0.62 to 0.92; concurrent chlamydia cOR: 0.25, CI 0.19 to 0.34). Women were also less likely to be infected with N. gonorrhoeae with a ceftriaxone MIC ≥0.015 mg/L than men (cOR: 0.57, CI 0.46 to 0.71).

    Table 2

    Univariate and multivariable analyses of patient characteristics associated with Neisseria gonorrhoeae with a ceftriaxone MIC ≥0.015 mg/L among heterosexual men and women, 2011–2013

    In the multivariable model, the association with age, year of diagnosis, ethnicity and concurrent chlamydial infection, gender and isolation site remained; heterosexuals older than 24 years (25–34 years: aOR: 1.56, CI 1.34 to 1.82; 35+ years: aOR: 1.96, CI 1.66 to 2.31), who were diagnosed in 2009, 2010 or 2011 compared with 2007 (2009: aOR 1.89, CI 1.50 to 2.39; 2010: aOR: 1.85, CI 1.46 to 2.39, 2011: aOR: 1.42, CI 1.12 to 1.81), with a rectal or throat isolation site compared with a genital isolation site (rectal aOR: 1.69, CI 1.46 to 1.96; throat aOR: 1.84, CI 1.44 to 2.34) were more likely to be infected with N. gonorrhoeae with a ceftriaxone MIC ≥0.015 mg/L. Women compared with men, patients of black Caribbean, black African or black other ethnicity compared with patients of white ethnicity, patients with a concurrent chlamydial infection or who were diagnosed in 2008 compared with 2007 were less likely to be infected with N. gonorrhoeae with a ceftriaxone MIC ≥0.015 mg/L (women aOR: 0.42, CI 0.34 to 0.52; black Caribbean: aOR: 0.36, CI 0.28 to 0.47; black African: aOR: 0.50, CI 0.35 to 0.71; black other: aOR: 0.32, CI 0.20 to 0.51; concurrent chlamydia: aOR: 0.58, CI 0.50 to 0.68; 2008: aOR: 0.60, CI 0.45 to 0.80).

    Strain-type analysis

    Between 2007 and 2013, 69 different NG-MAST STs were identified but most of these (90.3%: 561/621) formed a closely related group of strains (G1407), which were either ST 1407 (69.4%; 428/621) or >99% similar to this type. G1407 predominated every year in both heterosexual and MSM patients; however, ST1407 has become less predominant over time in both patient groups with greater diversity of other types observed within G1407, particularly in 2012 and 2013 (figure 2). The proportion of STs not part of the G1407 cluster has increased in isolates recovered from MSM in particular 2012–2013 (figure 2).

    Figure 2

    Neisseria gonorrhoeae-Multi Antigen Sequence Typing (NG-MAST) types observed in selected Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) isolates from men who have sex with men and heterosexual patients from 2007 to 2013. ST, sequence type.

    Discussion

    Reduced susceptibility of N. gonorrhoeae to ceftriaxone in England and Wales is widespread. Ceftriaxone MIC ≥0.015 mg/L is common in N. gonorrhoeae isolates from MSM, although the modal ceftriaxone MIC for gonococci infecting MSM appears to have stabilised in recent years. In comparison, although less common, there is a drift towards higher MICs in gonococci infecting heterosexual men and women, with those in higher risk sexual networks more likely to be infected with a N. gonorrhoeae strain with a ceftriaxone MIC ≥0.015 mg/L. Given this, the emergence and spread of N. gonorrhoeae with increasing ceftriaxone MICs in the UK seem a realistic prospect, which could potentially lead to an increase in treatment failures, onward transmission of resistant infections and an increase in associated sequelae. Surveillance of N. gonorrhoeae AMR should remain a priority in the UK, and actions are taken now to develop alternative gonorrhoea treatment strategies in preparation for an increase in ceftriaxone-resistant N. gonorrhoeae.

