Two new antibiotics offer hope for people with gonorrhoea that is resistant to currently available drugs, yet it might be years before these drugs can be used in South Africa, writes Catherine Tomlinson for Spotlight.
Gonorrhoea is known for its ability to quickly mutate to evade the antibiotics used to treat it. Symptoms include pain when urinating and genital discharge, but many people don’t notice any symptoms at all. However, if it is not treated, it can cause serious problems including infertility, chronic pain and complications in babies, who risk developing infections that can cause eye damage and blindness.
But treatment has been something of a cat-and-mouse game, as the bacteria has continuously developed resistance against the antibiotics used to treat it. From the 1990s to the early 2000s, ciprofloxacin was used to treat the disease in South Africa, sometimes combined with doxycycline.
Yet as high levels of ciprofloxacin resistance emerged, the country changed this course of therapy with a regimen of cefixime and doxycycline. Treatment was changed again in 2015, due to concerns regarding the emergence of cefixime-resistance.
The treatment regimen adopted in 2015 remains the standard of care in South Africa and much of the world today. It involves an intramuscular injection of ceftriaxone, combined with oral azithromycin pills, although some countries now recommend using high-dose injectable ceftriaxone on its own, due to high levels of azithromycin resistance.
While most gonorrhea cases are still treatable with ceftriaxone, the emergence of ceftriaxone-resistant gonorrhoea has been identified as a major global health threat.
“The last effective drug we have, ceftriaxone, already indicates increasing gonococcal resistance. Without new antibiotics, we will have no easy treatment options. This is a great concern that will have a major impact on disease control efforts,” warned the World Health Organisation (WHO).
This is why two new antibiotics, zoliflodacin and gepotidacin, are considered such a big deal. They are the first new medicines developed for gonorrhoea in more than 30 years. Both are in new classes of antibiotics, so attack the bacterium differently way from previous medicines.
Because of this, they have little cross-resistance with existing treatments, therefore offering important options for people for whom the old medicines no longer work.
How widespread is ceftriaxone-resistance in SA?
How urgently we need access to the new medicines in South Africa will depend largely on how many people here are resistant to ceftriaxone. Unfortunately, we don’t have a clear picture of drug-resistant gonorrhoea in the country.
A syndromic management approach for sexually transmitted infections (STIs) was introduced here in the mid-1990s, as recommended by the WHO, meaning people reporting STI symptoms at health facilities are treated according to their symptoms, rather than results of a lab test.
This approach helps to reduce the cost burden of laboratory diagnosis and allows for immediate treatment initiation without waiting for lab results, as some patients are “lost” over this period as they do not return to health facilities for results and treatment.
A challenge with treating STIs according to symptoms rather than laboratory results is that many STIs present with similar symptoms. This can lead to misdiagnosis and incorrect treatment as well as asymptomatic infections going undiagnosed and untreated.
Thus, without lab testing, combined with routine STI screening to identify asymptomatic cases, it is difficult to understand the true burden of gonorrhoea in the country or to measure the extent of drug resistance.
A systematic review, however, indicates that while azithromycin resistance is a challenge here, there was not yet evidence of ceftriaxone resistance as of 2022.
The National Institutes of Communicable Diseases (NICD) classified ceftriaxone-resistant gonorrhoea as a notifiable condition in 2017, but did not respond to a query from Spotlight on whether there have yet been any confirmed cases of ceftriaxone-resistant gonorrhoea.
While we are not yet facing a ceftriaxone-resistance crisis, experts say it is only a matter of time before this public health challenge reaches our borders, as global cases are increasing and the drug-resistant strain is transmittable.
Some access to zoliflodacin
Given the risk of a ceftriaxone-resistance crisis, it is important that the new antibiotics, zoliflodacin and gepotidacin, become available here as soon as possible. The two have quite different histories.
Zoliflodacin was developed by GARDP – the non-profit organisation working to accelerate the development of new antibiotics – with private biopharmaceutical company Innoviva.
