What oral regimen should be used to treat uncomplicated gonorrhea in a non‑pregnant adult without a cephalosporin allergy?

Oral Management for Gonorrhea

There is no recommended oral-only regimen for uncomplicated gonorrhea in non-pregnant adults without cephalosporin allergy—the CDC explicitly recommends ceftriaxone 500 mg intramuscularly (not oral) plus azithromycin 1 g orally as the only first-line treatment. 1, 2

Why Oral Therapy Alone Is Not Recommended

The CDC removed oral cephalosporins from first-line recommendations in 2012 due to documented treatment failures in Europe and rising resistance patterns. 1 Cefixime, the only oral cephalosporin previously used, is now relegated to an alternative regimen only when ceftriaxone is unavailable. 1, 3

Critical Limitations of Oral Regimens

Pharyngeal infections are the Achilles' heel of oral therapy. 2 Pharyngeal gonorrhea is significantly more difficult to eradicate than urogenital or anorectal sites, and most documented ceftriaxone treatment failures involve pharyngeal infections, not urogenital sites. 1, 2 The pharynx serves as a critical reservoir for antimicrobial resistance development through DNA exchange with commensal Neisseria species. 2

• Cefixime 400 mg orally achieves only 97.4% cure rate for uncomplicated urogenital and anorectal infections, compared to ceftriaxone's 99.1% cure rate. 1, 2
• In a 2024 randomized trial, cefixime 800 mg plus doxycycline failed to achieve noninferiority to ceftriaxone plus azithromycin, with all treatment failures occurring in pharyngeal gonorrhea cases. 4
• Cefixime's efficacy for pharyngeal infections is particularly poor—only 78.9% (CI 54.5%-94%) at the 200 mg dose. 5

Alternative Regimen When Ceftriaxone Is Unavailable

If ceftriaxone is truly unavailable, use cefixime 400 mg orally single dose PLUS azithromycin 1 g orally single dose, with mandatory test-of-cure at 1 week. 1, 3

Mandatory Follow-Up Requirements

• Test-of-cure is mandatory at 1 week (7 days post-treatment) for all patients treated with cefixime-based regimens due to rising cefixime MICs and declining effectiveness. 1
• Test-of-cure should ideally use culture (allows antimicrobial susceptibility testing) or NAAT if culture is unavailable. 1
• If NAAT is positive at follow-up, confirm with culture and perform phenotypic antimicrobial susceptibility testing. 1

Why Azithromycin Alone Fails

Never use azithromycin 1 g alone for gonorrhea treatment—it is explicitly contraindicated by CDC guidelines. 1, 2 Azithromycin 1 g orally has only 93% efficacy against gonorrhea and risks rapid resistance emergence. 1, 2

Even the higher 2 g dose of azithromycin, while achieving 98.9% cure rate in clinical trials, causes significant gastrointestinal distress (35.3% of patients experience GI side effects, with 2.9% severe) and is not recommended due to concerns about emerging macrolide resistance. 2, 6

Common Pitfalls to Avoid

• Never assume oral therapy is equivalent to injectable ceftriaxone—pharyngeal infections require ceftriaxone for reliable cure. 2
• Never use fluoroquinolones (ciprofloxacin, ofloxacin) for gonorrhea treatment due to widespread resistance, despite their historical 99.8% cure rates. 5, 1
• Never skip test-of-cure when using alternative regimens—all non-ceftriaxone regimens require mandatory follow-up culture at 1 week. 1, 2
• Cefixime should not be used as monotherapy without azithromycin or doxycycline, as this violates CDC dual therapy recommendations. 1

Dual Therapy Rationale

The CDC recommends dual therapy to address chlamydial coinfection (occurring in 10-50% of gonorrhea cases) and potentially delay cephalosporin resistance. 1 Co-infection is extremely common, making presumptive treatment for both organisms essential when empiric therapy is indicated. 1

Partner Management

All sexual partners from the preceding 60 days must be evaluated and treated with the recommended dual therapy regimen for both gonorrhea and chlamydia. 1, 2 Partners should receive expedited partner therapy with cefixime 400 mg plus azithromycin 1 g if they cannot be linked to timely evaluation. 1 Patients should avoid sexual intercourse until therapy is completed and both they and their partners are asymptomatic. 5, 1

Treatment Failure Management

If symptoms persist after treatment, obtain specimens for culture with antimicrobial susceptibility testing immediately. 1 Report the case to local public health officials within 24 hours and consult an infectious disease specialist. 1 Recommended salvage regimens include gentamicin 240 mg IM plus azithromycin 2 g orally or ertapenem 1 g IM for 3 days. 1