Solna, Sweden : Neisseria gonorrhoea continues to show high levels of resistance to azithromycin across the European Union and European Economic Area, according to the results of the European Gonococcal Antimicrobial Surveillance Programme (Euro-GASP), the European Centre for Disease Prevention and Control (ECDC) reported today.
This threatens the effectiveness of the currently recommended dual therapy regimen for gonorrhoea. Overall, the rates of resistance to cefixime, ceftriaxone and azithromycin have remained stable when compared to recent years.
The main antibiotics currently recommended for gonorrhoea treatment in Europe, so-called third generation cephalosporins, are the last remaining options for effective first-line antimicrobial single therapy. As susceptibility of Neisseria gonorrhoea to these antimicrobials had decreased in the past, the European treatment guidelines suggest the addition of azithromycin to the basic course of the cephalosporins ceftriaxone or cefixime.
In order to monitor the continued effectiveness of this treatment regimen, countries of the European Union and European Economic Area (EU/EEA) participate in Euro-GASP sentinel surveillance programme. Each year they submit isolates to test susceptibility of Neisseria gonorrhoeae to the antibiotics commonly used to treat gonorrhoea.
In 2016, 25 EU/EEA countries collected and tested 2 660 gonococcal isolates showing stable rates of resistance against cefixime (2.1%), ciprofloxacin and azithromycin (7.5%) compared with 2015. No isolates with resistance to ceftriaxone were detected compared with one in 2015, five in 2014 and seven in 2013.
While the absence of ceftriaxone resistance among the tested isolates in 2016 is encouraging, the persistent level of resistance to azithromycin is of concern as it threatens to reduce the effectiveness of the recommended dual therapy with ceftriaxone and azithromycin.
Among those patients for whom information on their treatment course was reported in 2016, 86% were administered ceftriaxone and more than half received combined treatment with azithromycin. The use of two antimicrobials for gonorrhoea treatment has likely contributed to increased susceptibility to ceftriaxone. However, Euro-GASP data completeness for the variable ‘treatment used’ has still some way to go overall with just 37% in 2016.
Minimising the threat of untreatable gonorrhoea
With more than 75 000 reported cases in 2016, gonorrhoea is the second most commonly notified sexually transmitted infection (STI) in the EU/EEA countries. Apart from these reports, many more asymptomatic infections are know to occur.
Successful gonorrhoea treatment with antibiotics not only reduces the risk of complications such as pelvic inflammatory disease, ectopic pregnancies, infertility or increased HIV transmission in some settings. Combined with regular testing to diagnose and treat infections at an early stage, it also serves as one of the main public health strategies in order to reduce further transmission.
In light of limited alternatives to the current combination therapy introduced in 2012, ECDC launched a regional response plan to control multidrug-resistant gonorrhoea to minimise the threat of drug-resistant gonorrhoea in Europe. ECDC is currently revising the plan, also following recent reports of extensively drug resistant gonorrhoea strains that reached Europe.
Within a matter of weeks, three cases of gonorrhoea that are resistant to the recommended first line antibiotic treatment have been detected in Europe and Australia. These are the first global reports of Neisseria gonorrhoeae with high-level resistance to azithromycin and ceftriaxone resistance that also show resistance to several other vital antibiotics. At a time with limited alternatives to the current dual therapy, lack of a vaccine and insufficient surveillance capacity in some regions, these cases highlight the growing threat of drug-resistance – which could lead to untreatable gonorrhoea.
Gonorrhoea is the second most commonly notified sexually transmitted infection (STI) in Europe. Successful gonorrhoea treatment with antibiotics not only reduces the risk of complications such as pelvic inflammatory disease, ectopic pregnancies, infertility or increased HIV transmission in some settings, but – combined with regular testing – also serves as one of the main public health strategies for reducing further transmission. However, over the past decades, Neisseria gonorrhoeae has been developing resistance to several antimicrobial classes.
Between February and March 2018, the United Kingdom (1) and Australia (2) notified the first three cases globally of extensively drug-resistant Neisseria gonorrhoeae with high-level resistance to azithromycin and ceftriaxone resistance that are thus not susceptible to the currently recommended first line dual therapy for gonorrhoea (ceftriaxone intramuscularly and azithromycin orally). These cases were not epidemiologically linked.
