What is the recommended dosing for syphilis treatment?

Syphilis Treatment Dosing

For early syphilis (primary, secondary, or early latent), treat with a single intramuscular injection of benzathine penicillin G 2.4 million units, which is equally effective as three weekly doses and reduces treatment burden. 1

Primary and Secondary Syphilis

First-Line Treatment (Adults)

• Benzathine penicillin G 2.4 million units IM as a single dose 2
• Recent high-quality evidence demonstrates that one dose is noninferior to three weekly doses, with 76% serologic response at 6 months regardless of HIV status 1
• This single-dose regimen reduces clinic visits, improves completion rates, and causes less injection-site pain compared to multiple doses 1

Pediatric Dosing (≥1 month old)

• Benzathine penicillin G 50,000 units/kg IM (maximum 2.4 million units) as a single dose 2
• Children require CSF examination to exclude neurosyphilis before treatment 2

Penicillin-Allergic Patients (Non-Pregnant)

• Doxycycline 100 mg orally twice daily for 14 days (preferred alternative per CDC) 2, 3, 4
• Tetracycline 500 mg orally four times daily for 14 days (more GI side effects, lower compliance) 2
• Avoid azithromycin due to widespread T. pallidum resistance and documented treatment failures in the United States 2
• Ceftriaxone 1 g IM or IV daily for 10-14 days may be considered, though optimal dosing remains undefined 2

Critical caveat: Pregnant patients with penicillin allergy must be desensitized and treated with penicillin—no alternatives are acceptable 2, 3

Latent Syphilis

Early Latent Syphilis (acquired within past year)

• Benzathine penicillin G 2.4 million units IM as a single dose 2
• Diagnosis requires documented seroconversion, recent symptoms of primary/secondary syphilis, or partner with early syphilis within the past year 2

Late Latent Syphilis or Unknown Duration

• Benzathine penicillin G 2.4 million units IM weekly for 3 consecutive weeks (total 7.2 million units) 2
• If a dose is missed, intervals up to 10-14 days between injections may be acceptable for non-pregnant patients 2
• Pregnant patients cannot miss doses—restart the sequence if necessary 2

Pediatric Dosing for Latent Syphilis

• Early latent: 50,000 units/kg IM (max 2.4 million units) as a single dose 2
• Late latent/unknown duration: 50,000 units/kg IM (max 2.4 million units) weekly for 3 weeks (total 150,000 units/kg, max 7.2 million units) 2

Penicillin-Allergic Patients with Latent Syphilis

• Early latent: Same alternatives as primary/secondary syphilis 2
• Late latent/unknown duration: Doxycycline 100 mg orally twice daily for 28 days OR tetracycline 500 mg orally four times daily for 28 days 2, 3
• These alternatives require close serologic and clinical follow-up 2

Neurosyphilis

Standard Regimen

• Aqueous crystalline penicillin G 18-24 million units per day IV, administered as 3-4 million units every 4 hours (or continuous infusion) for 10-14 days 2, 5
• Alternative: Procaine penicillin G 2.4 million units IM daily PLUS probenecid 500 mg orally four times daily, both for 10-14 days 2
• Many experts recommend additional therapy with benzathine penicillin G 2.4 million units IM weekly for 3 doses after completing IV therapy 5

Syphilitic Eye Disease

• Treat as neurosyphilis with the same IV penicillin regimen 2
• Manage in collaboration with ophthalmology 2
• Perform CSF examination on all patients with ocular syphilis 2

Pediatric Neurosyphilis

• 200,000-300,000 units/kg/day IV (administered as 50,000 units/kg every 4-6 hours) for 10-14 days 5

Tertiary Syphilis (Non-Neurologic)

• Benzathine penicillin G 2.4 million units IM weekly for 3 weeks (total 7.2 million units) 2
• Perform CSF examination before treatment to exclude neurosyphilis 2
• Cardiovascular syphilis may warrant neurosyphilis treatment regimen—consult infectious disease specialist 2

Follow-Up and Treatment Failure

Monitoring Schedule

• Clinical and serologic evaluation at 6 months and 12 months after treatment for early syphilis 2
• HIV-infected patients should be evaluated every 3 months instead of every 6 months 3
• Late latent syphilis: evaluate at 6,12, and 24 months 3

Defining Treatment Failure

Treatment failure is suspected if: 2

• Nontreponemal titers fail to decline fourfold (two dilutions) within 6 months for primary/secondary syphilis
• Nontreponemal titers fail to decline fourfold within 12-24 months for late latent syphilis
• Signs or symptoms of syphilis develop

Retreatment

• Benzathine penicillin G 2.4 million units IM weekly for 3 weeks, unless CSF examination indicates neurosyphilis 2
• Perform CSF examination before retreatment to exclude neurosyphilis 2

Special Populations

HIV-Infected Patients

• Use same treatment regimens as HIV-negative patients 2, 1
• More frequent follow-up (every 3 months) is prudent 3
• Consider CSF examination for late latent syphilis with RPR titers ≥1:32 or CD4 count <350 cells/mm³ 6
• Single-dose benzathine penicillin G remains effective (76% serologic response at 6 months) 1

Pregnancy

• Same penicillin regimens as non-pregnant patients 2
• Penicillin-allergic pregnant patients must undergo desensitization—no alternative antibiotics are acceptable 2, 3
• Screen three times: first prenatal visit, third trimester, and at delivery 7

Key Clinical Pitfalls

• Do not use azithromycin in men who have sex with men, pregnant women, or as routine therapy due to widespread resistance 2
• Do not perform routine CSF examination for primary or secondary syphilis without neurologic or ophthalmic symptoms 2
• Do not use additional doses of penicillin beyond recommended regimens—they do not enhance efficacy 2
• Nontreponemal titers decline more slowly in patients with prior syphilis—this does not indicate treatment failure 2
• All patients with syphilis should be tested for HIV 2