What is the preferred sequence of antibiotics for treating gonorrhea among ceftriaxone, doxycycline, azithromycin, cefixime, levofloxacin, and moxifloxacin?

Gonorrhea Treatment Sequence

The correct treatment sequence for gonorrhea is ceftriaxone 250-500 mg IM PLUS azithromycin 1 g orally as first-line dual therapy, with cefixime 400 mg orally PLUS azithromycin 1 g orally as the alternative when ceftriaxone is unavailable. 1

First-Line Treatment

• Ceftriaxone 250-500 mg IM single dose PLUS azithromycin 1 g orally single dose is the only CDC-recommended first-line regimen for uncomplicated gonococcal infections of the cervix, urethra, rectum, and pharynx 1, 2
• This dual therapy must be administered together on the same day, preferably simultaneously and under direct observation 3, 4, 5
• Ceftriaxone achieves 99.1% cure rate for urogenital and anorectal gonorrhea, with superior efficacy for pharyngeal infections compared to all alternatives 1, 2

Alternative Regimen (When Ceftriaxone Unavailable)

• Cefixime 400 mg orally single dose PLUS azithromycin 1 g orally single dose is the alternative when ceftriaxone cannot be administered 1, 6
• Mandatory test-of-cure at 1 week is required with the cefixime regimen due to rising MICs and declining effectiveness 1
• Cefixime is FDA-approved for uncomplicated cervical/urethral gonorrhea but has inferior pharyngeal efficacy compared to ceftriaxone 6

Critical Medications to AVOID

• Never use quinolones (levofloxacin, moxifloxacin) for gonorrhea treatment due to widespread resistance, despite historical 99.8% cure rates 1, 2
• Never use doxycycline for gonorrhea treatment—it has no role in gonorrhea therapy and is only used for chlamydia coverage in non-pregnant patients 1
• Never use azithromycin 1 g alone for gonorrhea—it has only 93% efficacy, which is inadequate 1, 7

Rationale for Dual Therapy

• Dual therapy addresses rising antibiotic resistance patterns and improves treatment efficacy while potentially delaying emergence of cephalosporin resistance 1
• Co-infection with chlamydia occurs in 40-50% of gonorrhea cases, making presumptive dual treatment essential 1
• Azithromycin is preferred over doxycycline due to single-dose convenience and substantially higher prevalence of gonococcal resistance to tetracyclines 1

Site-Specific Considerations

• Pharyngeal gonorrhea is significantly more difficult to eradicate than urogenital or anorectal infections 1, 2
• Ceftriaxone is the only reliably effective treatment for pharyngeal infections and is strongly preferred over cefixime 1, 2
• Spectinomycin has only 52% efficacy for pharyngeal infections and should be avoided 1

Special Populations

• Pregnant women: Use ceftriaxone 500 mg IM PLUS azithromycin 1 g orally; never use quinolones or tetracyclines in pregnancy 1
• Men who have sex with men (MSM): Only use ceftriaxone-based regimens due to higher prevalence of resistant strains; never use quinolones 1
• Severe cephalosporin allergy: Use azithromycin 2 g orally single dose with mandatory test-of-cure at 1 week, though this has lower efficacy (93%) and high GI side effects 1, 7

Follow-Up Requirements

• Patients treated with recommended ceftriaxone/azithromycin regimen do not need routine test-of-cure unless symptoms persist 1, 2
• Consider retesting at 3 months due to high reinfection risk 1, 3, 4, 5
• If cefixime or azithromycin monotherapy is used, mandatory test-of-cure at 1 week is required 1, 7

Partner Management

• All sexual partners from the preceding 60 days should be evaluated and treated with the same dual therapy regimen 1
• Patients should avoid sexual intercourse until therapy is completed and both patient and partners are asymptomatic 1, 2