Antimicrobial resistance

As we prepare to confront the emergence of yet another wave of decreased susceptibility to current therapies for gonorrhoea, the review by Lewis5 describes the history of the amazing versatility of this bacterium to successfully overcome all our previous attempts at control by antimicrobial therapy. The gonococcus is adept at acquiring or selecting resistance determinants with the subsequent dissemination of these resistance strains. There are many lessons to be learnt as we prepare to deal with gonorrhoea as a potentially difficult or untreatable infection.

Surveillance of the emergence of, and the trends in, resistance will be vital for informing local treatment strategies and individual patient management, but the approach taken needs to be global. This is particularly important as movement between countries and continents becomes widespread. Cole et al6 describe surveillance data from a recently initiated European network, which provides both country-specific and European-wide trends in resistance. While such surveillance programmes will guide and inform clinical management guidelines, Unemo et al7 remind us that, even when guidelines exist and are appropriate, this does not ensure compliance. They report that, in Eastern Europe adherence to guidelines was poor, particularly in the private sector. In Portugal, national surveillance is not well established, but Florindo et al8 show the power of using susceptibility data and molecular typing for understanding sexual networks to inform public health control. In Sweden, where surveillance is well established, longitudinal studies are shown to be particularly valuable for detecting the emergence of new mechanisms of resistance. Golparian et al9 examined isolates collected over a 10-year period with decreased susceptibility to the extended spectrum cephalosporins, and showed that, although a number of molecular types were found, one (ST 1407) was predominant.

While the global approach to the control of gonorrhoea will be concentrated on reducing transmission and on finding new agents or novel approaches to therapy, Sadiq et al10 discuss the value of point-of-care tests for antimicrobial resistance markers. Such tests could enable patients with highly susceptible strains to be treated with agents no longer applicable for empirical therapy, potentially prolonging the useful life of the cephalosporins. This novel and controversial idea may be horizon scanning, but if the technology can deliver in a short time frame, then point-of-care tests for resistance markers could become another weapon in our armoury.

Treatment

As isolates with decreased susceptibility to cephalosporins accumulate, the possibility of therapeutic failure to these previously highly active agents will need to be addressed. At this time, the relationship between in vitro susceptibility, dosage and therapeutic failure is not known, but recent pharmacodynamic analysis indicates that the levels of decreased susceptibility currently being detected are on the limit of responsiveness to current regimens.11 New therapies for gonorrhoea will need to be considered. Azithromycin has been considered the panacea of drugs for a number of sexually transmitted infections, but data on cure rates, side effects and potential for use as first-line therapy for gonorrhoea have rarely been addressed. Bignell and Garley12 have performed a valuable systematic review of the available data and present little evidence to support the use of azithromycin, at either 1 g or 2 g dose, as first-line therapy, primarily because of concerns about resistance and the relationship between in vitro susceptibility testing and clinical failure. However, they recognise that there may be occasions when azithromycin could usefully be considered.

Molecular testing technologies

The era of molecular detection of N gonorrhoeae for the diagnosis of gonorrhoea is with us. There have been concerns over recent years that nucleic acid amplification tests (NAATs) for N gonorrhoeae were not as robust as those for Chlamydia, were less specific, and, together with the lower prevalence of the infection, would produce large numbers of false-positive tests. In a number of countries, guidance has been produced advising caution with their use to minimise the distress and likelihood of a misdiagnosis.13 14 However, accumulating evidence indicates that NAATs for gonorrhoea are now the method of choice and give higher positivity rates than culture, particularly for extragenital samples.15 The positive predictive value (PPV) should be greater than 90% to limit false-positive results, and, in order to achieve this, a supplementary NAAT using a different target is required. Pope et al16 have performed a service evaluation of the Becton Dickinson ProbeTec GC Qx, using the BD Viper platform, and found the PPV to be >90% without confirmation. This platform and the Cobas 4800,17 which is also evaluated in this issue of the journal, are of a new generation of NAATs for gonorrhoea and chlamydia that are fully automated, have high-throughput, and the performance of which may indicate that confirmation is not always required to achieve the required PPV. Confirmation using a supplementary assay is a challenge for laboratories with only a single platform, and so in-house assays, if they have similar sensitivity and specificity to the original test, can be useful. The choice of a supplementary assay is crucial, and Verma et al18 report that the 16S ribosomal assay lacks specificity and compares poorly with the porA pseudogene, widely reported as being more specific and highly sensitive.19

Culture is no longer considered the ‘gold standard’ for the diagnosis of gonorrhoea, but, as options for treatment diminish, we must remember that a viable isolate of N gonorrhoeae is an absolute requirement for detecting emerging resistance where the mechanism is unknown, as molecular detection is only possible for known resistance determinants. Ensuring we have sufficient and representative samples for resistance testing will be the greatest challenge. Testing symptomatic patients or those screened NAAT positive in a genitourinary medicine clinic will give substantial numbers of isolates. In primary care settings, this will be more difficult, although Moller20 presents data that show patients recalled within a week will collect swabs and provide sufficient isolates to monitor susceptibility.

Reducing transmission through expanded testing

Gonorrhoea remains prevalent in high-risk groups, and in the UK these are predominantly MSM and black Caribbean or black British communities.21 Targeted testing of groups such as MSM22 23 will continue to be vital for infection control, and the decline in gonorrhoea diagnoses in the UK between 2000 and 2008, most notably among the black Caribbean population, may have resulted from such targeted interventions.21 Identification of potential undiagnosed reservoirs of infection such as the pharynx, as described here by Kinghorn,24 and unusual cases25 using the more sensitive molecular tests could also contribute to reducing infection transmission. However, molecular tests that can easily be used on self-taken specimens also offer an opportunity for testing or screening larger numbers of patients in many different settings without compromising the accuracy of the result. Gonorrhoea has always been considered an infection found primarily in large cities in individuals with increased number of sexual partners. The evolution of chlamydia NAATs to offer additional testing for gonorrhoea and the roll out of the National Chlamydia Screening Programme has fuelled the debate on who to screen or not to screen, as discussed by Ross,26 even though an evidence base to screen asymptomatic individuals is lacking. The reality is that dual NAATs for GC/CT are being used, and it is important that a robust system for the management of the patient is initiated and monitored, particularly in areas where gonorrhoea has not been traditionally diagnosed, as discussed by Downing et al.27

Primary prevention

Testing individuals attending for sexual healthcare and treatment of infected patients and their partners have been the mainstay of public health control of gonorrhoea. However, with the concern that gonorrhoea may become untreatable in the foreseeable future, the focus needs to shift towards effective primary prevention. Developing effective strategies for reducing sexual risk behaviour will be challenging and will require a robust evidence base, but reductions in gonococcal transmission through behaviour change can be achieved.28–32 Many patients diagnosed with gonorrhoea have been diagnosed previously and re-infection likely plays an important role in persistence of gonorrhoea in the population, as discussed by Chen.33 Intensive risk-reduction counselling of patients with gonorrhoea to help prevent re-infection could also have a significant impact on infection transmission.