Gianfranco Spiteri

Emerging cephalosporin and multidrug-resistant gonorrhoea in Europe

Neisseria gonorrhoeae has consistently developed resistance to antimicrobials used therapeutically for gonorrhoea and few antimicrobials remain for effective empiric first-line therapy. Since 2009 the European gonococcal antimicrobial surveillance programme (Euro-GASP) has been running as a sentinel surveillance system across Member States of the European Union (EU) and European Economic Area (EEA) to monitor antimicrobial susceptibility in N. gonorrhoeae. During 2011, N. gonorrhoeae isolates were collected from 21 participating countries, and 7.6% and 0.5% of the examined gonococcal isolates had in vitro resistance to cefixime and ceftriaxone, respectively. The rate of ciprofloxacin and azithromycin resistance was 48.7% and 5.3%, respectively. Two (0.1%) isolates displayed high-level resistance to azithromycin, i.e. a minimum inhibitory concentration (MIC) ≥256 mg/L. The current report further highlights the public health need to implement the European response plan, including further strengthening of Euro-GASP, to control and manage the threat of multidrug resistant N. gonorrhoeae.

Surveillance of human immunodeficiency virus suggests that younger men who have sex with men are at higher risk of infection, European Union, 2003 to 2012.

In 2012, newly reported human immunodeficiency virus diagnoses in the European Union /European Economic Area remained stable at around 30,000 cases. Since 2003, cases in men who have sex with men (MSM) aged 20 to 29 years-old doubled, while the proportion of late presenters in this group remained stable. Persistent declines occurred among older MSM age groups, particularly that between 30 and 39 years-old. Interventions targeting younger MSM are needed to prevent a resurgence of the epidemic in Europe.

Risk factors for antimicrobial-resistant Neisseria gonorrhoeae in Europe.

Background The European Gonococcal Antimicrobial Surveillance Programme performs antimicrobial resistance surveillance and is coordinated by the European Centre for Disease Prevention and Control. This study used epidemiological and behavioral data combined with the gonococcal susceptibility profiles to determine risk factors associated with harboring resistant gonococci in Europe. Methods From 2009 to 2011, gonococcal isolates from 21 countries were submitted to the European Gonococcal Antimicrobial Surveillance Programme for antimicrobial susceptibility testing. Patient variables associated with resistance to azithromycin, cefixime, and ciprofloxacin were identified using univariate and multivariable logistic regression analyses of odds ratios. Geometric means for ceftriaxone and cefixime minimum inhibitory concentrations (MICs) were compared for patients of different sexual orientation and sex. Results A total of 5034 gonococcal isolates were tested from 2009 to 2011. Isolates exhibiting resistance to cefixime (MIC > 0.125 mg/L) and ciprofloxacin (MIC > 0.5 mg/L) were significantly associated with infection in heterosexuals (males only for ciprofloxacin), older patients (>25 years of age), or those without a concurrent chlamydial infection in the multivariable analysis. The geometric mean of cefixime and ceftriaxone MICs decreased from 2009 to 2011, most significantly for men who have sex with men, and isolates from male heterosexuals exhibited the highest MICs in 2011. Conclusions The linking of epidemiological and behavioral data to the susceptibility profiles of the gonococcal isolates has allowed those at higher risk for acquiring antimicrobial resistant Neisseria gonorrhoeae to be identified. Improved data numbers and representativeness are required before evidence-based risk groups can be identified, and subsequent focused treatments or public health intervention strategies can be initiated with confidence.

The European Gonococcal Antimicrobial Surveillance Programme (Euro-GASP)-a sentinel approach in the European Union (EU)/European Economic Area (EEA)

Antimicrobial resistance in Neisseria gonorrhoeae is monitored in the European Union/European Economic Area through the European Gonococcal Antimicrobial Surveillance Programme (Euro-GASP) coordinated by the European Centre for Disease Prevention and Control. Euro-GASP includes a sentinel surveillance programme which aims to detect in a timely manner changes in resistance patterns and inform treatment guidelines. The programme aims to test a representative number of isolates from each European Union/European Economic Area member state per year for a range of therapeutically relevant antimicrobials through a biannual hybrid centralised/decentralised system. Testing is supported by an External Quality Assurance programme and a laboratory training programme. Participation in the programme has increased to 21 countries in 2012. Euro-GASP has been able to detect the rapid spread of isolates with decreased susceptibility to cefixime across Europe in 2010 and 2011. Results from the programme have informed changes in European treatment guidelines for gonorrhoea and led to the development of the ‘Response plan to control and manage the threat of multidrug resistant gonorrhoea in Europe’. Future challenges for Euro-GASP include supporting countries to participate in Euro-GASP through decentralised testing, improving timeliness and epidemiological data quality, and increasing participation from Eastern Europe.

