What is the recommended treatment for syphilis?

Treatment for Syphilis

Benzathine penicillin G is the only FDA-approved and guideline-recommended first-line treatment for all stages of syphilis, with dosing determined by disease stage. 1, 2, 3

Primary and Secondary Syphilis

Administer benzathine penicillin G 2.4 million units intramuscularly as a single dose. 1, 2, 4

• This regimen is effective for early-stage disease and achieves cure in all patients when properly administered 1
• All patients with syphilis should be tested for HIV infection 1
• Patients should be informed about the Jarisch-Herxheimer reaction, an acute febrile response that may occur within 24 hours of treatment, particularly common in early syphilis 1

Early Latent Syphilis

Treat with benzathine penicillin G 2.4 million units intramuscularly as a single dose. 1, 2

• Early latent syphilis is defined as infection acquired within the preceding year, documented by seroconversion, fourfold increase in titer, history of symptoms within the past year, or having a sex partner with documented early syphilis 1

Late Latent Syphilis and Tertiary Syphilis

Administer benzathine penicillin G 7.2 million units total as three doses of 2.4 million units intramuscularly at weekly intervals. 1, 2

• If a dose is missed, an interval of 10-14 days between doses may be acceptable before restarting the sequence 1
• CSF examination is recommended before treatment for patients with neurologic or ophthalmic signs/symptoms, evidence of active tertiary syphilis, treatment failure, HIV infection with late latent syphilis, or serum nontreponemal titer ≥1:32 1

Neurosyphilis

Treat with aqueous crystalline penicillin G 18-24 million units IV daily (administered as 3-4 million units every 4 hours or continuous infusion) for 10-14 days. 1, 3

• Procaine penicillin without probenecid does not achieve adequate CSF levels and is inadequate for neurosyphilis 1
• CSF examination is essential for diagnosing neurosyphilis in patients with neurological signs/symptoms, tertiary syphilis, or those whose serological titers fail to decline appropriately 1

Penicillin-Allergic Patients (Non-Pregnant Adults)

For primary, secondary, or early latent syphilis: doxycycline 100 mg orally twice daily for 14 days. 1, 2, 3

For late latent syphilis: doxycycline 100 mg orally twice daily for 28 days. 1, 2, 3

• Ceftriaxone 1 gram IV/IM daily for 10 days is a reasonable alternative based on randomized trial data showing comparable efficacy to benzathine penicillin 1, 3
• Azithromycin should NOT be used in the United States due to widespread macrolide resistance and documented treatment failures 1, 3

Pregnancy

All pregnant women with penicillin allergy MUST undergo desensitization followed by penicillin treatment—no exceptions. 5, 1, 2, 3

• Penicillin is the only therapy with documented efficacy for preventing maternal transmission to the fetus and treating fetal infection 5, 1, 2
• Screen all pregnant women for syphilis at first prenatal visit, during third trimester, and at delivery 1
• Some experts recommend a second dose of benzathine penicillin 2.4 million units IM administered 1 week after the initial dose for women with primary, secondary, or early latent syphilis 5
• Women treated during the second half of pregnancy are at risk for premature labor and/or fetal distress from Jarisch-Herxheimer reaction; they should seek immediate medical attention if they notice contractions or changes in fetal movements 5, 1
• Tetracycline, doxycycline, erythromycin, azithromycin, and ceftriaxone are inadequate—erythromycin does not reliably cure fetal infection 5

HIV-Infected Patients

Use the same treatment regimens as non-HIV-infected patients. 1, 2

• Penicillin regimens should be used for all stages of syphilis in HIV-infected patients 5
• Patients with penicillin allergy should undergo skin testing and desensitization, then be treated with penicillin 5
• Limited data suggest no benefit to multiple doses of benzathine penicillin for early syphilis in HIV-infected patients compared to a single dose 1
• Closer follow-up is mandatory to detect potential treatment failure or disease progression 1

Follow-Up and Monitoring

Perform quantitative nontreponemal serologic tests (RPR or VDRL) at 3,6,12, and 24 months after treatment. 1, 3

• A fourfold decline in titer is expected within 6 months for primary/secondary syphilis and within 12-24 months for late syphilis 1, 2
• Treatment failure is defined as failure of nontreponemal test titers to decline fourfold within 6 months after therapy for primary or secondary syphilis 1, 2
• If treatment failure occurs, re-evaluate for HIV infection and perform CSF examination 1
• Critical pitfall: Do not switch between different nontreponemal test methods (e.g., VDRL and RPR) when monitoring serologic response, as results cannot be directly compared 1
• Do not rely solely on treponemal test antibody titers to assess treatment response, as they correlate poorly with disease activity 1

Management of Sex Partners

Persons exposed within 90 days preceding diagnosis of primary, secondary, or early latent syphilis should be treated presumptively, even if seronegative. 1, 2

• Persons exposed >90 days before diagnosis should be treated presumptively if serologic test results are not immediately available and follow-up is uncertain 1
• Time periods for at-risk partners: 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 1

Pediatric Considerations

For children with acquired primary or secondary syphilis: benzathine penicillin G 50,000 units/kg IM, up to the adult dose of 2.4 million units in a single dose. 1, 2

For children with late latent syphilis: benzathine penicillin G 50,000 units/kg IM, up to the adult dose of 2.4 million units, for three total doses at 1-week intervals (total 150,000 units/kg up to adult total dose of 7.2 million units). 1

• Children require CSF examination to exclude neurosyphilis before treatment 1
• Monitor all newborns treated with penicillins closely for clinical and laboratory evidence of toxic or adverse effects 6

Critical Pitfalls to Avoid

• Do not use oral penicillin preparations for syphilis treatment—they are ineffective 1
• Do not use enhanced penicillin therapy (standard benzathine penicillin combined with high-dose oral amoxicillin and probenecid)—it does not improve clinical outcomes and is not recommended 3
• Do not substitute inadequate alternatives in pregnancy—only penicillin prevents congenital syphilis 1