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.
- ANTIBIOTIC RESISTANCE
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Gonorrhoea, including its severe complications, remains a major public health concern worldwide. Effective control of gonorrhoea relies entirely on appropriate treatment with antimicrobials, along with effective prevention, timely diagnostics, contact tracing (including treatment of contacts), and surveillance. Worryingly, antimicrobial resistance (AMR) has emerged for essentially all antimicrobials following their introduction into clinical practice. Currently, the third generation, extended-spectrum cephalosporins (ESC), ceftriaxone (injectable) and cefixime (oral), are the only first-line options for antimicrobial monotherapy in most settings globally. However, during the latest decade, susceptibility to these antibiotics has markedly decreased internationally1–6 and clinical treatment failures with these ESCs have been verified.7–16 Furthermore, it is of grave concern that during the last 3 years, the first three extensively drug-resistant (XDR) Neisseria gonorrhoeae strains with high-level resistance to ceftriaxone also, the last remaining option for empiric antimicrobial monotherapy, were reported.8 ,9 ,17 XDR N gonorrhoeae strains are defined as those resistant to two or more of the antibiotic classes currently generally recommended for treatment (ESCs (oral and injectable ones considered separately) and spectinomycin) and three or more of the antibiotic classes now less frequently used or else proposed for more extensive use (eg, penicillins, fluoroquinolones, azithromycin, aminoglycosides and carbapenems) (1). The fear of widespread ceftriaxone resistance and untreatable gonorrhoea, particularly in settings where dual antimicrobial therapy is not feasible and/or affordable, is real. In response to this developing situation, WHO,18 ,19 European Centre for Disease Prevention and Control (ECDC) and the Centers for Disease Control and Prevention (CDC), USA, have published global and region-specific response plans for the European Union/European Economic Area (EU/EEA) countries20 and the USA,21 respectively. One main component of these action/response plans is to enhance the surveillance of AMR and treatment failures, which is essential to monitor the emergence and spread of AMR; to inform local, national and international treatment guidelines; and to prevent the spread of infection. Accordingly, valid and quality-assured AMR data for gonococci, globally, are crucial for public health purposes.
The present paper describes the perspectives from the WHO European Region, including the independent countries of the former Soviet Union, regarding gonorrhoea and gonococcal AMR surveillance networks.
WHO European Region
The WHO European Region comprises 53 countries, including those that are member states of the EU (n=28), EEA (n=2; Liechtenstein is an EEA country, however, not included in the WHO European Region) and 23 non-EU/EEA countries (table 1). The estimated population is around 900 million, of which about half are adults between 15 and 49 years of age. The WHO European Region is large and includes countries that are exceedingly diverse in regards to size (area and population), economy, migration, culture, social structure, health determinants and health systems. The region is undergoing important demographic and epidemiological changes that are shaping the needs for health promotion, disease prevention and care, which create new challenges and a mosaic of health situations and healthcare structure that requires specific approaches.
Epidemiology of STIs, with emphasis on gonorrhoea
According to the latest WHO global estimates, in 2008, there were 47 million new cases of the four curable STIs among adults (15–49 years of age) in the WHO European Region, that is, 22 million trichomoniasis cases (decrease by 16% since 2005), 21 million Chlamydia trachomatis infections (increase by 36%), 3.4 million gonorrhoea cases (decrease by 27%), and 0.2 million syphilis cases (decrease by 3%).22 ,23
In the WHO European Region, during the latest three to four decades in most countries the incidence of gonorrhoea (cases per 100 000 population) reported to WHO European Regional Office (http://data.euro.who.int/cisid) and ECDC (http://www.ecdc.europa.eu) has substantially decreased. However, particularly during the most recent decade several EU/EEA countries, such as Belgium (incidence of 7.3 in 2010), Norway (8.4 in 2010), Sweden (9.0 in 2010), Malta (11.3 in 2010), Ireland (14.0 in 2010), and The Netherlands (17.0 in 2010) have displayed increasing incidences (http://data.euro.who.int/cisid). For detailed surveillance data regarding gonorrhoea and other mandatorily reported STIs in the EU/EEA, see also the ECDC web site (http://www.ecdc.europa.eu).24 In most of the non-EU/EEA countries and several countries in the eastern part of EU, during the last two decades, the incidence has rapidly declined. Despite this decline, compared to the EU/EEA countries, the non-EU/EEA countries have, however, continued to have a higher mean incidence of gonorrhoea, and countries such as Russia (incidence of 42.0 in 2010), Belarus (36.2 in 2010) and Republic of Moldova (35.9 in 2010) have the highest incidences (figure 1; http://data.euro.who.int/cisid). Nevertheless, reliable data regarding the gonorrhoea incidence in many of the non-EU/EEA countries remain limited, and most probably many of the incidences are underestimated which is due, in most countries, to the large variation in healthcare settings, differences in access to testing, suboptimal diagnostics, case reporting and surveillance.25 ,26 Those issues are certainly challenges also in many of the EU/EEA countries, illustrated by the considerable geographic and gender variation in the reported distribution of gonorrhoea. In EU/EEA, the highest incidence of gonorrhoea is in young adults (15–29 years) and, in many countries, there is a disproportionate burden of disease in men who have sex with men, and some ethnic minorities and migrant populations.24 ,27–28