Gonorrhoea and gonococcal antimicrobial resistance surveillance networks in the WHO European Region, including the independent countries of the former Soviet Union

Antimicrobial resistance (AMR) in Neisseria gonorrhoeae has emerged for essentially all antimicrobials following their introduction into clinical practice. During the latest decade, susceptibility to the last remaining options for antimicrobial monotherapy, the extended-spectrum cephalosporins (ESC), has markedly decreased internationally and treatment failures with these ESCs have been verified. In response to this developing situation, WHO and the European Centre for Disease Prevention and Control (ECDC) have published global and region-specific response plans, respectively. One main component of these action/response plans is to enhance the surveillance of AMR and treatment failures. This paper describes the perspectives from the diverse WHO European Region (53 countries), including the independent countries of the former Soviet Union, regarding gonococcal AMR surveillance networks. The WHO European Region has a high prevalence of resistance to all previously recommended antimicrobials, and most of the first strictly verified treatment failures with cefixime and ceftriaxone were also reported from Europe. In the European Union/European Economic Area (EU/EEA), the European gonococcal antimicrobial surveillance programme (Euro-GASP) funded by the ECDC is running. In 2011, the Euro-GASP included 21/31 (68%) EU/EEA countries, and the programme is further strengthened annually. However, in the non-EU/EEA countries, internationally reported and quality assured gonococcal AMR data are lacking in 87% of the countries and, worryingly, appropriate support for establishment of a GASP is still lacking. Accordingly, national and international support, including political and financial commitment, for gonococcal AMR surveillance in the non-EU/EEA countries of the WHO European Region is essential.

Ten years after Dublin: principal trends in HIV surveillance in the EU/EEA, 2004 to 2013

In 2004, the 31 countries of the European Union and European Economic Area (EU/EEA) adopted the Dublin Declaration on Partnership to Fight HIV/AIDS in Europe and Central Asia. In 2013, 29,157 persons were diagnosed with HIV in 30 EU/EEA countries (adjusted rate: 6.2/100,000); new diagnoses have increased by 33% since 2004 among men who have sex with men and late diagnosis remains common. Evidence-based prevention measures and efforts towards earlier testing need to be expanded.

O03.1 Risk Factors For Antimicrobial Resistant Neisseria Gonorrhoeae in Europe

Introduction The European Centre for Disease Prevention and Control is responsible for the enhanced surveillance of sexually transmitted infections and co-ordinates the European gonococcal antimicrobial surveillance programme (Euro-GASP) in the European Union and the European Economic Area. Linked patient and antimicrobial susceptibility data from Euro-GASP allows those at risk of acquiring antimicrobial resistant Neisseria gonorrhoeae to be identified. Methods Seventeen countries in 2009 and 21 countries in 2010 and 2011 submitted gonococcal isolates to Euro-GASP, which were tested by Etest or agar dilution for cefixime, ceftriaxone, ciprofloxacin, azithromycin, spectinomycin and gentamicin. Additional patient data linked to the gonococcal isolates susceptibility profiles was collected. All three years antimicrobial susceptibility data and linked patient data were combined. Patient variables associated with resistance were established using a univariate and multivariable analyses of odds ratios. Geometric means for ceftriaxone and cefixime MICs were calculated. Results A total of 5034 gonococcal isolates were tested in Euro-GASP from 2009 to 2011. In the multivariable analysis heterosexuals (males only for ciprofloxacin), older patients and those without a concurrent chlamydia infection remained significantly more likely to be infected with isolates displaying cefixime decreased susceptibility and ciprofloxacin resistance. The geometric mean of cefixime and ceftriaxone MICs decreased from 2009 to 2011, most significantly for MSM; MSM had lower geometric means than heterosexuals in 2011. A bimodal MIC distribution of a ‘more susceptible’ and ‘less susceptible’ gonococcal population appears to be emerging alongside this geometric mean decrease. Conclusion This Euro-GASP data suggests that the burden of gonococcal antimicrobial resistance is more prevalent among heterosexuals and decreasing in MSM. This study shows the importance of collecting and analysing patient data along with susceptibility data, however improved data numbers and representativeness is required before any focused treatments or public health intervention strategies are initiated. Abstract O03.1 Table 1 Patient risk factors for antimicrobial resistance (OR, 95% CI from multivariable analysis) Cefixime decreased susceptibility Ciprofloxacin resistance MSM 1 1 Male heterosexuals 2.39 (1.58–3.61)* 1.49 (1.21–1.83)* Female 2.75 (1.68–4.5)* 1.04 (0.8–1.34) < 25 years 1 1 ≥ 25 years 2.07 (1.36–3.13)* 1.67 (1.37–2.05)* Chlamydia - yes 1 1 Chlamydia - no 1.87(1.1–3.16)* 2.2 (1.74–2.8)* * P value < 0.05 (from the Pearson Chi2-test)

