Treatment of Secondary Syphilis

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

First-Line Treatment Regimen

Benzathine penicillin G 2.4 million units IM in a single dose is the standard of care for adults with secondary syphilis. 2, 1
This single-dose regimen has been used effectively for decades to achieve local cure (healing of lesions and prevention of sexual transmission) and prevent late sequelae. 2
A recent 2025 randomized controlled trial confirmed that one dose of 2.4 million units is noninferior to three weekly doses, with 76% achieving serologic response at 6 months in both groups. 3

Children with acquired secondary syphilis should receive benzathine penicillin G 50,000 units/kg IM (up to the adult dose of 2.4 million units) as a single dose. 2, 1
All children require CSF examination before treatment to exclude neurosyphilis. 1

All patients with syphilis must be tested for HIV infection. 2, 1
Evaluate for neurologic symptoms (meningitis, cranial nerve dysfunction) or ophthalmic symptoms (uveitis, vision changes) that would indicate neurosyphilis requiring different treatment. 2, 1
If neurologic or ophthalmic signs are present, perform CSF analysis and slit-lamp examination before proceeding with standard treatment. 2
Routine lumbar puncture is not recommended for uncomplicated secondary syphilis without neurologic or ophthalmic manifestations. 2

For non-pregnant penicillin-allergic adults, doxycycline 100 mg orally twice daily for 14 days is the recommended alternative. 1
Tetracycline 500 mg orally four times daily for 14 days is another option, though compliance is typically better with doxycycline. 1
Pregnant women with penicillin allergy MUST undergo desensitization followed by penicillin treatment—no exceptions. 1 Penicillin is the only therapy with documented efficacy for preventing maternal transmission to the fetus. 1
Azithromycin should NOT be used due to widespread macrolide resistance and documented treatment failures in the United States. 1

Use the same benzathine penicillin G 2.4 million units IM single dose regimen as for HIV-negative patients. 1
The 2025 trial showed equivalent serologic response rates (76% in HIV-infected vs 76% in HIV-uninfected patients). 3
HIV-infected patients require more intensive monitoring at 3,6,9,12, and 24 months due to higher risk of treatment failure and atypical serologic responses. 1

Treat with benzathine penicillin G 2.4 million units IM as a single dose. 1
Some experts recommend an additional dose of 2.4 million units IM one week after the initial dose for pregnant women with secondary syphilis. 1
Warn pregnant women treated during the second half of pregnancy about Jarisch-Herxheimer reaction, which may precipitate premature labor or fetal distress. 1 They should seek immediate medical attention if they notice contractions or changes in fetal movements. 1

Perform quantitative nontreponemal serologic tests (RPR or VDRL) at 6 and 12 months after treatment. 1
Treatment success is defined as a fourfold decline in nontreponemal test titers (e.g., from 1:32 to 1:8) within 6 months. 1
For HIV-infected patients, monitor at 3,6,9,12, and 24 months. 1

Treatment failure is indicated by persistent or recurring clinical signs/symptoms, sustained fourfold increase in nontreponemal titers, or failure of initially high 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 involves benzathine penicillin G 2.4 million units IM weekly for 3 weeks, unless CSF examination indicates neurosyphilis requiring IV penicillin therapy. 1

Persons exposed within 90 days preceding the diagnosis of secondary syphilis should be treated presumptively, even if seronegative. 2, 1
The time period for identifying at-risk partners is 6 months plus duration of symptoms for secondary syphilis. 2
Persons 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 may occur within 24 hours after treatment, particularly in patients with active secondary syphilis lesions. 1 This acute febrile reaction includes headache, myalgia, and fever. 1
Patients should be counseled about this expected reaction before treatment. 1
Most patients experience local injection-site pain and tenderness (76% in recent trials). 3

Do not use oral penicillin preparations—they are ineffective for syphilis treatment. 1
Do not rely on treponemal test antibody titers (FTA-ABS, TP-PA) to assess treatment response, as they remain positive for life and correlate poorly with disease activity. 1
Do not switch between different nontreponemal testing methods (RPR vs VDRL) when monitoring serologic response, as results cannot be directly compared. 1
Do not substitute inadequate alternatives in pregnancy—only penicillin prevents congenital syphilis. 1