Gonococcal AMR and AMR surveillance
In general, the WHO European Region has a high prevalence of resistance to all previously recommended antimicrobials for treatment of gonorrhoea.4 ,29–31 Furthermore, most of the first strictly verified treatment failures with ESCs were also reported from Europe. Accordingly, treatment failures with cefixime have been strictly verified, according to WHO standards and criteria,32 in Norway,10 the UK,11 Austria12 and France.9 Furthermore, rare failures to treat pharyngeal gonorrhoea with ceftriaxone have been described in Sweden7 and Slovenia.13 It is also of grave concern that two of the three currently verified XDR gonococcal isolates with high-level resistance to ceftriaxone were identified in France9 and Spain.17
Accordingly, widespread and quality-assured AMR surveillance in the WHO European Region is essential. In the EU/EEA, from 2004 to 2008, the European gonococcal antimicrobial surveillance programme (Euro-GASP) was established and coordinated by the European Surveillance of STI (ESSTI) project. Since 2009, Euro-GASP has been funded and coordinated by the ECDC through a contract with the Health Protection Agency (now Public Health England), UK, Örebro University Hospital, Sweden, and Statens Serum Institut, Denmark, and this sentinel surveillance programme has been further developed across member states of the EU and EEA.4 ,33 ,34 Briefly, in 2011, 21/31 (68%) countries were participating in the Euro-GASP (table 1). Euro-GASP currently includes biannual centralised or decentralised AMR testing of gonococcal isolates, an external quality assessment (EQA) programme to ensure comparability of data, and a training module. Linking of AMR data and epidemiological data is promoted through an online reporting system, the European Surveillance System-TESSY (Tessy). Since its establishment in 2004, Euro-GASP has been exceedingly valuable in documenting the high prevalence of resistance to previous first-line antimicrobials, such as penicillin and tetracycline; increasing and currently high prevalence of resistance to ciprofloxacin; fluctuating and relatively high levels of azithromycin resistance; and in recent years increasing minimum inhibitory concentrations (MICs) and prevalence of decreased susceptibility or resistance to ceftriaxone and particularly cefixime (detected in most of the participating countries).4 ,33 Euro-GASP has also identified a high prevalence of multidrug resistance, the gonococcal N gonorrhoeae multiantigen sequence typing (NG-MAST) ST1407, including genetically highly related STs, clone that accounted for most of the decreased susceptibility or resistance to ESCs34 and continuing high in vitro susceptibility to the potential future treatment option gentamicin in the EU/EEA.35
Nevertheless, the Euro-GASP still only covers 21 (68%) of the EU/EEA countries, which represent only 40% of all the countries in the WHO European Region (n=53). Accordingly, in the non-EU/EEA countries, including many of the independent countries of the former Yugoslavia and Soviet Union, that is, in Eastern Europe and Central Asia, valid, quality assured and internationally reported AMR data have been exceedingly scarce. However, in Russia, the national Russian GASP (RU-GASP) has been running since 2004.29 ,30 The RU-GASP includes centralised AMR testing annually of gonococcal isolates from many sentinel sites distributed all over Russia using the agar dilution method according to the Clinical Laboratory and Standards Institute (CLSI), USA, for ceftriaxone, spectinomycin, ciprofloxacin, azithromycin, penicillin and tetracycline.29 ,30 The RU-GASP has also been quality assured in accordance with WHO standards and, for international comparability of AMR data, the 2008 WHO N gonorrhoeae reference strains36 are used as quality controls and in EQAs. The RU-GASP has reported high prevalence of resistance to penicillin (32% in 2010), tetracycline (42% in 2010) and ciprofloxacin (53% in 2010); relatively high prevalence of resistance to azithromycin (4.9% in 2010; but still no high-level resistant isolates (MIC≥256 mg/L)) and even to spectinomycin (4.4% in 2010; but still no high-level resistant isolates (MIC>256 mg/L)); increasing MICs of ceftriaxone; and a high prevalence of multidrug resistance.29 ,30 ,37 The WHO in collaboration with the Eastern European Network for Sexual Reproductive Health (EE SRH)38 has also, in recent years, initiated gonococcal AMR surveillance in some additional non-EU/EEA countries, which is detailed below.
