Treatment of Secondary Syphilis

The recommended treatment for secondary syphilis is benzathine penicillin G 2.4 million units intramuscularly as a single dose. 1, 2

First-Line Treatment Regimen

Benzathine penicillin G 2.4 million units IM in a single dose is the standard treatment for secondary syphilis in adults. 1, 2
This single-dose regimen has been proven effective for decades and remains the gold standard, with most patients achieving seroreversion or a fourfold decline in nontreponemal titers within 6 months. 1, 3
A recent 2025 randomized controlled trial confirmed that one dose of 2.4 million units is noninferior to three weekly doses for early syphilis (including secondary syphilis), with 76% achieving serologic response at 6 months. 4

All patients with secondary syphilis must be tested for HIV infection, as HIV co-infection affects monitoring frequency and may alter treatment response. 1, 2
CSF examination is not routinely recommended for secondary syphilis unless neurologic symptoms (meningitis, cranial nerve palsies) or ophthalmic symptoms (uveitis, vision changes) are present. 1, 2
If neurologic or ophthalmic involvement is suspected, perform CSF analysis and slit-lamp examination before initiating treatment, as neurosyphilis requires IV penicillin therapy instead. 1

For children with acquired 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 asymptomatic neurosyphilis and evaluation by child protective services to assess for sexual abuse. 1, 2

For non-pregnant, penicillin-allergic patients, doxycycline 100 mg orally twice daily for 14 days is the preferred alternative. 1, 2
Tetracycline 500 mg orally four times daily for 14 days is another option, though compliance is typically worse due to gastrointestinal side effects and more frequent dosing. 1, 2
Ceftriaxone 1 gram IM or IV daily for 8-10 days may be considered based on limited data, though optimal dosing is not well-established. 1
Azithromycin should NOT be used in the United States due to widespread macrolide resistance and documented treatment failures. 2
Close follow-up is essential for all alternative regimens, as efficacy data are limited compared to penicillin. 1

Pregnant patients with penicillin allergy MUST undergo desensitization followed by penicillin treatment—no alternatives are acceptable. 1, 2
Only penicillin is proven effective for preventing congenital syphilis and treating fetal infection. 1, 2
Counsel pregnant patients about Jarisch-Herxheimer reaction, which may precipitate premature labor or fetal distress, and advise them to seek immediate care if they notice decreased fetal movements or contractions after treatment. 2

HIV-infected patients receive the same single-dose benzathine penicillin G 2.4 million units IM regimen as HIV-negative patients. 1, 2
Some specialists recommend CSF examination before treatment in HIV-infected patients with secondary syphilis, though this is not universally required. 1
The 2025 trial showed equivalent serologic response rates (76% in HIV-infected vs. 76% in HIV-negative patients) with single-dose therapy. 4

Perform quantitative nontreponemal serologic tests (RPR or VDRL) at 6 and 12 months after treatment. 2
Expect a fourfold decline in nontreponemal titers within 6 months for secondary syphilis. 1, 2
HIV-infected patients require more frequent monitoring at 3-month intervals (3,6,9,12, and 24 months) due to higher risk of treatment failure. 1
Always use the same nontreponemal test method (RPR vs. VDRL) for serial monitoring, as results cannot be directly compared between different test types. 2

Treatment failure is defined as: persistent or recurring clinical signs/symptoms, sustained fourfold increase in nontreponemal titers, or failure of titers to decline fourfold within 6 months. 1
If treatment failure occurs, re-evaluate for HIV infection and perform CSF examination to exclude neurosyphilis. 1
Re-treatment typically consists of benzathine penicillin G 2.4 million units IM weekly for 3 weeks, unless CSF examination indicates neurosyphilis requiring IV therapy. 1
Note that 15% of patients with early syphilis treated appropriately will not achieve a two-dilution decline at 1 year—this does not always indicate treatment failure. 1

Presumptively treat all sexual partners exposed within 90 days preceding diagnosis, even if seronegative. 2
For secondary syphilis specifically, treat partners exposed within 6 months plus the duration of symptoms. 2
Partners exposed more than 90 days before diagnosis should be treated presumptively if serologic results are not immediately available and follow-up is uncertain. 2

Jarisch-Herxheimer reaction (acute fever, headache, myalgia) may occur within 24 hours of treatment, particularly in patients with secondary syphilis due to active lesions. 1, 2
Counsel all patients about this expected reaction before administering treatment. 2
The reaction is self-limited and does not indicate treatment failure or allergy. 2

Never use oral penicillin preparations—they are completely ineffective for syphilis treatment at any stage. 2, 5
Do not rely on treponemal antibody tests (FTA-ABS, TP-PA) to monitor treatment response—these remain positive for life and do not correlate with disease activity. 2
Do not switch between different nontreponemal test methods (RPR vs. VDRL) during follow-up monitoring. 2
Do not delay treatment in pregnant patients with penicillin allergy—proceed immediately with desensitization. 2