How dangerous is gonorrhoea resistance and can it be halted?

The bacterium that causes the common sexually transmitted infection (STI) gonorrhoea develops resistance to antibiotics easily, and some cases of multidrug-resistant gonorrhoea, originating from abroad, were reported from the UK this year, raising concerns that gonorrhoea could become untreatable.

However, a recent paper finds that gonorrhoea drug resistance is largely under control in the UK apart from these isolated cases, does not seem to be getting worse, and may be even improving in gay men.

These are the relatively reassuring findings of the study published in F1000Research that set out to test the opposite hypothesis. The authors aimed to show that resistance of gonorrhoea to antibiotics has increased due to more gay men getting tested – which has resulted in more taking antibiotic treatment.

The researchers compared antibiotic resistance in gonorrhoea treated in gay men and in women in the UK and in Belgium.

There are very different rates of rectal gonorrhoea testing in the two countries in gay men – in the UK, 70% of gay men who were recently screened for an STI reported they had an anal swab for gonorrhoea, compared with just 9% in Belgium.  

The authors’ hypothesis was that levels of treatment are directly related to levels of resistance – the more antibiotics are used, the more likely they are to create resistance. If levels of antibiotic treatment for gonorrhoea are related to resistance, then because far more gay men than women are tested for and diagnosed with gonorrhoea in the UK, gonorrhoea would be more resistant to the current drugs used to treat it in gay men than in women. But in Belgium, where testing and treatment rates are not higher in gay men, there would not be more drug-resistant gonorrhoea in gay men than women.

If the evidence supported this, it would pose a dilemma – should UK sexual health clinics continue to screen and treat high numbers of gay men for gonorrhoea if all it is doing is hastening the development of drug resistance in this notoriously adaptable bacterium?

Luckily the evidence appears to offer little support for this hypothesis at this point in time.

How gonorrhoea resistance has changed treatment guidelines

“At this point in time” is an important caveat. Originally treated with sulphonamides and then penicillin, gonorrhoea became progressively resistant to those drugs and then to tetracycline and ciprofloxacin, which replaced them.

As the proportion of gonorrhoea resistant to ciprofloxacin in the UK climbed to 50% in gay men and 20% in heterosexuals, a switch was made to a whole new class of antibiotics – the cephalosporins. Cefixime, a drug from this class, was used as the sole drug for gonorrhoea starting in 2006.

However, the proportion of gonorrhoea with resistance to cefixime rapidly increased in gay men from about 5% in 2008 to 31% in 2010. As a result, in 2011 the recommended therapy changed, to dual combination therapy. This combined another cephalosporin, ceftriaxone, with azithromycin, a drug of the macrolide class that has been used as part of gonorrhoea treatment since the mid-1980s and still retains significant activity, though not enough to be used alone.

Ceftriaxone has a longer half-life than cefixime and because of this was thought to be less likely to generate resistance by having suboptimal levels of it in the body in the presence of gonorrhoea.

Meanwhile Belgium switched directly from ciprofloxacin (or an old drug, spectinomycin) to ceftriaxone in 2008, but at a quarter of the dose now used in the UK (125 mg versus 500mg). Learning from the UK’s experience of cephalosporin resistance, they switched to ceftriaxone 500mg and azithromycin in 2012 and since then the two countries have had similar regimens, although Belgium uses a higher azithromycin dose.

This study

How has this impacted on drug resistance in gonorrhoea? The researchers compared what are called Minimum Inhibitory Concentrations (MICs) of azithromycin, cefixime and ceftriaxone in samples sent to the Belgian and UK surveillance laboratories. MIC is the minimum amount of drug needed to stop the growth of the organism in the lab dish. A higher MIC indicates more drug resistance. In HIV drug level and resistance testing, a similar measure called the IC­­­­_{90 ­}is used, which stands for 90% inhibitory concentration – it measures the amount of drug needed to reduce viral replication by 90%.

The researchers looked at gonorrhoea resistance in the UK at two time-points – 2011, before the switch to ceftriaxone/azithromycin – and 2014. They compared these to resistance in Belgium during the year 2013-14. They compared resistance rates in gay men with heterosexual women (heterosexual men were excluded because of the possibility some might be non-disclosing men who have sex with men).

The researchers’ original hypothesis was partly supported by the fact that in 2011 in the UK the MIC for all three drugs in the UK was higher in gay men than in women.

In the UK, the MIC for azithromycin was 0.25 milligrams per litre (mg/L) for gay men, while for women it was 0.06 mg/L. For ceftriaxone it was 0.008 mg/L for gay men and 0.002 mg/L in women (although this drug was not part of the recommended therapy before 2011, it was being used). For cefixime, the median MIC was the same in gay men and women (0.008 mg/L) but there was a minority of gay men (15%) who had more than a 15-fold higher MIC at 0.125 mg/L. This “bimodal distribution”, where a sizeable minority has considerably higher MICs than the rest, suggests that significant resistance may be developing.

In contrast in the data from Belgium, gathered two years later, there was little evidence of more resistance in gay men than in women. The median MIC for all three drugs was the same for both populations.

Interestingly, however, this was not because there was less resistance in Belgian gay men than in UK gay men – it was because there was more resistance in Belgian women. For instance, the MIC of azithromycin was 0.25 mg/L in both gay men and women in Belgium. And in the two cephalosporin drugs, it was in women, not gay men, that there were signs of bimodal distribution: for cefixime, over 20% of women had MICs of 0.125mg/L or more (eight times the median) compared with about 5% of gay men, and for ceftriaxone 39% of women had MICs over 0.03 mg/L (three times the median) compared with 18% of gay men.

Why might this be? One explanation is that the spread of drug resistance is connected to cases acquired in Asia, which is the part of the world with the highest prevalence of drug-resistant gonorrhoea. The initial reports of multidrug-resistant gonorrhoea in Europe suggested that they were more often acquired by heterosexuals abroad, even if they later spread to the gay population. This, combined with less treatment of asymptomatic gonorrhoea in gay men compared with the UK, might well lead to more resistance in women than gay men (though we must be careful here as the Belgian numbers – only 189 cases in women – are relatively small).

Finally, we come to the UK in 2014 after dual gonorrhoea therapy was adopted. Here we see promising signs that resistance might actually be decreasing in gay men. The median MIC of azithromycin in gay men, for instance, was 0.125mg/L – half of what it was three years earlier and only double, rather than four times, what it was in women. The MICs of cefixime were still slightly ‘right shifted’ in gay men versus women (i.e. there were slightly more high ones and slightly fewer low ones). But the MICs for ceftriaxone had completely changed and were now almost identical in gay men and women at 0.004 mg/dL.

Conclusions

These are promising signs – more promising than the researchers expected. They are not unprecedented, however and should perhaps not have been unexpected. In 2012 the US also changed its gonorrhoea treatment guidelines to ceftriaxone plus either azithromycin or doxycycline. Resistance to cefixime fell fourfold, and to ceftriaxone more than tenfold, between 2011 and 2013.

This is no reason to become complacent about gonorrhoea resistance. This organism has managed so far to become resistant to every class of antibiotic used against it. One warning sign in this study may be that the UK samples in 2014 included a handful of cases with very high-level resistance to azithromycin, with MICs anything from ten to 3000 times the average.

However, while in many diseases such as HIV and TB, resistance is due to poor adherence to drugs that may have to be taken over long periods of time, in most cases gonorrhoea treatment consists of at most two pills and two injections. The key to overcoming resistance is therefore improving the regimen rather than improving adherence, and in particular in using combination therapy. Phenotypic resistance tests, as seen in this study, can be used to guide prescribing and to forewarn of new resistance.