What is the recommended treatment regimen for syphilis in a healthy adult, including dosing for primary, secondary, early latent, late latent, and neurosyphilis?

Treatment of Syphilis

Benzathine penicillin G remains the definitive first-line treatment for all stages of syphilis except neurosyphilis, with dosing determined by disease stage: a single 2.4 million unit IM injection for early syphilis and three weekly 2.4 million unit IM injections for late latent disease. 1, 2

Primary, Secondary, and Early Latent Syphilis (≤1 year)

Benzathine penicillin G 2.4 million units IM as a single dose is the recommended treatment for all patients with early-stage syphilis, achieving 90-100% treatment success rates. 3, 1, 4, 5

• Early latent syphilis is defined as infection acquired within the preceding year, documented by seroconversion, fourfold titer increase, symptoms within the past year, or a sex partner with confirmed early syphilis. 2
• A recent 2025 randomized controlled trial demonstrated that one dose is noninferior to three doses for early syphilis, with 76% serologic response at 6 months in both HIV-infected and HIV-uninfected patients. 5
• All patients with syphilis should be tested for HIV at diagnosis. 1, 2

Penicillin-Allergic Patients (Non-Pregnant)

Doxycycline 100 mg orally twice daily for 14 days is the preferred alternative for penicillin-allergic non-pregnant adults with early syphilis. 1, 6, 2

• Tetracycline 500 mg orally four times daily for 14 days is an acceptable alternative, though adherence is generally better with doxycycline due to less frequent dosing. 2
• Ceftriaxone 1 gram IM or IV daily for 10-14 days may be considered based on randomized trial data showing comparable efficacy to benzathine penicillin, but remains second-line. 3, 2
• Azithromycin should NOT be used in the United States due to widespread macrolide resistance and documented treatment failures. 3, 2

Late Latent Syphilis or Syphilis of Unknown Duration (>1 year)

Benzathine penicillin G 7.2 million units total, administered as three doses of 2.4 million units IM at weekly intervals, is the standard regimen for late latent disease. 3, 1, 6, 2

• CSF examination should be performed before treatment to exclude neurosyphilis in patients with: neurologic or ophthalmic signs/symptoms, evidence of active tertiary syphilis, treatment failure, HIV infection with late latent syphilis, or nontreponemal titer ≥1:32. 3, 2
• If a dose is missed during weekly therapy, an interval of 10-14 days between doses might be acceptable before restarting the sequence. 2
• Pregnant women who miss any dose must repeat the entire course of therapy—no partial-dose exceptions are allowed. 2

Penicillin-Allergic Patients (Non-Pregnant)

Doxycycline 100 mg orally twice daily for 28 days is the recommended alternative for penicillin-allergic non-pregnant adults with late latent syphilis. 1, 6, 2

• Tetracycline 500 mg orally four times daily for 28 days is also acceptable. 2
• A CSF examination must exclude neurosyphilis before using any non-penicillin regimen for late latent infection. 2

Neurosyphilis

Aqueous crystalline penicillin G 18-24 million units per day IV (administered as 3-4 million units every 4 hours or by continuous infusion) for 10-14 days is the recommended treatment for neurosyphilis. 3, 1, 2

• Some clinicians add three weekly IM doses of benzathine penicillin G 2.4 million units after the IV course to provide additional coverage, though consensus on this practice has not been reached. 2
• An alternative outpatient regimen is procaine penicillin 2.4 million units IM once daily plus probenecid 500 mg orally four times daily for 10-14 days when adherence can be assured. 3, 2
• Procaine penicillin without probenecid is inadequate because it fails to achieve therapeutic CSF penicillin levels. 2
• Benzathine penicillin G should never be used for neurosyphilis—it does not achieve adequate CSF concentrations. 6

Neurosyphilis Follow-Up

• If CSF pleocytosis was documented at baseline, repeat CSF analysis every 6 months until the white-cell count normalizes. 2
• Consider retreatment when the CSF white-blood-cell count has not decreased after 6 months or when CSF abnormalities persist beyond 2 years. 2

Tertiary Syphilis (Cardiovascular or Gummatous Disease)

Benzathine penicillin G 7.2 million units total, administered as three doses of 2.4 million units IM at weekly intervals, is recommended for tertiary syphilis. 6

• CSF examination must be performed before initiating therapy to rule out neurosyphilis. 3, 6
• The complexity of tertiary syphilis management warrants consultation with an infectious disease specialist. 3

Special Populations

Pregnant Women

All pregnant women with syphilis must receive the penicillin regimen appropriate for the disease stage, administered >4 weeks before delivery to optimize fetal outcomes. 2

