What is the preferred first‑line oral regimen for uncomplicated chlamydial infection and when should azithromycin be used instead of doxycycline?

Doxycycline vs Azithromycin in STI Treatment

Doxycycline 100 mg orally twice daily for 7 days and azithromycin 1 g orally as a single dose are co-equal first-line treatments for uncomplicated chlamydial infection, both achieving 97–98% cure rates, but azithromycin should be used when compliance with a multi-day regimen is questionable or when directly observed therapy is needed. 1, 2, 3

When to Choose Azithromycin Over Doxycycline

Azithromycin is specifically preferred in the following clinical scenarios:

• Populations with erratic health-care-seeking behavior (homeless individuals, adolescents, transient populations) where returning for follow-up or completing a 7-day course is unlikely 1, 2, 3

• When directly observed therapy is feasible, as the medication can be dispensed on-site and the single dose observed in the clinic to guarantee treatment completion 1, 2, 3

• Pregnancy, where azithromycin 1 g single dose is the preferred treatment and doxycycline is absolutely contraindicated due to teratogenic risk 1, 2, 3

• **Pediatric patients <8 years or <45 kg**, where doxycycline cannot be used; azithromycin 1 g is appropriate for children ≥8 years weighing >45 kg 2, 3

When to Choose Doxycycline Over Azithromycin

Doxycycline is specifically preferred in these situations:

• Rectal chlamydia infections, where doxycycline demonstrates superior efficacy (94–100% cure) compared to azithromycin single dose (79–87% cure), with an adjusted odds ratio of 0.43 (95% CI 0.21–0.91, p = 0.0274) 2

• Cost-conscious settings where the patient can reliably complete a 7-day course, as doxycycline is significantly less expensive than azithromycin 2, 3

• When azithromycin has failed, doxycycline 100 mg twice daily for 7 days is the recommended alternative first-line treatment 3

Critical Implementation Steps

For azithromycin:

• Dispense the medication on-site and directly observe the single dose to maximize treatment success 1, 2, 3
• Patients must abstain from all sexual intercourse for 7 full days after taking azithromycin, even though it's a single dose, because tissue concentrations build over time 1, 2, 3

For doxycycline:

• The full 7-day course is mandatory; shorter courses (e.g., 3 days) have not been validated by CDC guidelines despite some research suggesting equivalence 2, 4
• A delayed-release formulation (200 mg once daily for 7 days) is FDA-approved and achieves equivalent 95.5% cure rates with fewer gastrointestinal side effects (13% nausea vs 21% with standard dosing) 2

Partner Management (Identical for Both Regimens)

• All sex partners from the preceding 60 days must be evaluated, tested, and empirically treated with the same regimen, regardless of symptoms or test results 1, 2, 3
• If the last sexual contact was >60 days before diagnosis, treat the most recent partner anyway 1, 2
• Partners should receive empiric treatment without waiting for their own test results, as delaying treatment increases risk of complications and ongoing transmission 2

Follow-Up and Retesting

• Test-of-cure is NOT recommended for non-pregnant patients treated with either recommended regimen, as cure rates exceed 97% and testing before 3 weeks can yield false-positives from dead organism DNA 1, 2, 3

• Mandatory retest at 3 months post-treatment for all women to screen for reinfection, which occurs in up to 39% of adolescent populations regardless of whether partners were reportedly treated 1, 2, 3

• Pregnant women require mandatory test-of-cure 3–4 weeks after treatment due to potential maternal and neonatal complications 1, 2

Concurrent Gonorrhea Management

• Test all patients for gonorrhea, syphilis, and HIV at the initial visit when chlamydia is diagnosed 1, 2

• If gonorrhea is confirmed or highly suspected (>5% prevalence in the population), treat presumptively for both infections concurrently with ceftriaxone 250 mg IM single dose PLUS azithromycin 1 g orally single dose 5, 2

Common Pitfalls to Avoid

• Do not use erythromycin as first-line therapy; it has lower efficacy (not specified in guidelines) and gastrointestinal side effects that lead to poor compliance 1, 2, 3

• Do not wait for test results if compliance with return visits is uncertain in high-prevalence populations—treat presumptively 1, 2

• Do not assume partners were treated—directly verify or use expedited partner therapy strategies 2

• Do not perform test-of-cure in asymptomatic non-pregnant patients treated with recommended regimens, as this wastes resources and may yield false-positive results 2, 3