The control of gonorrhoea depends on primary prevention, including promoting safer sex practices (in particular the use of condoms), regular testing of individuals at risk as well as treatment with effective antibiotics to reduce the chance of further transmission. Even a small change in drug resistance may have a broader impact as those infected can continue to transmit the infection without knowing. Spread of extensively drug-resistant strains like the ones identified in the UK and Australia can have an even more serious impact on the control of gonorrhoea.
How do we keep gonorrhoea treatable?
In its Rapid Risk Assessment, ECDC outlines the necessary steps to respond to the threat of multidrug- and extensively drug-resistant gonorrhoea: across disciplines, clinicians, microbiologists, epidemiologists and public health authorities at national and international level need to work closely together to preserve ceftriaxone and azithromycin as viable treatment options for this bacterial infection.
The most important actions needed are:
- primary prevention interventions, such as sexual education and promotion of barrier methods (condom use), aiming to reduce the overall prevalence of gonorrhoea;
- effective identification and management of infected patients, by ensuring that all those infected are promptly diagnosed and appropriately treated and receive a followup test of cure as recommended in current patient management guidelines;
- reminding those diagnosed with gonorrhoea of the importance of partner notification and of attending for their test of cure.
- The reported cases of extensively drug-resistant gonorrhoea also highlight the need for developing novel antimicrobials for this disease as well as prioritisation and funding of an effective vaccine
Rapid Risk Assessment: Extensively drug-resistant (XDR) Neisseria gonorrhoeae in the United Kingdom and Australia
This rapid risk assessment aims to assess the risk of XDR Neisseria gonorrhoeae spreading further in the EU/EEA and provide some options for response.
The first three cases of infection with extensively drug-resistant (XDR) Neisseria gonorrhoeae displaying resistance to ceftriaxone (MIC = 0.5 mg/L) and high-level resistance to azithromycin (MIC >256 mg/L) at a global level were reported by the United Kingdom (one case) and Australia (two cases) in February and March 2018, respectively. The case from the UK and one case from Australia were travel-associated and both acquired gonorrhoea in South-East Asia. These strains are the first global reports of high-level azithromycin resistant N. gonorrhoeae which is also resistant to ceftriaxone as well as most other alternative antimicrobials. Consequently, they are resistant to the first line dual therapy for gonorrhoea (ceftriaxone intramuscularly and azithromycin orally) recommended by European, Australian, World Health Organisation and other guidelines. They highlight the increasing threat of multidrug- (MDR) and extensively drug-resistant (XDR) gonorrhoea in the context of limited therapeutic alternatives, lack of vaccine and limited surveillance capacity in many regions globally.
Effective response to this threat will require strengthened collaboration between clinicians, microbiologists, epidemiologists and public health authorities at national and international level through the adoption of measures to preserve ceftriaxone and azithromycin as viable treatment options for gonorrhoea. The recently reported cases indicate a need to continue to increase awareness of the issue among the public, clinicians, laboratory staff, epidemiologists and other healthcare and public health professionals.
Prevention efforts need to be focused on measures to reduce the overall number of gonorrhoea cases, by emphasising the importance of safer sex practices, in particular the use of condoms, and following any national guidelines on STI testing after unprotected sexual activity with new or casual partners. Considering that two of the three XDR gonorrhoea cases reported here were travel-related, provision of information on safer sex practice should be considered as routine advice for travellers. All patients diagnosed with gonorrhoea, need to be reminded of the importance of partner notification and attending for test of cure.
Clinicians need to ensure that all gonorrhoea cases are managed according to national and/or international guidelines, be aware of the possibility of further cases which are resistant to ceftriaxone and azithromycin, ensure that tests of cure are performed for all diagnosed cases, and submit samples for culture and antimicrobial susceptibility testing from all suspected or proven positive sites of infection. In case of XDR gonorrhoea, clinicians should consider taking pharyngeal samples irrespective of reported sexual practices. Sexual health services also need to ensure that partner notification is undertaken for all cases. Particular attention should be paid to effective detection and treatment of pharyngeal gonorrhoea, which is frequently more difficult to eradicate compared to urogenital infections.
Antimicrobial resistance surveillance for N. gonorrhoeae in EU/EEA countries and globally, needs to continue to be prioritised and strengthened. Reporting of treatment failures should be implemented and/or strengthened at the national and European level to enable rapid implementation of interventions to prevent the spread of MDR- and XDR N. gonorrhoeae. Timely sharing of data between national authorities on treatment failures will also facilitate a more effective global response.