What is the recommended treatment for syphilis?

Treatment of Syphilis

Parenteral penicillin G is the only acceptable treatment for all stages of syphilis, with the specific formulation, dose, and duration determined by disease stage. 1, 2

Primary and Secondary Syphilis

Benzathine penicillin G 2.4 million units intramuscularly as a single dose is the definitive treatment. 1, 2

• This single injection rapidly eliminates clinical symptoms and promotes serological clearance, with Treponema pallidum disappearing from lesions within approximately 7 hours of treatment 3
• For children with acquired primary or secondary syphilis, administer benzathine penicillin G 50,000 units/kg IM (up to the adult dose of 2.4 million units) as a single dose 1, 2
• Children require CSF examination before treatment to exclude neurosyphilis 1

Early Latent Syphilis

Benzathine penicillin G 2.4 million units IM as a single dose. 1, 2

• Early latent syphilis is defined as infection acquired within the preceding year, documented by seroconversion, fourfold titer increase, history of symptoms within the past year, or having a sex partner with documented early syphilis 1
• Some experts recommend a second dose of benzathine penicillin 2.4 million units IM one week after the initial dose for pregnant women with primary, secondary, or early latent syphilis 1

Late Latent Syphilis and Syphilis of Unknown Duration

Benzathine penicillin G 7.2 million units total, administered as three doses of 2.4 million units IM at weekly intervals. 1, 2

• If a dose is missed, an interval of 10-14 days between doses may be acceptable before restarting the sequence, though 7-9 days is more optimal if feasible 1, 4
• Missed doses are never acceptable for pregnant women—the sequence must be restarted. 4
• For children with late latent syphilis, administer benzathine penicillin G 50,000 units/kg IM (up to 2.4 million units) for three total doses at weekly intervals (total 150,000 units/kg up to 7.2 million units) 1

Tertiary Syphilis

Before treating tertiary syphilis, perform CSF examination to exclude neurosyphilis, as the tertiary regimen is inadequate for CNS involvement. 5

• If neurosyphilis is excluded, treat with benzathine penicillin G 7.2 million units total as three weekly doses of 2.4 million units IM 2, 5
• Some specialists treat all cardiovascular syphilis cases with neurosyphilis regimens due to concern about CNS involvement 5

Neurosyphilis

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. 1, 5

• CSF examination is indicated for patients with neurologic or ophthalmic signs/symptoms, evidence of active tertiary syphilis, treatment failure, HIV infection with late latent syphilis or syphilis of unknown duration, or serum nontreponemal titer ≥1:32 1
• Procaine penicillin without probenecid does not achieve adequate CSF levels and is inadequate for neurosyphilis 1
• Ceftriaxone 2 grams daily IV for 10-14 days may be considered if penicillin cannot be used, though supporting data are extremely limited 1

Penicillin-Allergic Patients (Non-Pregnant)

For primary, secondary, and early latent syphilis: doxycycline 100 mg orally twice daily for 14 days. 1, 2

For late latent syphilis: doxycycline 100 mg orally twice daily for 28 days. 1, 2

• Tetracycline 500 mg orally four times daily is an alternative (14 days for early syphilis, 28 days for late latent) 1
• Ceftriaxone 1 gram IM/IV daily for 10-14 days may be considered for early syphilis based on randomized trial data showing comparable efficacy to benzathine penicillin 1
• Never use azithromycin in the United States due to widespread macrolide resistance and documented treatment failures 1
• Patients with severe penicillin allergy (such as Stevens-Johnson syndrome) may also be allergic to ceftriaxone, as both are beta-lactam antibiotics 1

Pregnant Women

Penicillin is the only therapy with documented efficacy for preventing maternal transmission and treating fetal infection—all pregnant women with penicillin allergy MUST undergo desensitization followed by penicillin treatment. 1, 2, 5

• No alternative antibiotics are acceptable in pregnancy; erythromycin, tetracycline, doxycycline, azithromycin, and ceftriaxone do not reliably cure fetal infection 1
• Screen all pregnant women for syphilis at first prenatal visit, during third trimester, and at delivery 1
• Women treated during the second half of pregnancy are at risk for premature labor and/or fetal distress from Jarisch-Herxheimer reaction; they should seek immediate medical attention if they notice contractions or changes in fetal movements 1
• Up to 40% of fetuses with in-utero exposure to syphilis are stillborn or die from infection during infancy 6

HIV-Infected Patients

Use the same treatment regimens as non-HIV-infected patients for all stages of syphilis. 1, 2

• Limited data suggest no benefit to multiple doses of benzathine penicillin for early syphilis in HIV-infected patients compared to a single dose 1
• Closer follow-up is mandatory to detect potential treatment failure or disease progression 1, 5
• HIV-infected patients may have atypical serologic responses but generally respond well to standard treatment 1

Follow-Up and Monitoring

Perform quantitative nontreponemal serologic tests (RPR or VDRL) at 6 and 12 months after treatment for primary/secondary syphilis. 1, 2

• For latent syphilis, repeat tests at 6,12, and 24 months 1, 2
• Expect a fourfold decline in titer within 6 months for primary/secondary syphilis and within 12-24 months for late syphilis 1, 2
• Treatment failure is defined as persistent or recurring clinical signs/symptoms, sustained fourfold increase in nontreponemal titers, or failure of initially high titer to decline at least fourfold within expected timeframes 1, 2
• If treatment failure occurs, re-evaluate for HIV infection, perform CSF examination, and retreat with three weekly injections of benzathine penicillin G 2.4 million units IM unless neurosyphilis is diagnosed 1, 5
• 15-25% of successfully treated patients remain "serofast" with persistent low titers (<1:8) that do not indicate treatment failure 1

Management of Sex Partners

Persons exposed within 90 days preceding diagnosis of primary, secondary, or early latent syphilis should be treated presumptively, even if seronegative. 1, 2

• Time periods for at-risk partners: 3 months plus duration of symptoms for primary syphilis, 6 months plus duration of symptoms for secondary syphilis, and 1 year for early latent syphilis 1
• Persons exposed >90 days before diagnosis should be treated presumptively if serologic test results are not immediately available and follow-up is uncertain 1
• Long-term sex partners of patients with late syphilis should be evaluated clinically and serologically 2

Critical Pitfalls to Avoid

• Never use oral penicillin preparations for syphilis treatment—they are completely ineffective 1, 5
• Do not rely solely on treponemal test antibody titers to assess treatment response, as they correlate poorly with disease activity 1
• Do not switch between different testing methods (RPR vs VDRL) when monitoring serologic response, as results cannot be directly compared 1, 5
• Do not substitute non-penicillin antibiotics in pregnant women or patients with neurosyphilis without desensitization 1, 2, 5
• Inform patients about Jarisch-Herxheimer reaction, an acute febrile reaction with headache and myalgia that may occur within 24 hours after treatment, especially in early syphilis 1, 5
• All patients with syphilis should be tested for HIV infection 1