    The use of a sentinel surveillance data set, GRASP, for this analysis is both a strength and weakness. GRASP provides an invaluable and unique resource within the UK to explore associations between AMR and patient characteristics. However, as a sentinel programme it may not be entirely representative of all infections in England and Wales, which may limit the generalisability of the findings. The strain typing analysis should be interpreted with considerable caution due to the inherent selection bias of the isolates chosen for typing. We do not know the strain types of the cefixime susceptible isolates (MIC <0.125 mg/L), isolates with a ceftriaxone MIC <0.015 mg/L or of all isolates with ceftriaxone MIC >0.015 mg/L. Another limitation of this study is that the MIC threshold chosen for the outcome (MIC ≥0.015 mg/L) is not clinically relevant, as treatment failure has only been documented where the ceftriaxone MIC is ≥0.125 mg/L. However, the current prevalence of isolates in England and Wales with ceftriaxone MIC ≥0.125 mg/L is extremely low. By reducing the MIC threshold for the outcome of this study, we have been able to identify population groups most at risk of infection with N. gonorrhoeae with higher ceftriaxone MICs, which may be the same groups at risk of infection with N. gonorrhoeae with ceftriaxone MIC ≥0.125 mg/L.

    We present evidence that, among heterosexuals, N. gonorrhoeae with a ceftriaxone MIC ≥0.015 mg/L may be circulating in sexual networks characterised by older age (especially ≥35 years), rapid partner turnover and sex abroad. N .gonorrhoeae with a ceftriaxone MIC ≥0.015 mg/L may have been introduced into these networks from other populations where the circulating gonococci exhibit higher ceftriaxone MICs such as in Asia6 ,14 and Europe.15 ,16 Recently, the European Gonococcal Antimicrobial Surveillance Programme found the mean geometric MIC for ceftriaxone to be higher in heterosexual men than MSM,16 suggesting the emerging trend identified in the UK is already well established in heterosexuals than in other European countries. An alternative explanation is the potential introduction of these strains from bridging populations (eg, bisexual men) between the heterosexual and MSM networks. A drift towards higher ceftriaxone MICs has also been identified in China and India,17 ,18 although there is limited patient data available to ascertain which groups are most affected by this increase.

    Women, heterosexuals of black ethnicity (Caribbean, African or any other black ethnicity) and those diagnosed with chlamydia were significantly less likely to be infected with N. gonorrhoeae with a ceftriaxone MIC ≥0.015 mg/L, repeating patterns seen for other antimicrobials including cefixime.19 ,20 These characteristics may reflect different sexual networks and their distance from bridging populations.21 ,22 In England, heterosexuals with a concurrent chlamydial infection are likely to have been referred to specialist STI services through the National Chlamydia Screening Programme (NCSP). The NCSP opportunistically tests sexually active people aged 15–24 years attending general practice, reproductive health services and other non-healthcare settings, who may belong to sexual networks with few links to older heterosexuals and MSM.23

    N. gonorrhoeae with a ceftriaxone MIC ≥0.015 mg/L is more evenly spread across MSM diagnosed with gonorrhoea compared with heterosexuals, although MSM with a history of previous gonorrhoea were more at risk than MSM without a history of previous gonorrhoea. Repeated exposure to gonorrhoea treatment could create a selection pressure for reduced susceptibility to ceftriaxone within commensal Neisseria sp. or related species which could serve as reservoirs for gonococcal resistance,24 or this association may reflect a greater frequency of higher risk sexual activity, increasing the likelihood of acquiring a less susceptible strain.

    MSM with an asymptomatic infection were also at greater risk of infection with N. gonorrhoeae with a ceftriaxone MIC ≥0.015 mg/L. Asymptomatic N. gonorrhoeae infections, particularly asymptomatic pharyngeal infections, are more likely to develop genetic mutations or acquire DNA conferring higher MICs to ceftriaxone as these infections remain undetected and untreated for longer.24 However, there was no difference in ceftriaxone susceptibility between isolation sites among MSM in our sample.

