Treatment of Late Latent Syphilis
For late latent syphilis, administer benzathine penicillin G 7.2 million units total as three doses of 2.4 million units IM given at weekly intervals. 1, 2
Pre-Treatment Evaluation
Before initiating treatment, perform a lumbar puncture if any of the following criteria are present: 1, 2
- Neurologic or ophthalmic signs or symptoms
- Evidence of active tertiary syphilis (aortitis, gumma, iritis)
- Treatment failure from prior therapy
- HIV infection with late latent syphilis
- Nontreponemal serologic titer ≥1:32
If CSF examination reveals abnormalities consistent with neurosyphilis, treat with aqueous crystalline penicillin G 18-24 million units IV daily for 10-14 days instead of the standard late latent regimen. 1, 2
All patients with syphilis should be tested for HIV infection before treatment. 3
Standard Treatment Regimen
The definitive treatment is benzathine penicillin G 2.4 million units IM administered once weekly for three consecutive weeks (total 7.2 million units). 1, 2, 4
This regimen applies to late latent syphilis (infection >1 year duration) and latent syphilis of unknown duration. 1, 2 The treatment aims to prevent progression to tertiary complications rather than prevent transmission, as patients with late latent disease are generally not infectious. 1
Missed Dose Protocol
If a patient misses a weekly dose, an interval of 10-14 days between injections may be acceptable before restarting the sequence. 1 However, pregnant patients who miss any dose must repeat the entire three-week course from the beginning. 1
Alternative Regimens for Penicillin Allergy
For non-pregnant patients with documented penicillin allergy, doxycycline 100 mg orally twice daily for 28 days is the only acceptable alternative. 1, 2, 4 Tetracycline 500 mg orally four times daily for 28 days is also acceptable but less preferred due to compliance issues with four-times-daily dosing. 1, 4
Critical caveat: These alternative regimens have not been well-documented for efficacy and require close serologic and clinical follow-up. 1 Their efficacy in HIV-infected persons is unknown and must be used with extreme caution. 1
Pregnancy Considerations
Pregnant patients with penicillin allergy must undergo desensitization followed by penicillin treatment—there are no acceptable alternatives. 1, 2 Only penicillin has documented efficacy in preventing congenital syphilis. 3
Follow-Up Protocol
Perform quantitative nontreponemal serologic tests (RPR or VDRL) at 6,12, and 24 months after treatment. 1, 2, 4
Re-treat the patient if any of the following occur: 1, 2
- Titers increase fourfold (two dilutions)
- An initially high titer (>1:32) fails to decline at least fourfold within 12-24 months
- Signs or symptoms attributable to syphilis develop
If serologic titers fail to decline despite negative CSF examination and repeated therapy, the need for additional treatment or CSF re-examination is unclear. 1 In these rare instances, consultation with an infectious disease specialist is warranted.
HIV-Infected Patients
HIV-infected patients receive the same benzathine penicillin G regimen (three weekly doses of 2.4 million units IM). 4, 3 However, they require more intensive monitoring with serologic testing every 3 months rather than the standard 6-month intervals. 4 CSF examination before treatment is strongly recommended for all HIV-infected patients with late latent syphilis to exclude neurosyphilis. 1, 2, 4
Pediatric Dosing
For children with late latent syphilis, administer benzathine penicillin G 50,000 units/kg IM (up to adult dose of 2.4 million units) as three doses at weekly intervals, totaling 150,000 units/kg up to the adult total dose of 7.2 million units. 1, 2 Children require CSF examination before treatment to exclude neurosyphilis. 1, 2, 3
Common Pitfalls
Do not use oral penicillin preparations—they are ineffective for syphilis treatment. 3 Do not switch between different nontreponemal tests (RPR vs VDRL) during follow-up, as results cannot be directly compared. 3 Ensure adequate fluid intake with doxycycline to reduce risk of esophageal irritation. 5