Gonococcal Resistance To Antimicrobials Surveillance Programme Research Articles

Projecting the development of antimicrobial resistance in Neisseria gonorrhoeae from antimicrobial surveillance data: a mathematical modelling study

BackgroundThe World Health Organization recommends changing the first-line antimicrobial treatment for gonorrhoea when ≥ 5% of Neisseria gonorrhoeae cases fail treatment or are resistant. Susceptibility to ceftriaxone, the last remaining treatment option has been decreasing in many countries. We used antimicrobial resistance surveillance data and developed mathematical models to project the time to reach the 5% threshold for resistance to first-line antimicrobials used for N. gonorrhoeae.MethodsWe used data from the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) in England and Wales from 2000–2018 about minimum inhibitory concentrations (MIC) for ciprofloxacin, azithromycin, cefixime and ceftriaxone and antimicrobial treatment in two groups, heterosexual men and women (HMW) and men who have sex with men (MSM). We developed two susceptible-infected-susceptible models to fit these data and produce projections of the proportion of resistance until 2030. The single-step model represents the situation in which a single mutation results in antimicrobial resistance. In the multi-step model, the sequential accumulation of resistance mutations is reflected by changes in the MIC distribution.ResultsThe single-step model described resistance to ciprofloxacin well. Both single-step and multi-step models could describe azithromycin and cefixime resistance, with projected resistance levels higher with the multi-step than the single step model. For ceftriaxone, with very few observed cases of full resistance, the multi-step model was needed to describe long-term dynamics of resistance. Extrapolating from the observed upward drift in MIC values, the multi-step model projected ≥ 5% resistance to ceftriaxone could be reached by 2030, based on treatment pressure alone. Ceftriaxone resistance was projected to rise to 13.2% (95% credible interval [CrI]: 0.7–44.8%) among HMW and 19.6% (95%CrI: 2.6–54.4%) among MSM by 2030.ConclusionsNew first-line antimicrobials for gonorrhoea treatment are needed. In the meantime, public health authorities should strengthen surveillance for AMR in N. gonorrhoeae and implement strategies for continued antimicrobial stewardship. Our models show the utility of long-term representative surveillance of gonococcal antimicrobial susceptibility data and can be adapted for use in, and for comparison with, other countries.

Antimicrobial-resistant gonorrhoea: the national public health response, England, 2013 to 2020.

Neisseria gonorrhoeae has developed resistance to all antimicrobials used to treat gonorrhoea, and the emergence of ceftriaxone-resistant strains threatens the last-line option for empirical treatment. The 2013 Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) Action Plan recommended measures to delay the spread of antimicrobial resistance (AMR) in N. gonorrhoeae in England. We reviewed trends in gonococcal AMR since then and the experience of implementing the Action Plan’s recommendations to respond to incidents of resistant N. gonorrhoeae. Between 2013 and 2019, diagnoses of gonorrhoea in England rose by 128% to 70,922, the largest annual number ever reported. Over this period, N. gonorrhoeae isolates have become less susceptible to azithromycin (minimum inhibitory concentration > 0.5 mg/L), increasing from 4.7% in 2016 to 8.7% in 2020; this led to a change in first-line treatment for gonorrhoea in the United Kingdom (UK) from dual therapy (ceftriaxone/azithromycin) to ceftriaxone monotherapy in 2019. We also detected the first global treatment failure for pharyngeal gonorrhoea with a dual-therapy regimen (ceftriaxone/azithromycin), followed by an additional six ceftriaxone-resistant strains. Continued engagement of sexual health clinicians and laboratories with the UK Health Security Agency (UKHSA) is essential for the timely detection of N. gonorrhoeae strains with ceftriaxone resistance and to rapidly contain transmission of these strains within England.

Phylogenomic analysis of Neisseria gonorrhoeae transmission to assess sexual mixing and HIV transmission risk in England: a cross-sectional, observational, whole-genome sequencing study

