What is the recommended treatment for syphilis?

Treatment of Syphilis

Benzathine penicillin G is the only acceptable treatment for all stages of syphilis, with dosing and duration determined by disease stage. 1

Primary and Secondary Syphilis

Administer benzathine penicillin G 2.4 million units intramuscularly as a single dose. 1, 2

• This single injection is curative for early-stage disease and rapidly eliminates clinical symptoms, with Treponema pallidum disappearing from lesions within 7 hours on average. 3
• For children with acquired primary or secondary syphilis, dose is 50,000 units/kg IM (up to adult dose of 2.4 million units) as a single injection. 1
• All patients must be tested for HIV infection at diagnosis. 1

Penicillin-Allergic Patients (Non-Pregnant)

• Doxycycline 100 mg orally twice daily for 14 days is the alternative regimen. 1, 2
• Ceftriaxone 1 gram IM/IV daily for 10-14 days may be considered based on randomized trial data showing comparable efficacy, though it remains second-line. 1
• Never use azithromycin in the United States due to widespread macrolide resistance and documented treatment failures. 1

Early Latent Syphilis

Treat with benzathine penicillin G 2.4 million units IM as a single dose—identical to primary/secondary syphilis. 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
• For penicillin-allergic non-pregnant adults, use doxycycline 100 mg orally twice daily for 14 days. 1

Late Latent Syphilis and Tertiary Syphilis

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

• This regimen applies to late latent syphilis (>1 year duration), latent syphilis of unknown duration, and tertiary syphilis. 1, 4
• Before treating tertiary syphilis, perform CSF examination to exclude neurosyphilis, particularly in patients with cardiovascular or gummatous disease. 4
• If a dose is missed during weekly therapy, an interval of 10-14 days between doses may be acceptable before restarting the sequence, though 7-9 days is more optimal. 5
• For penicillin-allergic non-pregnant adults, doxycycline 100 mg orally twice daily for 28 days is the alternative. 1, 2

Neurosyphilis

Treat with aqueous crystalline penicillin G 18-24 million units IV daily (administered as 3-4 million units every 4 hours or continuous infusion) for 10-14 days. 1, 4

• CSF examination is indicated for patients with neurologic/ophthalmic signs or symptoms, evidence of active tertiary syphilis, treatment failure, HIV infection with late latent syphilis, or serum nontreponemal titer ≥1:32. 1
• Procaine penicillin without probenecid does not achieve adequate CSF levels and is inadequate for neurosyphilis. 1
• If neurosyphilis is diagnosed, the tertiary syphilis regimen (weekly benzathine penicillin) is completely inadequate. 4

Special Populations

Pregnant Women

Penicillin is the only therapy proven effective for preventing maternal transmission and treating fetal infection—no exceptions. 1, 2

• All pregnant women with penicillin allergy MUST undergo desensitization followed by penicillin treatment. 1, 2, 4
• Screen all pregnant women for syphilis at first prenatal visit, during third trimester, and at delivery. 1
• Some experts recommend a second dose of benzathine penicillin 2.4 million units IM one week after the initial dose for women with primary, secondary, or early latent syphilis. 1
• Jarisch-Herxheimer reaction during the second half of pregnancy may precipitate premature labor or fetal distress—women should seek immediate medical attention if they notice contractions or changes in fetal movements after treatment. 1
• Tetracycline, doxycycline, erythromycin, azithromycin, and ceftriaxone are all inadequate in pregnancy. 1

HIV-Infected Patients

• Use the same treatment regimens as non-HIV-infected patients for all stages of syphilis. 1, 2
• Closer follow-up is mandatory to detect potential treatment failure or disease progression. 1
• Limited data suggest no benefit to multiple doses of benzathine penicillin for early syphilis in HIV-infected patients compared to a single dose. 1

Follow-Up and Monitoring

Perform quantitative nontreponemal serologic tests (RPR or VDRL) at 6 and 12 months for primary/secondary syphilis, and at 6,12, and 24 months for latent syphilis. 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, 4
• 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, 4
• 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

Treat sex partners presumptively if exposed within 90 days preceding diagnosis of primary, secondary, or early latent syphilis, 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

Critical Pitfalls to Avoid

• Never use oral penicillin preparations for syphilis treatment—they are completely ineffective. 1, 4
• Do not use different testing methods (RPR vs VDRL) when monitoring serologic response, as results cannot be directly compared. 1, 4
• Do not rely solely on treponemal test antibody titers to assess treatment response, as they correlate poorly with disease activity. 1
• Do not skip CSF examination before treating tertiary syphilis, as this may miss neurosyphilis requiring different treatment. 4
• Warn patients about Jarisch-Herxheimer reaction—an acute febrile reaction with headache, myalgia, and other symptoms that may occur within 24 hours after any syphilis therapy, especially in early syphilis. 1, 4