In November 2023, GARDP shared the results of its phase 3 trial of zoliflodacin, which took place in South Africa, Thailand, Belgium, the Netherlands and the United States. It tested the effectiveness of a single dose of oral zoliflodacin compared with the current standard of care treatment for gonorrhoea – the injection of ceftriaxone combined with oral azithromycin.
The trial showed that a single dose of zoliflodacin works just as well as the standard of care. The results have not yet been published in a peer-reviewed journal.
“Zoliflodacin has also been shown to be active against all multidrug-resistant strains of Neisseria gonorrhoeae, including those resistant to ceftriaxone, the last remaining recommended antibiotic treatment,” GARDP’s R&D Project Leader for STIs Pierre Daram told Spotlight.
He said Innovia was in the process of applying for approval to use zoliflodacin in the United States. At the same time, GARDP is planning to apply for approval in some of its own regions, starting with Thailand and South Africa.
GARDP is also working on a programme to make the unregistered drug available for patients who have no other treatment options.
“The zoliflodacin managed access programme is about to be activated,” he said. “The aim is to provide early access to zoliflodacin, before regulatory approval in a country, in response to individual patient requests by clinicians and where certain regulatory and clinical criteria are met.” South Africa will be one of the countries covered under this programme.
He said individual patient requests for treatment will be received from treating clinicians through an online platform. “Based on information provided by the clinician and certain pre-determined regulatory and clinical criteria being met, GARDP will make a case-by-case decision on whether zoliflodacin will be made available,” he added. “Consideration is given to both clinical as well as diagnostic criteria for documentation of treatment failure.”
Access to gepotidacin remains uncertain
Shortly after results for zoliflodacin were announced, GlaxoSmithKline (GSK) also shared positive findings for its new antibiotic in treating gonorrhoea. In April 2024, the company reported that a phase 3 trial showed that taking two doses of oral gepotidacin worked just as well as the standard treatment.
The results of this trial, conducted in Australia, Germany, Mexico, Spain, the United Kingdom, and the United States, were published in in The Lancet last month.
While gepotidacin represents an important new treatment option for gonorrhoea, there is no indication that it will be available in South Africa any time soon.
Gepotidacin has not yet been registered for the treatment of gonorrhoea but was approved in March in the United States for treating uncomplicated urinary tract infections (UTIs) in women and girls over 12. The medicine will thus have a much larger market in the US than if it were only registered for treating gonorrhoea.
The price GSK will charge for gepotidacin has not yet been disclosed, but a spokesperson told Spotlight it is due to be launched in the US in the second half of 2025, and the cost “will be disclosed when the product is commercialised”.
The company did not respond to questions regarding the company’s plans to register and market gepotidacin in South Africa.
What happens next?
With the launch of the zoliflodacin managed access programme, clinicians in South Africa will soon be able to apply for the medicine for patients who are resistant to existing drugs. Given that ceftriaxone-resistance is rare here, the number of patients who will be eligible is likely to be small.
Securing broader access to zoliflodacin or gepotidacin, potentially for use as a first line gonorrhoea treatment, appears to be a long way off. While GARDP is planning to file for registration of zoliflodacin in South Africa, GSK has not indicated whether it will follow suit for gepotidacin.
Providing the new antibiotics for first line gonorrhoea treatment could expand delivery and uptake, as the new drugs are both oral tablets and would remove the need for an injection to treat gonorrhoea, said Professor Nigel Garret, head of HIV Pathogenesis and Vaccine Research at the Centre for the Aids Programme of Research in South Africa.
If zoliflodacin and gepotidacin are approved and made affordable in South Africa, they could also play a vital role in strengthening efforts to preserve the long-term effectiveness of other antibiotics.
“Ceftriaxone is a really important drug to keep, to make sure there isn’t too much resistance against it,” he told Spotlight, adding that the medicine is needed to treat sepsis occurring in hospitals, as well as meningitis.
See more from MedicalBrief archives:
NHS England rolls out ‘world-first’ gonorrhoea jab as cases rise
Antibiotic to fight STDs is double-edged sword, say experts
Meningitis vaccine may cut risk of untreatable gonorrhoea
WHO warns oral sex is helping spread of dangerous gonorrhoea