Challenges and actions to enhance the surveillance of gonococcal AMR in the entire WHO European Region
As mentioned above, Euro-GASP is acting successfully in EU/EEA. Nevertheless, Euro-GASP will be further strengthened by including additional countries, enhancing the number and representativeness of N gonorrhoeae samples, increasing the quality of associated epidemiological information, and by providing additional training to enable capacity building, as described in the ECDC response plan to control and manage the threat of multidrug-resistant gonorrhoea in EU/EEA.20 Decentralised testing will be further promoted to improve timeliness of reporting and to facilitate the sustainability of Euro-GASP. Finally, the awareness of policy makers, clinicians, patients and key populations also needs to be enhanced.
However, as aforementioned in the non-EU/EEA countries of the WHO European Region, quality assured and internationally reported AMR surveillance is exceedingly scarce. This is worrying because many of those countries have a relatively high burden of gonorrhoea, suboptimal diagnostics and surveillance (gonorrhoea cases and AMR), and antimicrobials (appropriate as well as suboptimal) are easily available without any prescription from a physician. Furthermore, the knowledge and awareness of gonococcal AMR and its prevalence remains limited, and antimicrobials of many different types, sources and quality are used for gonorrhoea treatment.25 ,26 All these factors result in a high risk for the emergence and rapid spread of gonococcal AMR and gonorrhoea, which may become a problem locally, nationally as well as internationally, due to the high rate of migration in the WHO European Region.
With the aims of establishing an international GASP, based on WHO standards and protocols, in the independent countries of the former Soviet Union, in 2008–2009, the first actions were undertaken by the EE SRH38 in collaboration with WHO through two detailed surveys.25 ,26
Accordingly, in a first survey, information was collected regarding the types, doses and manufacturers of the antimicrobials recommended for gonorrhoea treatment in 11 countries (Armenia, Azerbaijan, Belarus, Estonia, Georgia, Kazakhstan, Kyrgyzstan, Russia, Tajikistan, Ukraine and Uzbekistan).25 Ceftriaxone (250–1000 mg, intramuscularly×1) was reported as first-line antimicrobial in all countries, but the adherence, especially among private physicians, to these public sector recommendations was highly questioned. Worryingly, many of the second-line and alternative treatments reported (eg, ciprofloxacin, ofloxacin, roxithromycin, kanamycin, erythromycin and doxycycline) should not be used for empirical treatment of gonorrhoea. In most countries, primarily antimicrobials manufactured nationally, regionally or, for example, in India were used, which was due to the substantially lower cost of those antimicrobials. In general, antimicrobials were also easily available without any prescriptions from medical doctors and some of the used antimicrobials might be of questionable quality.25 All this generates prerequisites for emergence and rapid spread of gonococcal AMR and gonorrhoea. In the countries of this subregion similar to other regions globally, it would be very valuable to monitor and regulate the type of antimicrobials used, including the amount, manufacturers and quality of all the different antimicrobials.
As the next step to establish an international GASP, a second survey aimed to detail the N gonorrhoeae laboratory diagnostics in the aforementioned 11 countries and to establish an international GASP network of laboratories.26 Thirteen laboratories responsible for specialist work regarding gonococci were identified. Worryingly, in all countries, with exception of the EU country, Estonia, the large majority of the diagnostics was performed using microscopy of Gram-stained and/or methylene blue-stained smears only. Four of the 11 countries did not culture for gonococci at all, and in countries where culture existed, this was mainly performed in tubes (slant agar) with 2–3 mL of non-selective or suboptimal selective agar, for example, only including lincomycin. This culture diagnostics has a highly suboptimal sensitivity and results in large problems to obtain pure culture for AMR testing. Furthermore, the availability of chemical reagents (culture agar, discs/Etest strips/antimicrobial powder, species confirmatory tests) and equipment (low-temperature freezers (−70–80°C) or liquid nitrogen to preserve gonococcal isolates) for quality controlled and quality assured AMR testing according to WHO and other international evidence-based standards was low in many of the countries.26 To improve the diagnostic situation and promote more sensitive isolation methods, evidence-based international guidelines for laboratory diagnosis of N gonorrhoeae in countries of Eastern Europe and Central Asia have been elaborated. These have been published by the EE SRH38 in English,39–41 Russian and a number other national languages, and have been endorsed and implemented in many of these countries. There is a need to further promote international evidence-based diagnostic guidelines and to ensure that they are substantially more widely implemented. This is essential for gonococcal AMR surveillance and also for improving sensitivity of diagnostics (particularly among women, asymptomatic cases and for extragenital gonorrhoea), in general, gonorrhoea case management, case reporting and overall surveillance.
