In recent years, public health officials and experts in sexually transmitted infections (STIs) alike have been warning about the threat of antibiotic-resistant gonorrhea, and the impact that rising resistance could have on treatment for the more than 82 million gonorrhea cases that occur worldwide every year.
The threat comes from rising resistance to ceftriaxone, an antibiotic that has been a mainstay of treatment regimens for uncomplicated gonorrhea for four decades and is currently the last remaining recommended empiric treatment option. In a recent report, the World Health Organization (WHO) warned that in the 13 high-burden countries targeted for gonorrhea surveillance, resistance to ceftriaxone is growing, with some countries seeing a nearly sixfold increase.
The WHO has labeled drug-resistant gonorrhea a serious and urgent public health threat. If left untreated, gonorrhea infections can cause pelvic inflammatory disease in women and infertility in men and women. It can also increase the risk of ectopic pregnancy (implantation of a fertilized egg outside the uterus) and HIV infection.
“It’s under-appreciated because it’s an STI, but it’s a major infectious disease threat for which we don’t have very many options,” Amesh Adalja, MD, an infectious disease physician and senior scholar at the Johns Hopkins Center for Health Security, told CIDRAP News.
But the results of a large, multinational phase 3 trial indicate a new option is on the horizon. The results, published yesterday in The Lancet Infectious Diseases, show that a single dose of the novel oral antibiotic zoliflodacin was noninferior to the standard treatment regimen of intramuscular ceftriaxone and oral azythromicin for treating uncomplicated urogenital gonorrhea and had a similar safety profile.
Those results are likely to pave the way for approval of zoliflodacin by the US Food and Drug Administration (FDA) as soon as next week. In related news, GSK announced yesterday that the FDA has approved its oral antibiotic, gepotidacin (Blujepa) for uncomplicated gonorrhea. Gepotidacin had previously been approved for uncomplicated urinary tract infections.
It’s a major infectious disease threat for which we don’t have very many options.
Scientists involved with the zoliflodacin trial believe it’s a significant development in efforts to manage one of the world’s most common STIs. “It will really broaden our ability to treat gonorrhea in a number of different ways,” said Edward Hook, MD, a senior author of the study and emeritus professor of medicine at the University of Alabama-Birmingham Medical School.
High cure rate, similar efficacy to comparator
Developed through a public-private partnership between US drugmaker Innoviva Specialty Therapeutics and the nonprofit Global Antibiotic Research & Development Partnership (GARDP), zoliflodacin is a first-in-class antibiotic from the spiropyrimidinetrione class, with a unique mechanism of action against Neisseria gonorrhoeae, the bacterium that causes gonorrhea.
In earlier lab studies, the drug was found to be highly active against multidrug-resistant strains of N gonorrhoeae, making it a promising candidate for further development.
“We identified this molecule as being a really high priority for us,” said Seamus O’Brien, PhD, study co-author and research and development director at GARDP, which entered into an agreement with Entasis Therapeutics (now a subsidiary of Innoviva) in 2019 to run and sponsor the phase 3 trial for zoliflodacin. In return, GARDP received the rights to register and commercialize the drug in more than three-quarters of the world’s countries. It’s a unique arrangement that many believe could overcome some of financial barriers to antibiotic development.
The randomized controlled trial—the largest to date in gonorrhea patients—was conducted in 17 STI clinics in Belgium, the Netherlands, South Africa, Thailand, and the United States from November 6, 2019, to March 16, 2023. Eligible participants were randomly assigned 2:1 to receive a single dose of zoliflodacin, delivered as a liquid, or an injection of ceftriaxone plus an oral dose of azithromycin, which at the time was the first-line treatment recommended by the US Centers for Disease Control and Prevention (CDC) and remains the recommended treatment in several countries (the current recommendation from the CDC is a shot of ceftriaxone).
The primary end point was the proportion of patients in each group with microbiological cure (ie, patients whose gonorrhea infection was eradicated) at the test-of-cure visit.
A total of 930 patients (mean age, 29.7 years; 88% male, 55% Black, 31% Asian, 12% White) were randomized to zoliflodacin (621 patients) or the comparator (309). Most of the participants were from South Africa (46%) and Thailand (29%). Twenty-one percent were living with HIV.
The cure rates were high in both groups: 90.9% of patients in the zoliflodacin arm and 96.2% in the ceftriaxone plus azithromycin arm. Though the estimated treatment difference was 5.3 percentage point in favor of the comparator, that fell within the pre-defined 12% noninferiority margin. Noninferiority studies aim to show that a new drug works about as well as a standard-of-care treatment in terms of efficacy.
