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What is the strongest treatment for gonorrhea?

Gonorrhea is a sexually transmitted infection (STI) caused by the bacterium Neisseria gonorrhoeae. It is a common infection globally, with over 80 million new cases estimated per year. Gonorrhea can cause infections in the genital tract, rectum, and throat. It is also a leading cause of pelvic inflammatory disease in women and epididymitis in men. If untreated, gonorrhea can lead to long-term health problems like infertility and increased risk of HIV infection. Therefore, prompt and effective treatment is essential for the management of gonorrhea.

What are the recommended first-line treatments?

For many years, antibiotics like penicillin, tetracycline, and fluoroquinolones were used as first-line treatments for gonorrhea. However, increasing antibiotic resistance has made many of these drugs ineffective, especially in recent years. Currently, dual therapy with ceftriaxone (a third-generation cephalosporin antibiotic) and azithromycin is the only recommended first-line treatment for gonorrhea in most countries.


Ceftriaxone is a broad-spectrum, injectable beta-lactam antibiotic. It binds to penicillin-binding proteins and inhibits the synthesis of the bacterial cell wall, thereby killing susceptible bacteria. Ceftriaxone is highly potent against N. gonorrhoeae and generally recommended at a dose of 250mg given intramuscularly as a single shot.


Azithromycin is a macrolide antibiotic that inhibits bacterial protein synthesis to stop growth. It is given orally, usually as a single 1g dose. Adding azithromycin to ceftriaxone provides synergy and may help prevent the emergence of resistance to ceftriaxone.

Some key advantages of dual therapy with ceftriaxone and azithromycin:

  • High efficacy – Clinical cure rates over 95% in most gonococcal infections
  • Rapid relief of symptoms
  • Prevents dissemination of infection
  • Treats possible co-existing chlamydia infection

Therefore, this first-line regimen remains the most effective empiric treatment for gonorrhea globally.

Are there alternative options for treatment?

In some limited cases, the following antibiotics may be used as alternative treatment options:


Cefixime is an oral third-generation cephalosporin that has been used in combination regimens for gonorrhea treatment. Although cefixime has lower efficacy than ceftriaxone, a single 400mg oral dose may be used when ceftriaxone is not available. However, if pharyngeal gonorrhea is suspected, cefixime should not be used.


Gentamicin is an injectable aminoglycoside antibiotic that has been evaluated in combination with azithromycin for gonorrhea treatment, especially when ceftriaxone is limited. Although efficacious, disadvantages include the need for injection and lack of data on optimal dosing.


Spectinomycin is an injectable antibiotic that remains effective for urogenital and anorectal gonorrhea in some regions. However, it is not recommended for pharyngeal infections and lacks efficacy data for co-existing chlamydia. It requires a high 2g intramuscular dose.

When are dual therapies preferred over monotherapies?

Currently, monotherapy with any single antibiotic is no longer recommended for empirical treatment of gonorrhea due to concerns over emerging antimicrobial resistance. Dual therapy combining two antibiotics with different mechanisms of action is preferred as it:

  • Delivers high cure rates exceeding 95%
  • Slows the development of resistance to either drug
  • Provides synergistic activity for enhanced efficacy
  • May treat co-existing infections like chlamydia

Some key clinical practice guidelines recommending dual therapy:

Guidelines Recommended Regimen
CDC STD Treatment Guidelines, 2021 Ceftriaxone + Azithromycin
European Guideline, 2016 Ceftriaxone + Azithromycin
WHO Guidelines, 2016 Ceftriaxone + Azithromycin

Therefore, dual therapy is strongly preferred over monotherapy for gonorrhea.

What are the limitations of current treatments?

While ceftriaxone plus azithromycin remains an effective first-line empirical treatment, there are some limitations:

  • Increasing ceftriaxone minimum inhibitory concentrations (MICs) indicating declining susceptibility
  • High-level azithromycin resistance outbreaks reported globally
  • Treatment failures reported, especially in pharyngeal gonorrhea
  • Limited alternative oral treatment options as cefixime efficacy decreases
  • Difficulty ensuring medication adherence with multi-drug regimens
  • Need to administer ceftriaxone injection

These limitations emphasize the urgent need for continued efforts like enhanced surveillance, antibiotic stewardship, research on new agents, and development of vaccines against gonorrhea.

What new or investigational drugs may be options in future?

With increasing drug-resistant gonorrhea, the development of new therapeutic options is critical. Some pipeline drugs with potential include:


Zoliflodacin is a novel spiropyrimidinetrione antibiotic that inhibits bacterial DNA synthesis. In phase 3 trials, a single 3g oral dose of zoliflodacin had 100% efficacy in urogenital gonorrhea. Further evaluation for drug-resistant infections is underway.


Gepotidacin is a novel triazaacenaphthylene antibacterial that inhibits bacterial DNA replication. Phase 2 data indicates high efficacy for urogenital gonorrhea with a single 1.5g oral dose.


Solithromycin is a fourth-generation macrolide antibiotic. Oral solithromycin has shown promise against azithromycin-resistant gonococcal infections in small studies. Larger trials are needed.


Delafloxacin is a fluoroquinolone antibiotic that may retain activity against some ciprofloxacin-resistant gonorrhea. More research is required on efficacy and optimal dosing.


ETX0914 is a novel spiropyrimidinetrione antibiotic related to zoliflodacin. Early phase 1 studies show activity against drug-resistant N. gonorrhoeae strains. Further development is ongoing.

Hopefully, these new agents or re-engineered older antibiotics will provide valuable treatment options in the future to combat multidrug-resistant gonorrhea.


Currently, the strongest empiric treatment for gonorrhea is dual therapy with the injectable antibiotic ceftriaxone plus the oral azithromycin. This first-line regimen provides high cure rates and slowing of resistance. However, rising antimicrobial resistance threatens treatment efficacy, making continued public health efforts and new antibiotic development urgent priorities. Promising investigational drugs like zoliflodacin are on the horizon, but more research is needed to expand and preserve gonorrhea treatment options. Dual therapy will remain vital to ensure all individuals with gonorrhea can be effectively cured.