SummaryBackgroundCharacterising sexual networks with transmission of sexually transmitted infections might allow identification of individuals at increased risk of infection. We aimed to investigate sexual mixing in Neisseria gonorrhoeae transmission networks between women, heterosexual men, and men who report sex with men (MSM), and between people with and without HIV.MethodsIn this cross-sectional observational study, we whole-genome sequenced N gonorrhoeae isolates from the archive of the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP).w Isolates that varied by five single nucleotide polymorphisms or fewer were grouped into clusters that represented sexual networks with N gonorrhoeae transmission. Clusters were described by gender, sexual risk group, and HIV status.FindingsWe sequenced 1277 N gonorrhoeae isolates with linked clinical and sociodemographic data that were collected in five clinics in England during 2013–16 (July 1 to Sept 30 in 2013–15; July 1 to Sept 9 in 2016). The isolates grouped into 213 clusters. 30 (14%) clusters contained isolates from heterosexual men and MSM but no women and three (1%) clusters contained isolates from only women and MSM. 146 (69%) clusters comprised solely people with negative or unknown HIV status and seven (3%) comprised only HIV-positive people. 60 (28%) clusters comprised MSM with positive and negative or unknown HIV status.InterpretationN gonorrhoeae molecular data can provide information indicating risk of HIV or other sexually transmitted infections for some individuals for whom such risk might not be known from clinical history. These findings have implications for sexual health care, including offering testing, prevention advice, and preventive treatment, such as HIV pre-exposure prophylaxis.FundingNational Institute for Health Research Health Protection Research Unit; Wellcome; Public Health England.

Does gonorrhoea screening intensity play a role in the early selection of antimicrobial resistance in men who have sex with men (MSM)? A comparative study of Belgium and the United Kingdom.

Background: It is unclear why antimicrobial resistance in Neisseriagonorrhoeae in the United Kingdom (UK) and the United States has tended to first appear in men who have sex with men (MSM). We hypothesize that increased exposure to antimicrobials from intensive STI screening programmes plays a role. Methods: We assess if there is a difference in the distribution of azithromycin, cefixime and ceftriaxone minimum inhibitory concentrations (MICs) between MSM and women in the United Kingdom (UK) where 70% of MSM report STI screening in the past year vs. Belgium where 9% report STI screening in the past year. Our hypothesis is that MICs of the MSM should be higher than those of the women in the UK but not Belgium. Data for the MICs were taken from the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) in the UK in 2010/2011 and 2014 and a similar national surveillance programme in Belgium in 2013/2014 (the first most complete available data). We used the Mann-Whitneytest to compare the MIC distributions between MSM and women within each country Results: In the UK the MICs for all three antimicrobials were significantly higher in MSM than women at both time points (P all <0.0005). In Belgium only the MIC distribution for azithromycin was higher in MSM (P<0.0005). Conclusion: The findings for cefixime and ceftriaxone, but not azithromycin are compatible with our hypothesis that screening-intensity could contribute to the emergence of AMR. Numerous other interpretations of our results are discussed.

Does gonorrhoea screening intensity play a role in the early selection of antimicrobial resistance in men who have sex with men (MSM)? A comparative study of Belgium and the United Kingdom

Background: It is unclear why antimicrobial resistance in Neisseria gonorrhoeae in the United Kingdom (UK) and the United States has tended to first appear in men who have sex with men (MSM). We hypothesize that increased exposure to antimicrobials from intensive STI screening programmes plays a role. Methods: We assess if there is a difference in the distribution of azithromycin, cefixime and ceftriaxone minimum inhibitory concentrations (MICs) between MSM and women in the United Kingdom (UK) where 70% of MSM report STI screening in the past year vs. Belgium where 9% report STI screening in the past year. Our hypothesis is that MICs of the MSM should be higher than those of the women in the UK but not Belgium. Data for the MICs were taken from the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) in the UK in 2010/2011 and 2014 and a similar national surveillance programme in Belgium in 2013/2014 (the first most complete available data). We used the Mann–Whitney test to compare the MIC distributions between MSM and women within each country Results: In the UK the MICs for all three antimicrobials were significantly higher in MSM than women at both time points (P all <0.0005). In Belgium only the MIC distribution for azithromycin was higher in MSM (P<0.0005). Conclusion: The findings for cefixime and ceftriaxone, but not azithromycin are compatible with our hypothesis that screening-intensity could contribute to the emergence of AMR. Numerous other interpretations of our results are discussed.

Does gonorrhoea screening intensity play a role in the early selection of antimicrobial resistance in men who have sex with men (MSM)? A comparative study of Belgium and the United Kingdom

