In December 2025, the FDA approved two new oral antibiotics for uncomplicated gonorrhea: zoliflodacin (Nuzolvence) and gepotidacin (Blujepa) FDA, Dec 2025. They're the first new antibiotic classes for gonorrhea in over 30 years. Neither replaces ceftriaxone as first-line treatment; they're reserve options, mostly for resistant infections.
500 mg IM injection, single dose — still the standard of care
Single oral dose; FDA approved Dec 2025; ~91% cure rate in trials
Oral tablets; FDA approved Dec 2025; for limited treatment alternatives
| Item | Value |
|---|---|
| Ceftriaxone (Rocephin) | First-line — 500 mg IM injection, single dose — still the standard of care |
| Zoliflodacin (Nuzolvence) | New oral option — Single oral dose; FDA approved Dec 2025; ~91% cure rate in trials |
| Gepotidacin (Blujepa) | Reserve oral option — Oral tablets; FDA approved Dec 2025; for limited treatment alternatives |
Why we needed new gonorrhea drugs
Neisseria gonorrhoeae is one of medicine's great escape artists. Over the decades it has shrugged off nearly every antibiotic class thrown at it — sulfonamides, penicillins, tetracyclines, macrolides like azithromycin, and the fluoroquinolones CDC STI Tx Guidelines. Each time a drug became unreliable, clinicians moved to the next one, and the cupboard kept emptying.
The most recent loss was azithromycin. It used to be paired with ceftriaxone to cover both bugs and slow resistance, but isolates with elevated azithromycin MICs climbed from 0.6% in 2013 to 4.6% in 2018 — fast enough that the CDC dropped it, leaving a single ceftriaxone injection as the lone first-line regimen Clin Infect Dis, 2020. Putting everything on one drug is a precarious place to be.
And ceftriaxone resistance is no longer theoretical. The resistant FC428 strain emerged in Japan in 2015 and has since spread internationally, against a backdrop the WHO estimates at 82 million new gonorrhea infections worldwide in 2020 WHO. The throat is a particular danger zone. Pharyngeal gonorrhea is usually symptomless, can persist for up to 16 weeks, and the pharynx lets gonorrhea swap resistance genes with harmless resident bacteria, breeding the next resistant strain. You can read more about how this unfolds in our explainer on antibiotic resistance and STIs.
Zoliflodacin (Nuzolvence): a single pill with a brand-new mechanism
Zoliflodacin is a first-in-class spiropyrimidinetrione antibiotic. It works by jamming bacterial DNA gyrase — specifically the GyrB subunit — which the bacterium needs to coil and uncoil its DNA in order to replicate. It binds at a different site than the fluoroquinolones do, so gonorrhea that's already resistant to those drugs doesn't have a head start against zoliflodacin. It isn't cross-resistant with the classes gonorrhea has already defeated.
It's given as a single oral dose for uncomplicated urogenital gonorrhea in patients age 12 and older who weigh at least 35 kg (about 77 lb). In its Phase 3 trial, zoliflodacin achieved roughly 91% microbiological cure and was non-inferior to the standard ceftriaxone-plus-azithromycin regimen. For patients, it's a pill you swallow instead of a shot in the buttock.
Gepotidacin (Blujepa): an oral reserve option
Gepotidacin is also oral and also targets bacterial DNA replication through a novel mechanism, but it's positioned more cautiously. The FDA approved it for uncomplicated urogenital gonorrhea in patients 12 and older weighing at least 45 kg (about 99 lb), specifically for situations where few or no other options exist because of resistance FDA, Dec 2025. Limited clinical safety data in gonorrhea make it a reserve drug rather than a first-line choice.
Gepotidacin isn't brand new to the FDA. It was first approved in March 2025 for uncomplicated urinary tract infections, and the gonorrhea indication came later in the year. It's a backstop, a way to treat someone whose infection has nowhere else to turn.
How do they compare to ceftriaxone — is the shot still first-line?
Yes. As of the latest CDC guidance, a single intramuscular ceftriaxone injection remains the recommended first-line treatment — 500 mg IM, or 1 g for people weighing 150 kg or more. The CDC 2021 STI guidelines have not been updated to include zoliflodacin or gepotidacin, and neither new drug replaces ceftriaxone. They expand the arsenal without reshuffling the front line. For the full picture of standard care, see how gonorrhea is treated.
| Feature | Ceftriaxone (first-line) | Zoliflodacin (Nuzolvence) | Gepotidacin (Blujepa) |
|---|---|---|---|
| Form | Intramuscular injection | Single oral dose | Oral tablets |
| Role | Standard of care, recommended first | New option, not yet in CDC guidelines | Reserve — when resistance limits options |
| Mechanism | Cephalosporin (cell-wall) | Spiropyrimidinetrione (DNA gyrase, GyrB) | Novel DNA-replication inhibitor |
| Eligible patients | All ages | ≥12 yrs, ≥35 kg (≥77 lb) | ≥12 yrs, ≥45 kg (≥99 lb) |
| Cure data | Long-standing standard | ~91% microbiological cure, non-inferior | Limited gonorrhea safety data |
Throat infections are harder to cure than genital ones. Even fully susceptible pharyngeal gonorrhea fails ceftriaxone about 4.6% of the time, which is why a test-of-cure 7–14 days after treatment is advised for throat infections Treatment Failure review. How the oral drugs perform in the throat specifically will shape where they fit over time.
What this means for treatment going forward
The strategic value of these two drugs is that they're chemically unrelated to anything gonorrhea has already learned to evade. That gives clinicians a real answer for ceftriaxone-resistant strains and for patients who can't take cephalosporins. And because both are pills, they sidestep the practical friction of an injection, useful for settings where giving a shot is hard.
The smart play is to protect them. If your infection is curable with standard ceftriaxone, that's still the right treatment; saving zoliflodacin and gepotidacin for resistant cases keeps them working. Overusing a new drug is the fastest way to lose it, and gonorrhea's track record shows how quickly that can happen.
It's also worth context: reported gonorrhea has actually been falling — about 601,000 cases in 2023, or 180 per 100,000, down from a 2021 peak of 214 per 100,000 CDC, 2023. But rates vary wildly by place, from the national figure up to 853 per 100,000 in Washington, DC, 311 in Alaska, and 288 in Louisiana CDC AtlasPlus, 2023. Falling case counts don't mean the resistance threat is gone. It's the reason these drugs were pushed through.
Can you get these drugs now?
Approval and availability aren't the same thing. Walk into a clinic today and the treatment you'll be offered is still the ceftriaxone shot. The new oral drugs are freshly approved, not yet widely stocked, and not yet covered by every insurance plan. Availability will expand over time.
Where they matter right now is the difficult case. If you've been told ceftriaxone didn't clear your infection, or you have a true cephalosporin allergy, these are real options your provider can reach for. Don't go hunting for them otherwise, because that burns through them. The first step in any of this is still knowing your status, so if it's been a while, get tested.