Most of the adverse events experienced by trial participants were primarily gastrointestinal and mild or moderate in severity, with no serious side effects reported. There was also no evidence in trial participants of the emergence of zoliflodacin resistance.
“Our findings provide evidence for zoliflodacin as a potential oral treatment for uncomplicated urogenital gonorrhea,” the study authors write.
The results were also positive for secondary end points, which included cure rates for gonorrhea infections in the rectum and the throat, which can be more difficult to treat. Zoliflodacin had cure rates of 79.2% for pharyngeal gonorrhea and 87.3% for rectal gonorrhea, compared with 78.6% and 88.6% for the comparator.
“The two drugs performed comparably at those sites,” said Hook.
Appealing drug characteristics
O’Brien said the data on pharyngeal gonorrhea in particular will be important for clinicians, “because they do see a number of patients that have pharyngeal gonorrrhea.” He believes findings from the trial, along with other data submitted to the FDA, should be enough for the agency to give the nod to zoliflodacin for uncomplicated urogenital gonorrhea.
“I think what it also does is give confidence to clinicians…that this drug can be used across a broad range of populations,” he said.
In addition to the high efficacy rate, Hook highlighted some of the other benefits of zoliflodacin. For example, he pointed out that at least 9% of Americans believe they have an allergy to beta-lactam antibiotics, which include ceftriaxone. And more important, it doesn’t require an injection.
What it also does is give confidence to clinicians…that this drug can be used across a broad range of populations.
“People don't like injections. We know that,” Hook said. He added that zoliflodacin doesn’t need to be mixed or refrigerated, either, which would make it easier to store in low-resource settings—a point echoed by O’Brien.
“We believe that there will be more opportunities for this to be accessible to patients in community outreach clinics, in addition to more dedicated STI clinics,” O’Brien said.
And it has a novel mechanism of action, “which is always good because that is something that may forestall inevitable drug resistance,” added Adalja, who was not involved in the study.
Questions about clinical use
If zoliflodacin, which will be marketed under the brand name Nuzolvence, is approved by the FDA, the next question is how it will be used clinically. Ceftriaxone remains highly effective, and because gonorrhea is notorious for developing resistance to the antibiotics used for treatment, there might be concern, from an antibiotic stewardship perspective, about making zoliflodacin the recommended treatment.
What distinguishes gonorrhea from many other infections, Hook explained, is that clinicians make the decision to treat patients before they know whether the patient has an infection that’s susceptible to antibiotics. Gonorrhea diagnosis is primarily based on clinical symptoms and the results from nucleic acid amplification tests, which don’t provide antibiotic susceptibility results.
That “really raises the bar,” Hook said, especially in low-resource settings where additional microbiologic testing is limited or patients aren’t able to wait for test results. And even in high-income countries, susceptibility testing can take several days.
“You need to have a drug that you know will be effective at the time you use it,” he said. “So I would think it would be recommended co-equally with ceftriaxone.” Hook also noted that since zoliflodacin is indicated only for gonorrhea at this point, that may further slow the development of resistance.
Adalja said he thinks zoliflodacin will likely be used initially in patients who have evidence of, or a high risk for, drug-resistant gonorrhea.
“We don’t have many antibiotics for drug-resistant gonorrhea, so you don’t want to use it when you could use other options,” he said.
Could be first option in high-resistance settings
For many gonorrhea patients, zoliflodacin could be a preferable alternative. As STI expert Kimberly Workowski, MD, of Emory University, writes in an accompanying commentary, having an antibiotic that’s easier to administer than ceftriaxone is an important advance for gonorrhea treatment.
“Ceftriaxone is difficult to administer (ie, requires an in-person visit and skill to administer), which also makes it less conducive to newer modalities of care, such as telehealth; many providers do not stock ceftriaxone in outpatient clinics or have alternative antimicrobials in cases of allergy,” she writes. In addition, some patients might have ceftriaxone-resistant gonorrhea and need an alternative option.
I think zoliflodacin, in that sort of high-resistance setting, would definitely be a first-line agent.
Workowski also notes that modeling studies have found that holding an antibiotic in reserve until ceftriaxone resistance reaches a certain threshold would likely be an ineffective strategy.
There’s also the reality that other treatment options are already at risk in countries like Vietnam, where the WHO surveillance report found that 24% of N gonorrhoeae isolates tested in 2024 were ceftriaxone-resistant.
“I think zoliflodacin, in that sort of high-resistance setting, would definitely be a first-line agent,” O’Brien said.
The FDA has set a target date of December 15 to make its decision. GARDP is also seeking approval for zoliflodacin in South Africa and Thailand.