Background: It is unclear why antimicrobial resistance in Neisseria gonorrhoeae in the United Kingdom (UK) and the United States has tended to first appear in men who have sex with men (MSM). We hypothesize that increased exposure to antimicrobials from intensive STI screening programmes plays a role. Methods: We assess if there is a difference in the distribution of azithromycin, cefixime and ceftriaxone minimum inhibitory concentrations (MICs) between MSM and women in the United Kingdom (UK) where 70% of MSM report STI screening in the past year vs. Belgium where 9% report STI screening in the past year. Our hypothesis is that MICs of the MSM should be higher than those of the women in the UK but not Belgium. Data for the MICs were taken from the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) in the UK in 2010/2011 and 2014 and a similar national surveillance programme in Belgium in 2013/2014 (the first most complete available data). We used the Mann-Whitneytest to compare the MIC distributions between MSM and women within each country Results: In the UK the MICs for all three antimicrobials were significantly higher in MSM than women at both time points (P all <0.0005). In Belgium only the MIC distribution for azithromycin was higher in MSM (P<0.0005). Conclusion: The findings for cefixime and ceftriaxone, but not azithromycin are compatible with our hypothesis that screening-intensity could contribute to the emergence of AMR. Numerous other interpretations of our results are discussed.

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

To describe trends in prevalence, susceptibility profile and risk factors for MDR Neisseria gonorrhoeae (MDR-NG) in England and Wales. 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. 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)]. 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.

P001 What is the evidence that previous azithromycin treatment for chlamydia or gonorrhoea is associated with neisseria gonorrhoeae azithromycin resistance?

IntroductionThe prevalence of azithromycin resistance in Neisseria gonorrhoeae (NG) including high-level resistance (HL-AziR NG) is increasing in England. It has been suggested that exposure to azithromycin at sub-optimal doses may...

Drifting towards ceftriaxone treatment failure in gonorrhoea: risk factor analysis of data from the Gonococcal Resistance to Antimicrobials Surveillance Programme in England and Wales

ObjectivesTreatment 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...

O035 Is cefixime back? Trends in gonococcal resistance to current and previous front line therapies in England and Wales since the 2011 guideline change

Background/introduction Antimicrobial resistance (AMR) in Neisseria gonorrhoeae threatens effective treatment and infection control. Treatment guidelines for gonorrhoea are revised when the prevalence of resistance to first-line therapy exceeds 5%; in the UK this last occurred in 2011, prompting a treatment guideline change from cefixime to dual therapy with ceftriaxone and azithromycin. Aim(s)/objectives Describe emerging trends in gonococcal resistance to current and previous first-line therapies using data from the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP). Methods GRASP collects N. gonorrhoeae isolates from July–September annually from 27 genitourinary medicine clinics in England and Wales. The minimum inhibitory concentration (MIC) of each isolate to seven antimicrobials is determined, then linked to demographic, clinical and behavioural data. Data from 2011–2014 were considered in this analysis. For each antimicrobial, the test for trend in resistance was determined and MIC distributions were compared using the Kolmogorov–Smirnov test. Results In 2014, there was no ceftriaxone resistance (MIC ≥ 0.125 mg/L), but the modal MIC drifted to 0.004 mg/L from 0.002 mg/L in 2011 (p Discussion/conclusion Despite the decline in resistance in cefixime, the drifting MIC distribution suggests isolates are less susceptible than previous years. Ongoing monitoring of AMR with strong compliance with national treatment guidelines is essential to retain gonorrhoea as a treatable infection.

O23 Porapseudogene deletion amongstneisseria gonorrhoeaeisolates from the gonococcal resistance to antimicrobials surveillance programme (GRASP)

Background/introduction In the last four years, isolates of N. gonorrhoeae have been identified in Australia, Sweden, Scotland and England which lack the gonococcal porA pseudogene and consequently result in negative results in the diagnostic porA pseudogene real-time-PCR (RT-PCR) for N. gonorrhoeae. Aim(s)/objectives This study sought to determine the prevalence of porA pseudogene negative isolates amongst isolates received at Public Health England (PHE) through the national gonococcal resistance to antimicrobials surveillance programme (GRASP). Methods DNA lysates were prepared from 533 N. gonorrhoeae isolates received from 20 centres via GRASP during 2011. Any isolate with a RT-PCR por A pseudogene negative result was repeated from a fresh culture and the porA gene was additionally DNA sequenced. Isolates were additionally tested using the gonococcal opa gene RT-PCR. Results Four isolates (4/533, 0.8%) were found to be reproducibly negative with the porA pseudogene RT-PCR, but were positive with opa gene RT-PCR. DNA sequencing determined that two isolates contained the Neisseria meningitidis porA gene. Both isolates were from patients attending a clinic in SouthLondon. Discussion/conclusion Less than one percent of the GRASP isolates from patients attending clinics across England expressed the meningococcal porA gene and therefore tested negative on the in-house porA assay. The low prevalence indicates that these isolates do not present a major diagnostic or public health problem. However, microbiologists should remain vigilant for any isolates giving anomalous results and when using the porA pseudogene RT-PCR consider multiplexing it with the opa -gene RT-PCR.

