How do you solve a problem like resistant gonorrhoea?

Carefully, says the WHO.

---

There are over 82 million cases of gonorrhoea worldwide, according to a recent WHO estimate.

With antimicrobial resistance fast rendering treatments useless, it’s a good thing there are a couple of new classes of drugs in the pipeline – but experts say we have to be careful not to burn these too.

Everybody’s worried

Neisseria gonorrhoeae is what the WHO calls a “priority pathogen”, WHO epidemiologist Dr Ismail Maatouk told delegates at the International Union against Sexually Transmitted Infections (IUSTI) conference in Sydney last month.

It’s tackling the problem across several fronts: antimicrobial surveillance, STI prevention and control, the development of new treatments, antibiotic stewardship and facilitating a vaccine.

The bug was certainly a priority for conference goers, who packed the room, elbows touching. (“Well of course – it’s gonorrhoea,” remarked one international delegate, unsurprised by the squeeze.)

It’s not just that numbers are climbing – though they certainly are. Australian figures showed a dip to around 25,000 cases during covid lockdowns in 2021 but they’ve since risen to around 40,000 in 2023.

It’s also that antimicrobial resistance to the available treatments is spreading across the globe. Data, which are based on often delayed or incomplete reporting, show that spread is uneven.

The situation in Cambodia, for instance, was described by Dr Maatouk as an emergency, with ceftriaxone resistance at almost 16%, cefixime resistance at 44% and azithromycin at 15%. Rates vary widely across China, with an overall resistance rate of 13% to azithromycin but over 50% in some cities, 2-64% resistance to cefixime and rates of over 75% to ciprofloxacin, penicillin and tetracycline.

“We clearly are having the same issues as the rest of the world,” said US epidemiologist Professor Barbara Van Der Pol, pointing to slides showing ciprofloxacin resistance rates of over 30%, over 20% for tetracycline, and around 15% for penicillin, in addition to elevated rates for azithromycin (around 6%), cefixime and ceftriaxone.

In Australia, where recommended first line treatment is a combination of ceftriaxone and azithromycin, under 1% of cases tested so far this year were resistant. Australia tests about a quarter of all cases, reporting on invasive gonococcal infections, as well as eye sites, joint infections, urethral and genital and other sites such as rectal and pharyngeal.

Microbiologist Professor Monica Lahra, director of the WHO Collaborating Centre for STI and AMR at NSW Health Pathology, said there had been an increase in both azithromycin and ceftriaxone resistance in the past two quarters.

“Since 2022 we have reported eight extensively drug resistant isolates as well in Australia,” she said.

“These are also a great concern to us, because we have not only imported but also local transmission being reported.”

What’s in the pipeline?

There haven’t been new drugs for N. gonorrhoeae for a long time, and now there are two that have successfully completed phase III trials. However, they are not without problems.

Zoliflodiacin is a first in class antibiotic developed by non-profit Swiss-based foundation GARDP. It is taken as a single oral 3g dose to treat uncomplicated gonorrhoea. Side-effects were similar across both arms of the phase III trial, which compared zoliflodiacin with ceftriaxone + azithromycin. In a phase III trial, the test group experienced more headaches, and the control arm had more gastrointestinal symptoms.

Gepotidacin, developed by pharmaceutical manufacturer GSK, is a first in class triazaacenaphthylene. In addition to uncomplicated gonorrhoea, the drug is also indicated for urinary tract infection. Unlike other gonorrhoea regimens, it is delivered in two oral 3g doses; the first dose on-site, the second administered by the patient 10-12 hours later. In the phase III trial, 74% of participants in the gepotidacin arm experienced gastrointestinal side-effects compared with 33% in the control ceftriaxone + azithromycin arm.

GP and deputy medical director of Sexual Health Victoria Dr Sara Whitburn said that would be a problem when it came to patients taking the second dose.

“I think anything that produces GI side effects is always a hard sell in primary care, especially when somebody comes back [with a repeat infection],” said Dr Whitburn.

“What we are seeing in primary care, is that often we are not treating just one episode of gonorrhoea. People are often getting a reinfection. One of the main reasons people stop medication is nausea and diarrhoea. It’s a really big driver for someone not to complete a course.”

If the second dose was not taken, the infection would not be cured.

“For many years we thought our patients too feckless to take multiple drugs,” joked Professor Jonathan Ross from University Hospital Birmingham, chairing an expert panel. “It’s not true. Of course, they can take drugs if they have to.”

Chlamydia is one example. The Australian guidelines recommend 100mg of oral doxycycline, twice a day for seven days.

“Most of the patients are very good about it – [at least] they say they’re very good about taking their seven days of doxycycline,” said Dr Whitburn.

“How much of our tested reinfections is actually not a doxy failure? We’ll never know.”

“There’s always the risk of [non] adherence with more tablets and more doses. It’s about having good education around why you’re taking it and how easy it is to take and not wanting to have a reinfection and things like that.”