    In the univariate heterosexual model, patients with symptoms were more likely to be infected with N. gonorrhoeae with a ceftriaxone MIC ≥0.015 mg/L. This association with a symptomatic infection is not sustained in the heterosexual multivariable model when adjusting for other variables, suggesting that the presence of symptoms is a proxy for patient gender, as men are more likely to have a symptomatic infection and men are more likely to be infected with N. gonorrhoeae with ceftriaxone MIC ≥0.015 mg/L. There was a difference in likelihood of N. gonorrhoeae exhibiting ceftriaxone MIC ≥0.015 mg/L between isolate sites in samples from heterosexuals. However, this association is likely due to misclassification of patient sexual orientation for patients with a rectal or throat sample, and therefore the association identified is representative of patients in the MSM sexual network rather than any difference in susceptibility between isolation sites.

    NG-MAST data for the isolates included in this study indicate that G1407 has declined in MSM but have persisted in heterosexuals since 2010. Genogroup 1407 is strongly associated with raised MICs for ceftriaxone and cefixime.13 Whereas most isolates with raised ceftriaxone MICs from heterosexuals remain part of G1407, a steadily increasing proportion of strains in MSM with raised ceftriaxone MICs were distinct from the G1407 cluster. Genetic diversification may indicate repeated emergence of N. gonorrhoeae with a ceftriaxone MIC ≥0.015 mg/L within MSM populations. ST 1407, which is the predominant ST within genogroup 1407, is thought to have originated in Japan but has disseminated globally.25 It has already been associated with numerous treatment failures using cefixime and ceftriaxone6 ,25 and is capable of developing a higher level of ceftriaxone resistance (MIC ≥0.125 mg/L).26 NG-MAST is recommended as a suitable tool for short-term epidemiological typing studies27 and is the method applied routinely within GRASP. It has clearly been identified that the burden of cefixime and ceftriaxone resistance in many parts of the world is due to strains within the G1407 group of closely related organisms. Given that NG-MAST examines fragments of just two hypervariable loci, it is inevitable that it will lack the discriminatory power to fully examine the evolution and dissemination of cephalosporin resistance. Next-generation sequencing provides the opportunity to examine variation within other markers such as penA and mtrA as well as across the whole genome, allowing greater exploration of strain differences within each patient group. This approach in the USA identified two major lineages of strains, which could be associated with different patient groups and differed in their geographical distributions.4 ,28 A similar approach within GRASP and Europe could provide insight into the dissemination of resistance, which would further improve our understanding of at-risk groups and facilitate targeted intervention.

    Despite the observed increasing drift in ceftriaxone MICs, there remain only a small number of cases where ceftriaxone MIC has exceeded 0.125 mg/L, the clinically relevant threshold which results in treatment failures. Dual therapy of ceftriaxone and azithromycin was introduced on the basis that it would delay the spread of ceftriaxone resistance, prolonging its lifespan for treatment.29 While this rationale has been challenged,30 it is evident that repeated recommendation of new monotherapies has failed to delay emergence of resistance. It remains to be seen how effective the dual therapy strategy will be long term. The importance of continued surveillance, adherence to the recommended guidelines, vigilance for possible treatment failure and test of cure to help preserve existing treatment options is clear.

    Key messages

    • Treatment of gonorrhoea with the first-line therapy ceftriaxone is threatened by the emergence of antimicrobial resistance.

    • Neisseria gonorrhoeae with a ceftriaxone minimum inhibitory concentration of ≥0.015 mg/L is common.

    • Patients at higher risk of infection with a ceftriaxone-reduced susceptible strain of N. gonorrhoeae are those involved in ‘rapid transmission’ or bridging sexual networks.