O25 Use of ceftriaxone and doxycycline when treating gonorrhoea: is it prescribed appropriately?

Background National gonorrhoea treatment guidelines recommend ceftriaxone with azithromycin as first-line therapy, but doxycycline is recommended instead of azithromycin for patients with gonococcal pelvic inflammatory disease (PID). In 2013, 86.5% of patients in the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) were treated with the recommended therapy, but 3.9% were treated with doxycycline instead of azithromycin. Objectives The objective of this analysis was to determine whether ceftriaxone plus doxycycline were prescribed for appropriate indications. Methods Using GRASP 2013 data, patients prescribed the recommended therapy were compared with patients prescribed ceftriaxone and doxycycline, and associations were assessed using univariate and multivariate logistic regression. Results In 2013, of the 913 patients prescribed ceftriaxone and azithromycin, 45.9% were men who have sex with men (MSM), 20% were women and 34.1% were heterosexual men while, of the 45 patients prescribed ceftriaxone and doxycycline, 64.4% were MSM, 28.9% were women and 6.7% were heterosexual men (p = 0.001). Of those prescribed ceftriaxone and doxycycline, 22.2% were MSM with chlamydia co-infection and 17.7% were women with PID. On multivariate analysis, MSM co-infected with chlamydia (aOR 3.4, 95% CI, 2.5–4.6; p = 0.001) and women diagnosed with gonococcal PID (OR,144.8, 95% CI, 24.2–864.0; p Conclusion Less than a fifth of prescriptions for ceftriaxone with doxycycline were issued to treat gonococcal PID. Use of ceftriaxone with doxycycline may be preferred to treat MSM co-infected with chlamydia by some clinicians. However, as levels of tetracycline resistance in gonorrhoea are high, this may not provide the dual treatment coverage required.

Evaluation of the activity of ertapenem against gonococcal isolates exhibiting a range of susceptibilities to cefixime

There is a need for new or alternative antimicrobial agents for the treatment of gonorrhoea as antimicrobial resistance emerges to current therapies. The aim was to investigate the activity of ertapenem against isolates of Neisseria gonorrhoeae with decreased susceptibility to cefixime. A panel of 52 clinical isolates and 10 control strains of N. gonorrhoeae were selected to represent a range of susceptibilities to cefixime. Susceptibility testing was performed using the methodology used for the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP). The isolates were typed by N. gonorrhoeae multi-antigen sequence typing (NG-MAST). The isolates comprised 42 different molecular types as defined by NG-MAST. The susceptibility of the clinical isolates to ertapenem was similar to that of cefixime, with a Pearson's correlation coefficient of R = 0.89. The MIC90 and MIC50 values of ertapenem were 0.25 and 0.12 mg/L, respectively, while those of cefixime were 0.12 and 0.06 mg/L, respectively. However, these isolates were more susceptible to ceftriaxone than ertapenem, with a Pearson's correlation coefficient of R = 0.65 and ceftriaxone MIC90 and MIC50 values of 0.03 and 0.016 mg/L, respectively. The isolates that were least susceptible to ertapenem were all non-producers of penicillinase. However, one isolate that was highly resistant to cefixime and ceftriaxone was more susceptible to ertapenem than either cefixime or ceftriaxone. This study has shown that ertapenem is not a suitable alternative for first-line treatment for gonorrhoea but that it may be useful for the treatment of highly resistant infections.

P2.056 Prevalence of Neisseria Gonorrhoeae Specimens Containing Por A Pseudogene Deletion Among Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP)Specimens at the Health Protection Agency

BackgroundThere has been an emergence of Neisseria gonorrhoeae strains which although phenotypically are indistinguishable from N. gonorrhoeae, vary in their genotype and require heightened surveillance. Isolates of N. gonorrhoeae were...

O03.3 Maximising the Efficiency of Gonorrhoea Treatment by Targeting the Use of Previous First Line Therapies to Susceptible Patients

BackgroundGonorrhoea treatment guidelines change when less than 95% of the infected population is successfully treated with the recommended antimicrobial. Isolates with decreased susceptibility to ceftriaxone, the current recommended therapy, have...

P3.120 Risk Factors, Antimicrobial Susceptibility Profiles and Public Health Implications of Patients Presenting with Pharyngeal Gonococcal Infection in England and Wales

BackgroundPharyngeal infection with Neisseria gonorrhoeae is usually asymptomatic and often under-diagnosed. It could therefore be an important source of ongoing transmission particularly among men who have sex with men (MSM)....