Women are not well represented in the trials, the panel noted, and therefore not much data on efficacy exists for both drugs at the urogenital site. It was also unclear how effective the treatments would be on oropharyngeal infections, which is most important in men who have sex with men.

Will this change treatment?

For now, these drugs are less necessary in countries like Australia, where ceftriaxone resistance rates are low, than they are in low- and middle-income countries like Cambodia and Vietnam.

Their eventual uptake in Australia would come down to the cost to the user, said Dr Whitburn. Here, ceftriaxone is cheap and can be accessed through doctor bag prescriptions, but is not often kept in the clinic, which can cause delays, especially in non-metro areas, with patients needing to get it from the pharmacy.

“So we have a cheap drug that is still working well, and we still have access barriers to that,” she said. “Anything that is not subsidised by our government is unlikely to come down into primary care.”

In the US, “I would kind of keep it a bit secret,” said Professor William Geisler from the University of Alabama.

“You’re going to have off-label and indiscriminate use when you promote the drugs out there. People would much rather have these pills than take a shot and it will be used in the US if you really market it that way.”

Which is a problem, because indiscriminate use, along with incorrect use, would just see us facing down the barrel of antimicrobial resistance again. And we’ll get there fast.

If we’re not careful, we’ll burn these too

Two new drugs is good news, said Professor Ross. “We require new drugs? We’ve got new drugs.

“But we also know history tells us that getting new drugs isn’t enough. We get them, we use them, we lose them quite quickly.”

Sooner rather than later, N. gonorrhoeae has developed resistance to all the treatments levelled against it since the 1920s – sulfonamides, penicillins, tetracyclines, spectinomycin, cephalosporins and macrolides.

“We need to start thinking,” Dr Remco Peters, clinician, epidemiologist and researcher in clinical microbiology & infectious diseases, told delegates. Resistance to azithromycin took just seven years, ciprofloxacin five years.

“The one thing you shouldn’t do is leave it on the shelf,” said Dr Peters. Instead, we should start thinking about whether it’s a first-line treatment or only for use after several failures, or in combination, in specific populations, for particular sites of infection, after a particular test, making it accessible where most needed, making it affordable.

“And last, surveillance is absolutely key,” said Dr Peters.

An evidence-based introduction of new drugs was important to maximise their clinical lifespan, “acknowledging that there’s very little evidence out there,” he said.

“I don’t think it’s going to be a one size fits all.” 

It’s all about context

Treatment regimens vary widely, with drugs and doses determined by geographical context and availability.

“In the old days it was simple,” said Professor David Lewis, director of the Western Sydney Sexual Health Centre and a technical advisor for the WHO.

“You had susceptible isolates, and then if you were unlucky, you had a few resistant ones. And they were easy to tell.”

As resistant strains spread, and with limited data, it’s become more complicated to work out treatments and dosages. “Sometimes they’ll respond to treatment, sometimes they won’t … Between different priority populations, the resistance prevalence can be very different.”

The CDC now recommends 500mg ceftriaxone as first-line treatment (or 1g for those weighing more than 150kg). It dropped dual therapy with azithromycin from its guideline in 2021.

The UK guidelines have also dropped dual therapy with azithromycin and now recommend first-line empirical treatment of ceftriaxone 1g, or ciprofloxacin 500mg if a susceptible strain is identified prior to treatment, and epidemiological treatment only for those presenting within 14 days of exposure.

On the basis of trying to avoid multidrug resistance, as was achieved in Australia, the European guidelines have kept the dual therapy (first line ceftriaxone 1g + azithromycin 2g) unless there was local susceptibility data and you were confident the patient would return, in which case you could drop the azithromycin. If so, test of cure was mandatory. Those with chlamydia also got doxycycline.

The Australian guidelines have ceftriaxone as their “cornerstone”, with dual therapy added in 2014 to successfully reduce the emergence of ceftriaxone resistant strains.

“Remember, we sit in a very difficult area in the region: Sydney is the inguinal lymph node in the groin of Asia,” said Professor Lewis, crediting the line to the late Professor John Tapsall, who founded the Australian Gonococcal Surveillance Programme in 1979.

The difference in guidelines was not something to fret over, said Professor Lewis.

The focus should be on two things: 1) what is the best treatment now, given the local and regional context; and 2) what is the best strategy to avoid increasing resistant strains.

“I’ve had so many calls – ‘the Americans are doing this, we look stupid that Australia isn’t doing the same thing’.

“Don’t worry about that,” he said. “Think about what your gonococci in your country need to get treated and what we need to keep the country safe for the future.”

Molecular testing allows for resistance-guided therapy. “ALWAYS collect samples for gonococcal culture before treating gonorrhoea, to determine antimicrobial sensitivity and contribute to antimicrobial resistance surveillance,” the Australian guideline emphasises.

Professor Van Der Pol reminded delegates that the presence of a mutation did not necessarily correlate with treatment failure, but the information could still guide treatment.

“Any one person might have some organisms that have a mutation. Those organisms may or may not be fit, may not be transmissible to partners, but we’re going to try to be conservative and try to keep those resistant genes out of the population,” she said.