Neisseria gonorrhoeae molecular typing for understanding sexual networks and antimicrobial resistance transmission: A systematic review.

OBJECTIVES: Neisseria gonorrhoeae (NG) is a significant global public health concern due to rising diagnoses rates and antimicrobial resistance. Molecular combined with epidemiological data have been used to understand the distribution and spread of NG, as well as relationships between cases in sexual networks, but the public health value gained from these studies is unclear. We conducted a systematic review to examine how molecular epidemiological studies have informed understanding of sexual networks and NG transmission, and subsequent public health interventions. METHODS: Five research databases were systematically searched up to 31st March 2017 for studies that used sequence-based DNA typing methods, including whole genome sequencing, and linked molecular data to patient-level epidemiological data. Data were extracted and summarised to identify common themes. RESULTS: Of the 49 studies included, 82% used NG Multi-antigen Sequence Typing. Gender and sexual orientation were commonly used to characterise sexual networks that were inferred using molecular clusters; clusters predominantly of one patient group often contained a small number of isolates from other patient groups. Suggested public health applications included using these data to target interventions at specific populations, confirm outbreaks, and inform partner management, but these were mainly untested. CONCLUSIONS: Combining molecular and epidemiological data has provided insight into sexual mixing patterns, and dissemination of NG, but few studies have applied these findings to design or evaluate public health interventions. Future studies should focus on the application of molecular epidemiology in public health practice to provide evidence for how to prevent and control NG

Is previous azithromycin treatment associated with azithromycin resistance in Neisseria gonorrhoeae? A cross-sectional study using national surveillance data in England.

OBJECTIVES: It has been suggested that treatment of STIs with azithromycin may facilitate development of azithromycin resistance in Neisseria gonorrhoeae (NG) by exposing the organism to suboptimal doses. We investigated whether treatment history for non-rectal Chlamydia trachomatis (CT), non-gonococcal urethritis (NGU) or NG (proxies for azithromycin exposure) in sexual health (GUM) services was associated with susceptibility of NG to azithromycin. METHODS: Azithromycin susceptibility data from the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP 2013-2015, n=4606) and additional high-level azithromycin-resistant isolates (HL-AziR) identified by the Public Health England reference laboratory (2013-2016, n=54) were matched to electronic patient records in the national GUMCAD STI surveillance dataset (2012-2016). Descriptive and regression analyses were conducted to examine associations between history of previous CT/NGU/NG and subsequent susceptibility of NG to azithromycin. RESULTS: Modal azithromycin minimum inhibitory concentration (MIC) was 0.25 mg/L (one dilution below the resistance breakpoint) in those with and without history of previous CT/NGU/NG (previous 1 month/6 months). There were no differences in MIC distribution by history of CT/NGU (P=0.98) or NG (P=0.85) in the previous 1 month/6 months or in the odds of having an elevated azithromycin MIC (>0.25 mg/L) (Adjusted OR for CT/NGU 0.97 (95% CI 0.76 to 1.25); adjusted OR for NG 0.82 (95% CI: 0.65 to 1.04)) compared with those with no CT/NGU/NG in the previous 6 months. Among patients with HL-AziR NG, 3 (4%) were treated for CT/NGU and 2 (3%) for NG in the previous 6 months, compared with 6% and 8%, respectively for all GRASP patients. CONCLUSIONS: We found no evidence of an association between previous treatment for CT/NGU or NG in GUM services and subsequent presentation with an azithromycin-resistant strain. As many CT diagnoses occur in non-GUM settings, further research is needed to determine whether azithromycin-resistant NG is associated with azithromycin exposure in other settings and for other conditions

Genomic and Phenotypic Variability in Neisseria gonorrhoeae Antimicrobial Susceptibility, England.

Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is a global concern. Phylogenetic analyses resolve uncertainties regarding genetic relatedness of isolates with identical phenotypes and inform whether AMR is due to new mutations and clonal expansion or separate introductions by importation. We sequenced 1,277 isolates with associated epidemiologic and antimicrobial susceptibility data collected during 2013-2016 to investigate N. gonorrhoeae genomic variability in England. Comparing genetic markers and phenotypes for AMR, we identified 2 N. gonorrhoeae lineages with different antimicrobial susceptibility profiles and 3 clusters with elevated MICs for ceftriaxone, varying mutations in the penA allele, and different epidemiologic characteristics. Our results indicate N. gonorrhoeae with reduced antimicrobial susceptibility emerged independently and multiple times in different sexual networks in England, through new mutation or recombination events and by importation. Monitoring and control for AMR in N. gonorrhoeae should cover the entire population affected, rather than focusing on specific risk groups or locations

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

BACKGROUND: Characterising 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. METHODS: In 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. FINDINGS: We 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. INTERPRETATION: N 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. FUNDING: National Institute for Health Research Health Protection Research Unit; Wellcome; Public Health England

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

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

Detection in the United Kingdom of the Neisseria gonorrhoeae FC428 clone, with ceftriaxone resistance and intermediate resistance to azithromycin, October to December 2018

We describe detection in the United Kingdom (UK) of the drug-resistant Neisseria gonorrhoeae FC428 clone, with ceftriaxone resistance and intermediate azithromycin resistance. Two female patients developed infection following contact with UK-resident men from the same sexual network linked to travel to Ibiza, Spain. One case failed treatment with ceftriaxone, and azithromycin and gentamicin, before successful treatment with ertapenem. Both isolates had indistinguishable whole-genome sequences. Urgent action is essential to contain this drug-resistant strain

Service evaluation of an educational intervention to improve sexual health services in primary care implemented using a step-wedge design: analysis of chlamydia testing and diagnosis rate changes

Abstract Background Providing sexual health services in primary care is an essential step towards universal provision. However they are not offered consistently. We conducted a national pilot of an educational intervention to improve staff’s skills and confidence to increase chlamydia testing rates and provide condoms with contraceptive information plus HIV testing according to national guidelines, known as 3Cs&HIV. The effectiveness of the pilot on chlamydia testing and diagnosis rates in general practice was evaluated. Methods The pilot was implemented using a step-wedge design over three phases during 2013 and 2014 in England. The intervention combined educational workshops with posters, testing performance feedback and continuous support. Chlamydia testing and diagnosis rates in participating general practices during the control and intervention periods were compared adjusting for seasonal trends in chlamydia testing and differences in practice size. Intervention effect modification was assessed for the following general practice characteristics: chlamydia testing rate compared to national median, number of general practice staff employed, payment for chlamydia screening, practice urban/rurality classification, and proximity to sexual health clinics. Results The 460 participating practices conducted 26,021 tests in the control period and 18,797 tests during the intervention period. Intention-to-treat analysis showed no change in the unadjusted median tests and diagnoses per month per practice after receiving training: 2.7 vs 2.7; 0.1 vs 0.1. Multivariable negative binomial regression analysis found no significant change in overall testing or diagnoses post-intervention (incidence rate ratio (IRR) 1.01, 95 % confidence interval (CI) 0.96–1.07, P = 0.72; 0.98 CI 0.84–1.15, P = 0.84, respectively). Stratified analysis showed testing increased significantly in practices where payments were in place prior to the intervention (IRR 2.12 CI 1.41–3.18, P < 0.001) and in practices with 6–15 staff (6–10 GPs IRR 1.35 (1.07–1.71), P = 0.012; 11–15 GPs IRR 1.37 (1.09–1.73), P = 0.007). Conclusion This national pilot of short educational training sessions found no overall effect on chlamydia testing in primary care. However, in certain sub-groups chlamydia testing rates increased due to the intervention. This demonstrates the importance of piloting and evaluating any service improvement intervention to assess the impact before widespread implementation, and the need for detailed understanding of local services in order to select effective interventions