Trends in HIV surveillance data in the EU/EEA, 2005 to 2014: new HIV diagnoses still increasing in men who have sex with men.

Human immunodeficiency virus (HIV) transmission remains significant in Europe. Rates of acquired immunodeficiency syndrome (AIDS) have declined, but not in all countries. New HIV diagnoses have increased among native and foreign-born men who have sex with men. Median CD4(+) T-cell count at diagnosis has increased, but not in all groups, and late diagnosis remains common. HIV infection and AIDS can be eliminated in Europe with resolute prevention measures, early diagnosis and access to effective treatment.

Surveillance of Zika virus infection in the EU/EEA, June 2015 to January 2017

Surveillance of Zika virus (ZIKV) infection in the European Union/European Economic Area (EU/EEA) was implemented in 2016 in response to the large outbreak reported in the Americas in 2015 associated with an increased number of infants born with microcephaly. Between June 2015 and January 2017, 21 EU/EEA countries reported 2,133 confirmed cases of ZIKV infection, of whom 106 were pregnant women. Cases infected in the Caribbean constituted 71% of reported cases. Almost all cases (99%) were most probably infected by mosquito bite during travel outside continental Europe, while only 1% were transmitted sexually. Considering that 584 imported cases were reported between May and October 2016 among residents of areas with established presence of Aedes albopictus, the absence of autochthonous vector-borne cases suggests that Ae. albopictus is not an efficient vector for ZIKV infection.

Public health surveillance of multidrug-resistant clones of Neisseria gonorrhoeae in Europe: a genomic survey

Summary Background Traditional methods for molecular epidemiology of Neisseria gonorrhoeae are suboptimal. Whole-genome sequencing (WGS) offers ideal resolution to describe population dynamics and to predict and infer transmission of antimicrobial resistance, and can enhance infection control through linkage with epidemiological data. We used WGS, in conjunction with linked epidemiological and phenotypic data, to describe the gonococcal population in 20 European countries. We aimed to detail changes in phenotypic antimicrobial resistance levels (and the reasons for these changes) and strain distribution (with a focus on antimicrobial resistance strains in risk groups), and to predict antimicrobial resistance from WGS data. Methods We carried out an observational study, in which we sequenced isolates taken from patients with gonorrhoea from the European Gonococcal Antimicrobial Surveillance Programme in 20 countries from September to November, 2013. We also developed a web platform that we used for automated antimicrobial resistance prediction, molecular typing (N gonorrhoeae multi-antigen sequence typing [NG-MAST] and multilocus sequence typing), and phylogenetic clustering in conjunction with epidemiological and phenotypic data. Findings The multidrug-resistant NG-MAST genogroup G1407 was predominant and accounted for the most cephalosporin resistance, but the prevalence of this genogroup decreased from 248 (23%) of 1066 isolates in a previous study from 2009–10 to 174 (17%) of 1054 isolates in this survey in 2013. This genogroup previously showed an association with men who have sex with men, but changed to an association with heterosexual people (odds ratio=4·29). WGS provided substantially improved resolution and accuracy over NG-MAST and multilocus sequence typing, predicted antimicrobial resistance relatively well, and identified discrepant isolates, mixed infections or contaminants, and multidrug-resistant clades linked to risk groups. Interpretation To our knowledge, we provide the first use of joint analysis of WGS and epidemiological data in an international programme for regional surveillance of sexually transmitted infections. WGS provided enhanced understanding of the distribution of antimicrobial resistance clones, including replacement with clones that were more susceptible to antimicrobials, in several risk groups nationally and regionally. We provide a framework for genomic surveillance of gonococci through standardised sampling, use of WGS, and a shared information architecture for interpretation and dissemination by use of open access software. Funding The European Centre for Disease Prevention and Control, The Centre for Genomic Pathogen Surveillance, Örebro University Hospital, and Wellcome.