What is the recommended treatment for latent syphilis?

Treatment of Latent Syphilis

For early latent syphilis, administer benzathine penicillin G 2.4 million units IM as a single dose; for late latent syphilis or latent syphilis of unknown duration, administer benzathine penicillin G 7.2 million units total as three doses of 2.4 million units IM at weekly intervals. 1

Defining the Stage of Latent Syphilis

Before initiating treatment, you must determine whether the patient has early versus late latent syphilis, as this dictates the treatment regimen:

• Early latent syphilis is diagnosed when the patient has documented seroconversion, unequivocal symptoms of primary or secondary syphilis within the past year, or a sex partner with documented early syphilis 1
• Late latent syphilis includes all other cases where infection occurred more than one year ago or the duration is unknown 2, 1
• Nontreponemal titers are typically higher in early latent disease, but titers alone cannot reliably distinguish early from late latent syphilis 2

Pre-Treatment Evaluation Requirements

Perform a lumbar puncture and CSF examination before treatment if the patient has any of the following high-risk features 1:

• Neurologic signs (cranial nerve dysfunction, meningitis, stroke, altered mental status, loss of vibration sense) or ophthalmic symptoms (iritis, uveitis) 2
• Evidence of active tertiary syphilis (aortitis, gumma) 2
• Treatment failure or serologic treatment failure 2
• HIV infection with late latent syphilis or syphilis of unknown duration 1
• Serum nontreponemal titer ≥1:32, unless duration of infection is known to be less than 1 year 1

If CSF shows abnormalities consistent with neurosyphilis, treat as neurosyphilis with aqueous crystalline penicillin G 18-24 million units per day IV for 10-14 days instead of the latent syphilis regimen. 1

Examine all accessible mucosal surfaces (oral cavity, perineum in women, underneath the foreskin in uncircumcised men) to evaluate for internal mucosal lesions that would indicate a different stage of disease 2. Test all patients with syphilis for HIV infection 2.

First-Line Treatment Regimens

Early Latent Syphilis

• Benzathine penicillin G 2.4 million units IM as a single dose 2, 1
• This regimen achieves 90-100% treatment success rates 3
• Recent evidence from a 2025 randomized controlled trial demonstrated that a single dose was noninferior to three doses for early syphilis, with 76% achieving serologic response at 6 months 4

Late Latent Syphilis or Latent Syphilis of Unknown Duration

• Benzathine penicillin G 7.2 million units total, administered as three doses of 2.4 million units IM at 1-week intervals 2, 1
• If a patient misses a dose, an interval of 10-14 days between doses may be acceptable before restarting the sequence 2
• Critical exception: Pregnant women who miss any dose must repeat the full course of therapy 2

Alternative Regimens for Penicillin Allergy

The effectiveness of alternatives to penicillin is not well documented, and these should only be used after CSF examination has excluded neurosyphilis 1, 5:

For Early Latent Syphilis (Non-Pregnant Patients)

• Doxycycline 100 mg orally twice daily for 14 days (preferred due to better compliance) 1, 5, 6
• Alternative: Tetracycline 500 mg orally four times daily for 14 days 1

For Late Latent Syphilis or Unknown Duration (Non-Pregnant Patients)

• Doxycycline 100 mg orally twice daily for 28 days 2, 1, 5, 6
• Alternative: Tetracycline 500 mg orally four times daily for 28 days 2, 1

Critical Caveat for Pregnant Patients

Pregnant patients allergic to penicillin must be desensitized and treated with penicillin—there are no acceptable alternatives. 1, 7, 5 This is non-negotiable as alternative regimens have not been proven safe or effective in pregnancy.

Follow-Up Protocol

Repeat quantitative nontreponemal serologic tests at 6,12, and 24 months after treatment 2, 1, 5:

• Serologic response should be evident by 6 months in early latent syphilis but may take 12-24 months for late latent syphilis 3
• For HIV-infected patients, monitor at 3-month intervals instead of 6-month intervals 5

Perform CSF examination and consider retreatment if: 2, 1

• Titers increase fourfold
• An initially high titer (≥1:32) fails to decline at least fourfold within 12-24 months of therapy
• Signs or symptoms attributable to syphilis develop

Even if CSF examination is negative in these circumstances, retreatment for latent syphilis should be initiated 2. A significant proportion of patients may remain seropositive (the "serofast state"), which does not necessarily indicate treatment failure 3.

Pediatric Considerations

After the newborn period, children diagnosed with syphilis require CSF examination to exclude neurosyphilis, and review of birth and maternal medical records to assess whether the child has congenital or acquired syphilis 1:

Early Latent Syphilis

• Benzathine penicillin G 50,000 units/kg IM (up to adult dose of 2.4 million units) as a single dose 2, 1

Late Latent Syphilis or Unknown Duration

• Benzathine penicillin G 50,000 units/kg IM (up to adult dose of 2.4 million units) administered as three doses at 1-week intervals (total 150,000 units/kg up to adult total dose of 7.2 million units) 2, 1

Common Pitfalls to Avoid

• Do not rely solely on nontreponemal titers to distinguish early from late latent syphilis—obtain a thorough sexual history and review prior serologic results 2
• Do not use alternative regimens in pregnant patients—desensitization is mandatory 1, 5
• Do not skip CSF examination in high-risk patients, as undiagnosed neurosyphilis requires a different treatment regimen 1
• Be aware of benzathine penicillin G shortages, which may require searching multiple facilities or temporarily using doxycycline while locating supply 8
• Close serologic and clinical follow-up is essential for all patients receiving alternative regimens, as their efficacy is less well documented 2, 5