Gonococcal Resistance to Cephalosporins in the U.K.

Dramatic changes in drug susceptibilities have been seen with Neisseria gonorrhoeae worldwide (JW Infect Dis Jan 9 2013). Thus, selection of empirical therapy can be difficult, and recommendations can change, depending on surveillance data in a region. Investigators recently analyzed data for 2007 through 2011 from the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) in England and Wales to …

Decreased susceptibility to cephalosporins among gonococci: data from the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) in England and Wales, 2007–2011

Effective treatment of gonorrhoea is fundamental to public health control; however, the ability of Neisseria gonorrhoeae to successively develop resistance to different treatments has hampered control efforts. The extended-spectrum cephalosporins--cefixime and ceftriaxone--have been recommended in the UK for treatment of gonorrhoea since 2005. We looked at surveillance data from England and Wales to ascertain the current usefulness of these drugs and to inform changes to national treatment guidelines. We obtained data from the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) for patients attending 26 genitourinary medicine clinics in England and Wales between 2007 and 2011. We did analyses with univariate and multivariable logistic regression methods to identify trends in susceptibility to cephalosporins and risk factors associated with infection with isolates with decreased susceptibility to cefixime, and we assessed changes in prescribing practices. We did molecular typing to investigate genetic relatedness of non-susceptible isolates. The prevalence of decreased susceptibility to both cefixime and ceftriaxone rose between 2007 and 2010 but was more noticeable for cefixime (an increase from 1·5% in 2007 to 17·1% in 2010), with a bimodal distribution of minimum inhibitory concentration recorded between 2009 and 2010. By multivariable analysis, isolates with decreased susceptibility to cefixime were associated with infection in men who have sex with men (odds ratio 5·47, 95% CI 3·99-7·48; p<0·0001) and year of isolation (in 2010, 13·08, 7·49-22·8; p<0·0001). Such isolates had a largely clonal population, with most belonging to genogroup G1407 and harbouring the penA mosaic gene. Data from 2011 showed a significant decline in prevalence of isolates with decreased cefixime susceptibility, falling from 17·1% in 2010 to 10·8% in 2011 (p<0·0001), concomitant with the change in prescribing practice in 2010 from cefixime to ceftriaxone plus azithromycin. Guidance for treatment of gonorrhoea in England and Wales was changed in 2010 to prolong the use of cephalosporins. The decline in prevalence of isolates with decreased cefixime susceptibility cannot be attributed unequivocally to this change in prescribing practice; however, the association is striking. Department of Health (England), Public Health England.

Emergence of a Neisseria gonorrhoeae clone showing decreased susceptibility to cefixime in England and Wales

The third-generation cephalosporins recommended in national guidelines are amongst the last remaining effective agents for treatment of gonorrhoea. This study characterizes gonococcal isolates with decreased cefixime susceptibility from England and Wales. A total of 96 isolates of Neisseria gonorrhoeae exhibiting cefixime MICs of ≥0.125 mg/L, either collected as part of the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) between 2005 and 2008 (54 from a total of 4649 isolates) or referred to the national reference laboratory in 2008 and 2009 (42 isolates), were tested for susceptibility to a range of antimicrobial agents and were typed using N. gonorrhoeae multiantigen sequence typing (NG-MAST). All 96 isolates were also resistant to tetracycline (MIC ≥2 mg/L) and ciprofloxacin (MIC ≥16 mg/L) and 56% showed low-level chromosomal resistance to penicillin. Where data were available, the mean patient age was 31 years, and 88% (83/94) of patients were men. Isolates referred through GRASP were predominantly from men who have sex with men (MSM; 29/44, 66%) and from patients of white British ethnicity (25/43, 58%). The majority of isolates belonged either to sequence type (ST) 1407 (71/96, 74%) or to a highly related ST that shares the tpbB allele (allele 110), but with a different por allele (20/96, 21%). ST1407 was found in both MSM (22/29, 76%) and heterosexual patients (12/15, 80%) and among all eight isolates from patients reporting sex abroad. The emergence of a clonal group of gonococci showing decreased susceptibility to cefixime in England and Wales highlights the need for continued surveillance.

Point-of-care antibiotic susceptibility testing for gonorrhoea: improving therapeutic options and sparing the use of cephalosporins

Antimicrobial therapy for Neiserria gonorrhoeae is a major public health concern with high rates of resistance to penicillin, tetracycline and fluoroquinolones detected in England and Wales in the Gonococcal Resistance...