• Penicillin is the only therapy with documented efficacy for preventing maternal transmission to the fetus and treating fetal infection—no alternative antibiotics are acceptable. 3, 2
• All pregnant patients with penicillin allergy MUST undergo desensitization followed by penicillin treatment—no exceptions. 3, 1, 2
• Some experts recommend an additional dose of benzathine penicillin 2.4 million units IM one week after the initial dose for women with primary, secondary, or early latent syphilis. 2
• Jarisch-Herxheimer reactions occurring in the second half of pregnancy can precipitate preterm labor or fetal distress; obstetric monitoring for 24 hours after therapy is advised for women >20 weeks gestation. 2
• Women should seek immediate medical attention if they notice contractions or changes in fetal movements after treatment. 3, 2
• Routine syphilis screening is recommended at the first prenatal visit, at 28 weeks gestation, and at delivery. 1, 2

HIV-Infected Patients

HIV-infected persons receive the same penicillin regimens as HIV-uninfected patients for all disease stages. 3, 2

• More intensive post-treatment monitoring is required: clinical and serologic evaluation at 3,6,9,12, and 24 months. 2
• For late latent syphilis, a CSF examination should be considered before therapy to exclude neurosyphilis. 2
• Penicillin-allergic HIV-infected patients should undergo skin testing and desensitization before receiving penicillin. 2
• Limited data suggest no benefit to multiple doses of benzathine penicillin for early syphilis in HIV-infected patients compared to a single dose. 3

Pediatric Patients

Children with acquired syphilis should have a CSF examination to exclude neurosyphilis before treatment. 3, 2

• For early latent syphilis: Benzathine penicillin G 50,000 units/kg IM (up to adult dose of 2.4 million units) as a single dose. 3, 2
• For late latent syphilis: Benzathine penicillin G 50,000 units/kg IM for three doses at weekly intervals (total 150,000 units/kg up to adult total of 7.2 million units). 3, 2

Follow-Up and Monitoring

Early Syphilis (Primary, Secondary, Early Latent)

Quantitative nontreponemal serologic tests (RPR or VDRL) should be repeated at 6 and 12 months after treatment. 1, 2

• A fourfold decline in titer is expected within 6 months for early syphilis. 1, 6
• Treatment failure is defined by: persistent or recurring signs/symptoms, sustained fourfold increase in nontreponemal titers, or failure of initially high titer (≥1:32) to decline at least fourfold within 6-12 months. 2

Late Latent Syphilis

Quantitative nontreponemal tests should be repeated at 6,12, and 24 months. 3, 1, 2

• A fourfold decline in titer is expected within 12-24 months for late syphilis. 6, 2
• 15-25% of successfully treated patients remain "serofast" with persistent low titers (<1:8) that do not indicate treatment failure. 2

Treatment Failure Management

If CSF findings are normal after a failed regimen, retreat with benzathine penicillin 7.2 million units administered as three weekly IM doses. 2

• When CSF remains abnormal after failure of the standard regimen, manage according to the neurosyphilis protocol (IV aqueous crystalline penicillin). 2
• Unless reinfection is likely, lumbar puncture should be performed to evaluate for neurosyphilis in cases of treatment failure. 2

Management of Sex Partners

Presumptive treatment with benzathine penicillin G 2.4 million units IM is indicated for persons exposed within 90 days preceding diagnosis of primary, secondary, or early latent syphilis, even if seronegative. 1, 2

• Partners exposed >90 days prior should be treated presumptively when serologic results are unavailable and reliable follow-up cannot be ensured. 2
• Time windows for presumptive treatment: 3 months plus duration of symptoms for primary syphilis, 6 months plus duration of symptoms for secondary syphilis, and 1 year for early latent syphilis. 2
• Long-term partners of patients with late syphilis should undergo clinical and serologic evaluation. 2

Common Pitfalls to Avoid

• Do not use oral penicillin preparations for syphilis treatment—they are ineffective. 2
• Do not rely solely on treponemal test antibody titers to assess treatment response—they correlate poorly with disease activity. 2
• Do not switch between different testing methods (e.g., VDRL and RPR) when monitoring serologic response—results cannot be directly compared. 2
• Do not assume that new genital lesions after treatment represent treatment failure—serologic criteria, not new lesions, define true treatment failure. 2
• Do not retreat a patient for syphilis unless there is documented serologic failure or confirmed reinfection. 2
• Patients with severe penicillin allergy (such as Stevens-Johnson syndrome) may also be allergic to ceftriaxone, as both are beta-lactam antibiotics. 2

Jarisch-Herxheimer Reaction

Patients should be informed about the possible Jarisch-Herxheimer reaction, an acute febrile reaction that may occur within 24 hours after any syphilis therapy, especially in early syphilis. 1, 2

• Symptoms may include headache, myalgia, fever, and other constitutional symptoms. 1, 2