How should latent syphilis be treated in adults, including regimens for early versus late latent disease, penicillin‑allergic alternatives, pregnancy and HIV co‑infection considerations, and follow‑up?

Latent Syphilis Management

First-Line Treatment Regimens

For early latent syphilis (infection acquired within the preceding year), administer benzathine penicillin G 2.4 million units IM as a single dose. 1

For late latent syphilis or latent syphilis of unknown duration, administer benzathine penicillin G 7.2 million units total, given as three doses of 2.4 million units IM at weekly intervals. 1

Defining Early vs. Late Latent Syphilis

Early latent syphilis is diagnosed when any of the following criteria are met within the past year: 1

• Documented seroconversion
• Unequivocal symptoms of primary or secondary syphilis
• A sex partner with documented primary, secondary, or early latent syphilis

If the patient does not meet these criteria, treat as late latent syphilis regardless of nontreponemal titer levels. 1

Penicillin-Allergic Patients (Non-Pregnant)

For early latent syphilis in penicillin-allergic non-pregnant adults, prescribe doxycycline 100 mg orally twice daily for 14 days. 2, 3

For late latent syphilis in penicillin-allergic non-pregnant adults, prescribe doxycycline 100 mg orally twice daily for 28 days. 2, 3

• Tetracycline 500 mg orally four times daily is an acceptable alternative (14 days for early latent, 28 days for late latent), but doxycycline is preferred due to better adherence. 2, 3
• Before using any non-penicillin regimen for late latent syphilis, a CSF examination must be performed to exclude neurosyphilis. 2, 3
• Ceftriaxone 1 gram IM/IV daily for 10–14 days may be considered for early syphilis, but evidence is limited and cross-reactivity with penicillin allergy is possible. 2
• Never use azithromycin due to widespread macrolide resistance and documented treatment failures. 2

Evidence for Doxycycline Efficacy

A 2019 study in HIV-infected patients found no statistically significant difference in serological response between doxycycline and benzathine penicillin (72% vs. 70%, P=0.753), supporting doxycycline as an acceptable alternative. 4

Pregnancy Considerations

All pregnant patients with syphilis must receive the penicillin regimen appropriate for their disease stage—no exceptions. 2, 3

Pregnant patients with penicillin allergy must undergo desensitization followed by penicillin therapy; no alternative antibiotics are acceptable. 2, 3

• Penicillin is the only therapy with documented efficacy for preventing congenital syphilis and treating fetal infection. 2, 3
• Tetracyclines, doxycycline, erythromycin, azithromycin, and ceftriaxone are inadequate—erythromycin does not reliably cure fetal infection. 2
• Treatment must be completed at least 4 weeks before delivery for optimal prevention of congenital syphilis. 2, 3
• Some experts recommend an additional dose of benzathine penicillin G 2.4 million units IM one week after the initial dose for pregnant women with primary, secondary, or early latent syphilis. 2

Jarisch-Herxheimer Reaction in Pregnancy

• Women treated during the second half of pregnancy are at risk for premature labor and/or fetal distress from Jarisch-Herxheimer reaction. 2
• Instruct patients to seek immediate medical attention if they notice contractions or changes in fetal movements within 24 hours of treatment. 2

HIV Co-Infection

HIV-infected patients receive the same penicillin regimens as HIV-negative patients for all stages of syphilis. 2, 3

HIV-positive individuals require more intensive monitoring: clinical and serologic evaluation at 3,6,9,12, and 24 months after treatment. 2, 3

• For late latent syphilis in HIV-infected patients, consider CSF examination before therapy to exclude neurosyphilis. 2, 3
• If treatment failure occurs and CSF is normal, retreat with benzathine penicillin G 7.2 million units (three weekly doses of 2.4 million units IM). 2
• Penicillin-allergic HIV-infected patients should undergo skin testing and desensitization, then be treated with penicillin. 2

Controversy: Single vs. Multiple Doses in HIV

A 2014 prospective study found that single-dose benzathine penicillin resulted in lower serological response rates (67.1% vs. 74.8%) and shorter time to treatment failure compared to three weekly doses in HIV-infected patients with early syphilis. 5 However, current CDC guidelines recommend the same single-dose regimen for early latent syphilis in HIV-infected patients, with enhanced monitoring to detect treatment failure. 2

Mandatory CSF Examination Indications

Perform CSF examination before treatment in patients with any of the following: 1, 2

• Neurologic or ophthalmic signs or symptoms
• Evidence of active tertiary syphilis (aortitis, gumma, iritis)
• Treatment failure (persistent symptoms or rising titers)
• HIV infection with late latent syphilis or syphilis of unknown duration
• Nontreponemal titer ≥1:32 (unless infection is documented to be <1 year)

If CSF examination indicates neurosyphilis, treat with aqueous crystalline penicillin G 18–24 million units per day IV for 10–14 days. 2, 3

Follow-Up Protocol

For latent syphilis, perform quantitative nontreponemal serologic tests (RPR or VDRL) at 6,12, and 24 months after treatment. 2, 3

• Treatment success is defined as a fourfold (two-dilution) decline in nontreponemal titers. 2, 3
• For early latent syphilis, expect a fourfold decline within 6–12 months. 2
• For late latent syphilis, expect a fourfold decline within 12–24 months. 2, 3

Treatment Failure Criteria

Treatment failure is indicated by: 2, 3

• Failure of nontreponemal titers to decline fourfold within the expected timeframe
• A fourfold increase in titers at any time after treatment
• Development of new clinical signs or symptoms attributable to syphilis

When treatment failure occurs, perform CSF examination and retreat accordingly. 2, 3

Management of Sexual Partners

Presumptively treat sexual partners exposed within 90 days before the index patient's diagnosis of early latent syphilis, even if seronegative. 2

• Partners exposed >90 days prior should be treated presumptively if serologic results are unavailable and reliable follow-up cannot be ensured. 2
• Long-term partners of patients with late syphilis should undergo clinical and serologic evaluation. 2

Critical Pitfalls to Avoid

• Never use oral penicillin preparations for syphilis treatment—they are ineffective. 2
• Do not switch between RPR and VDRL assays when monitoring treatment response; results cannot be directly compared. 2
• Do not use azithromycin due to widespread resistance. 2
• Do not omit CSF examination before using non-penicillin regimens for late latent syphilis. 2
• Never substitute non-penicillin antibiotics in pregnancy—desensitization is mandatory. 2, 3
• All patients with syphilis should be tested for HIV infection. 1, 2