    Acknowledgments

    The authors thank all GRASP collaborators including the following: members of the Sexually Transmitted Bacteria Reference Unit and the HIV/STI Department at Public Health England (J Anderson, M Cole, N Ellis, N Quaye, H Bolt, A Kundu, B Sile, H Mohammed); the GRASP collaborative steering group (DM Livermore, C Bignell, K Eastick, A Johnson, J Paul, A Robinson, J Ross, J Wade, C Ison, N Woodford, R Mulla, T Sadiq, H Fifer, A Andreasen) and the collaborating centres—Birmingham (M David, J Ross), Bristol (OM Williams, P Horner), Brighton (M Cubbon, G Dean), Cambridge (N Brown, C Carne), Cardiff (R Howe, R Drayton), Gloucester (P Moore, A DeBurgh-Thomas), Homerton (A Jepson, M Nathan), Kings (J Wade, M Tenant-Flowers), Leeds (M Denton, J Clarke), Liverpool (J Anson, M Bradley), London Charing Cross, Chelsea and Westminster (K McLean, A McOwan, G Paul, H Donaldson), Luton (T Balachandran), Manchester (A Qamruddin, A Sukthankar), Newcastle (M Valappil, KN Sankar), Newport (S Majumdar, H Birley), Northampton (M Minassian, L Riddell), Nottingham (V Weston, C Bignell, M Pammi), Reading (G Wildman, S Iyer), Sheffield (L Prtak, C Bowman, C Dewnsap), St George's (P Riley, P Hay), St Mary's (D Wilkinson), University College Hospital (B Macrae, A Robinson, E Jungmann), Wolverhampton (D Dobie, A Tariq) and Woolwich (M Dall'Antonia, J Russell).

    References

    View Abstract

    Footnotes

    • Handling editor Jackie A Cassell

    • Collaborators The GRASP collaborative steering group (DM Livermore, C Bignell, K Eastick, A Johnson, J Paul, A Robinson, J Ross, J Wade, C Ison, N Woodford, R Mulla, T Sadiq, H Fifer, A Andreasen) and the collaborating centers—Birmingham (M David, J Ross), Bristol (OM Williams, P Horner), Brighton (M Cubbon, G Dean), Cambridge (N Brown, C Carne), Cardiff (R Howe, R Drayton), Gloucester (P Moore, A DeBurgh-Thomas), Homerton (A Jepson, M Nathan), Kings (J Wade, M Tenant-Flowers), Leeds (M Denton, J Clarke), Liverpool (J Anson, M Bradley), London Charing Cross, Chelsea and Westminster (K McLean, A McOwan, G Paul, H Donaldson), Luton ( T Balachandran), Manchester (A Qamruddin, A Sukthankar), Newcastle (M Valappil, KN Sankar), Newport (S Majumdar, H Birley), Northampton (M Minassian, L Riddell), Nottingham (V Weston, C Bignell, M Pammi), Reading (G Wildman, S Iyer), Sheffield (L Prtak, C Bowman, C Dewnsap), St George's (P Riley, P Hay), St Mary's (D Wilkinson), University College Hospital (B Macrae, A Robinson, E Jungmann), Wolverhampton (D Dobie, A Tariq) and Woolwich (M Dall'Antonia, J Russell). GRASP has been funded totally (2000–2004) and partly (2005–2010) by the Department of Health (England) and by Public Health England.

    • Contributors KT, SC and GH collaborated in the writing of the manuscript. CO and NQ reviewed drafts. KT, SC, GH and CO were involved in the design of the study. KT conducted all analyses. CO collected clinical data and completed preliminary analyses. NQ and SC conducted MIC testing on samples.

    • Funding GRASP and authors of this study are funded by Public Health England.

    • Competing interests GH is a STI surveillance consultant for the Swiss government and has received grants for the National Institute of Health Research (NIHR) for Health Protection Research Units and also from NIHR for the Health Technologies Assessment Programme. SC has received grants from the European Centre for Disease Prevention and Control for the European Network for STI Microbiology and also a grant from the NIHR for a randomised controlled trial to compare the clinical effectiveness and safety of gentamicin and ceftriaxone in the treatment of gonorrhoea. In addition, SC was involved in small evaluations of other/novel antimicrobial compounds conducted for the following companies who provided funds to cover costs: Merck, Wockhardt Ltd and PTC Therapeutics.

    • Ethics approval Public Health England has permission to handle data obtained by GRASP under section 251 of the UK National Health Service Act of 2006 (previously section 60 of the Health and Social Care Act of 2001), which was renewed annually by the ethics and confidentiality committee of the National Information Governance Board (now the HRA Confidentiality Advisory Group).

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement Data sharing is per PHE HIV/STI department data sharing guidance (https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/423828/20150424_PHE_HIV_STI_Data_Sharing_Policy_v4.1.pdf).

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.