The two aforementioned survey studies25 ,26 were subsequently followed by a workshop, including participants from the 11 surveyed countries, at the WHO Collaborating Centre for Gonorrhoea and other STIs in Sweden that included theoretical and practical training in gonorrhoea epidemiology, antimicrobial treatment of gonorrhoea, laboratory diagnosis of N gonorrhoeae and AMR testing and surveillance using WHO evidence-based standards. Many of these participating countries, as well as additional non-EU/EEA countries, have also been provided with additional support by the EE SRH38 and WHO, in terms of site visits, additional training (theoretical and practical), and limited chemical reagents.
Through those actions and with excellent national collaborators, gonococcal AMR surveillance has been initiated and/or quality assured in accordance with WHO standards in Belarus (Lebedev F et al, unpublished),31 Poland (Mlynarzyk B et al, unpublished) and Kyrgyzstan (Karymbaeva S et al, unpublished). Recently, countries such as Georgia, Kazakhstan, Republic of Moldova and Ukraine also have made important progress and can hopefully soon report some nationally and internationally quality assured gonococcal AMR data.
In the WHO European Region, the susceptibilities to the extended-spectrum cephalosporins ceftriaxone and, particularly cefixime, have decreased quickly,4 ,20 ,29–31 ,33 and several treatment failures with cefixime9–12 and a few with ceftriaxone7 ,13 have been verified in the EU/EEA. However, internationally reported quality assured AMR data are only available from 40% (24/53) of the countries (68% of the EU/EEA countries and 13% of the non-EU/EEA countries). This emphasises the crucial public health need to implement WHO action plan18 ,19 and the ECDC response plan,20 including a substantially enhanced quality assured surveillance of gonococcal AMR as well as gonorrhoea treatment failures, for the whole WHO European Region to manage and control the threat of multidrug-resistant N gonorrhoeae. In the EU/EEA, Euro-GASP has been further strengthened annually. However, the major challenge remains the lack of gonococcal AMR surveillance in most of the non-EU/EEA countries, where internationally reported and quality assured gonococcal AMR data are lacking in 87% of the countries and, worryingly, appropriate national and international support for establishment of a GASP is still lacking. The challenges to establish national and international GASPs in the non-EU/EEA countries are numerous, including the lack of quality assured culture and AMR testing in many countries, no equipment (eg, incubators, −70–80°C freezers), facilities or resources to culture and preserve gonococcal isolates, lack of access to validated and quality assured international tests and chemical reagents in several countries, cultural and language differences, engagement of collaborators in a sustainable GASP, ownership of data, lack of clear national gonorrhoea guidelines, absence of gonococcal reference laboratories and, most importantly, lack of funding. Accordingly, appropriate 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.
National and international gonococcal AMR surveillance in the whole WHO European Region is crucial; to provide evidence-based data regarding relevant antimicrobials used for treatment, for regular and timely updating of local, national and international treatment guidelines; to monitor the emergence and spread of AMR; and to inform prevention, control and containment of gonococcal AMR and gonorrhoea.
Multidrug-resistant Neisseria gonorrhoeae strains are major public health concerns globally, and it is essential to enhance the surveillance of antimicrobial resistance and treatment failures.
The WHO European Region (53 countries) has a high prevalence of resistance to previously recommended antimicrobials, and treatment failures with extended-spectrum cephalosporins have been reported.
In the European Union/European Economic Area (EU/EEA), the European gonococcal antimicrobial surveillance programme (Euro-GASP) included 21 of the 31 (68%) EU/EEA countries in 2011.
In the non-EU/EEA countries, internationally reported gonococcal resistance data are only available in 13% of the countries and national and international support is essential.
We are grateful to the ECDC, European STI surveillance network and all staff involved in coordinating and running Euro-GASP; EE SRH (its coordinator, Marius Domeika, and all its participants); WHO; RU-GASP (coordinated by Anna Kubanova, Alexey Kubanov and Nataliya Frigo); and numerous most valuable colleagues in the EU/EEA and non-EU/EEA countries of the WHO European Region.
Handling editor Jakie A Cassell
Contributors MU prepared a first draft of the paper, which was finalised in collaboration with all coauthors.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.
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