30 Oct 2015
Written by Neil Woodford
Professor Neil Woodford is Head of the Antimicrobial Resistance and Healthcare-Associated Infections (AMRHAI) Reference Unit at Public Health England, and Advisor to the Longitude Prize.
Gonorrhoea is a sexually transmitted infection (STI) with almost 35,000 cases reported in England in 2014. Left untreated, gonorrhoea can cause serious and permanent health problems in both women and men, including infertility, and it can blind babies delivered normally if the mother is infected. Rarely, it can become a life-threatening condition if it spreads to blood or joints. Untreated gonorrhoea may also increase chances of contracting HIV.
Drug-resistant gonorrhoea is highlighted as a priority in the UK Five-Year Antimicrobial Resistance Strategy 2013 to 2018, as an ‘Urgent Threat’ by the US Centres for Disease Control, and as an infection of ‘international concern’ by the WHO. Unlike most other bacteria that present resistance challenges, gonorrhoea bacteria (Neisseria gonorrhoeae or ‘the gonococcus’ or just ‘GC’) spread in the community, not in healthcare settings.
Successful treatment should be easy. The gonococcus was one of the most sensitive bacteria at the start of the antibiotic era, when patients could be cured with tiny doses of penicillin. But, since penicillin was first used in the 1940s, gonococci have developed resistance to every antibiotic that has been used to treat them and are a perfect example of our current global antibiotic resistance crisis.
To ensure compliance and to reduce further transmission, doctors seek to treat gonorrhoea with a single antibiotic dose, which is given in a genitourinary medicine clinic when a patient first presents. It is widely agreed that once 5% of gonococci become resistant to this first choice antibiotic, treatment must be changed for everyone. Many drugs that were once used to treat gonorrhoea effectively (low-dose penicillin, high-dose penicillin, tetracycline, ciprofloxacin and cefixime) have been rendered useless one after another as resistance has crossed this 5% threshold. Repeated cycles, over 70 years, represent a classic evolutionary experiment in selecting resistance in the real world, not the laboratory!
This evolution has narrowed treatment options, tracked in the UK by Public Health England’s Gonococcal Resistance to Antimicrobials Surveillance Programme. Since 2011, the recommended first-line treatment for gonorrhoea relies not just on one antibiotic but on two, on a ‘belt and braces’ approach: an injected dose of ceftriaxone (a powerful cephalosporin) and an oral dose of azithromycin. But, already, we’re seeing gonococci with reduced susceptibility to ceftriaxone and high- or low- level resistance to azithromycin, with transmission of a highly azithromycin-resistant gonococcus recently identified among sexual partners in northern England.
If resistance to ceftriaxone and/or azithromycin accumulates and tips above the 5% threshold, there are no more licensed antibiotics left for reliable, empirical treatment of gonorrhoea. This might lead to increasing numbers of infections, poorer outcomes and more complications. There are new antibiotics in development, but they are some time away from the clinic, with no guarantees that they will succeed.
One possibility is to revisit antibiotics that were abandoned when resistance rates crossed the 5% boundary, and to use them selectively. Current Public Health England data show that almost 20% of gonococci in England are resistant to penicillin and almost 30% to ciprofloxacin but, if we turn the proportions on their heads for a moment, they mean that over 70% of gonorrhoea is treatable with oral ciprofloxacin and over 80% with classical penicillin. By using ceftriaxone plus azithromycin to prevent under-treating 20-30% of patients we are overtreating 70-80% of patients. To reverse this we need rapid diagnostics that allow prescribers to tailor the treatment of individual patients to match the susceptibility of their strain. These tests don’t yet exist.
The Longitude Prize seeks to reward innovative diagnostics that help to conserve the antibiotics we have and to reduce antibiotic resistance. Drug-resistant gonorrhoea is an attractive target involving one type of bacteria and a limited number of antibiotics, and so should pose a much simpler problem than, for example, hospital-acquired pneumonia. But it is still not straightforward. Resistance in gonococci is frequently tricky and the genetic signals used in many diagnostics are harder to detect reliably than those present in many other bacteria. However, the purpose of the Longitude Prize challenge is, of course, to tackle difficult-to-solve problems.
In one possible future, a shiny new diagnostic test for antibiotic resistance in gonorrhoea would be used on patients attending genitourinary medicine clinics. Most would be told, in less than 30 minutes, that a ciprofloxacin pill (for example) is all they need. Importantly, the test would identify the smaller number of patients with resistant infections who genuinely need more powerful antibiotics. This tailored approach would reduce the pressure that encourages gonococci to develop resistance to any universally-used treatment and would prevent patients being given drugs that will not work. What’s more, it will allow abandoned drugs to be used once again where suitable, and will help ensure that new gonorrhoea antibiotics (when we get them) are better conserved.
Gonococci have thrown down the gauntlet!
