What is the treatment for syphilis?

Treatment of Syphilis

Primary and Secondary Syphilis

Benzathine penicillin G 2.4 million units intramuscularly as a single dose is the definitive treatment for primary and secondary syphilis, with over 40 years of proven effectiveness in achieving cure, healing lesions, and preventing late complications. 1, 2

• This single-dose regimen applies regardless of HIV status 2
• Treatment success rates range from 90% to 100% 3
• The FDA-approved penicillin G formulation should be administered intramuscularly 4

Early Latent Syphilis

For early latent syphilis (acquired within the preceding year), benzathine penicillin G 2.4 million units IM as a single dose is recommended. 1, 2, 5

• Early latent syphilis is defined by documented seroconversion, fourfold increase in titer, history of symptoms within the past year, or having a sex partner with documented early syphilis 1, 2
• All other cases should be treated as late latent syphilis 2

Late Latent Syphilis and Syphilis of Unknown Duration

Benzathine penicillin G 7.2 million units total, administered as three doses of 2.4 million units IM at weekly intervals, is the standard treatment for late latent syphilis or syphilis of unknown duration. 1, 2, 5

• If a dose is missed, an interval of 10-14 days between doses might be acceptable before restarting the sequence, though 7-9 days may be more optimal 1, 6
• Missed doses are NOT acceptable for pregnant women 6

Neurosyphilis

Aqueous crystalline penicillin G 18-24 million units per day IV (administered as 3-4 million units every 4 hours or continuous infusion) for 10-14 days is the treatment for neurosyphilis. 1, 5

• CSF examination should be performed before treatment 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 1, 5
• Procaine penicillin without probenecid does NOT achieve adequate CSF levels and is inadequate for neurosyphilis 1

Penicillin-Allergic Patients (Non-Pregnant)

For penicillin-allergic non-pregnant adults with primary, secondary, or early latent syphilis, doxycycline 100 mg orally twice daily for 14 days is the preferred alternative. 1, 2, 5, 7

• For late latent syphilis in penicillin-allergic patients, extend doxycycline to 100 mg orally twice daily for 28 days 1, 2, 7
• Doxycycline is preferred over tetracycline due to better compliance with twice-daily versus four-times-daily dosing 2
• Tetracycline 500 mg orally four times daily is an alternative (14 days for early syphilis, 28 days for late latent) 1
• Azithromycin should NOT be used in the United States due to widespread macrolide resistance and documented treatment failures 1

Pregnancy

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

• Penicillin is the only therapy with documented efficacy for preventing maternal transmission to the fetus and treating fetal infection 1, 5
• 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 1
• Screen all pregnant women for syphilis at first prenatal visit, during third trimester, and at delivery 1, 5
• Tetracycline, doxycycline, erythromycin, azithromycin, and ceftriaxone are inadequate—erythromycin does not reliably cure fetal infection 1

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 1
• Women should seek immediate medical attention if they notice contractions or changes in fetal movements after treatment 1

HIV-Infected Patients

HIV-infected patients receive the same penicillin regimens as HIV-negative patients, but require closer follow-up every 3 months. 1, 2

• For late latent syphilis in HIV-infected patients, perform CSF examination before treatment to exclude neurosyphilis 2
• Limited data suggest no benefit to multiple doses of benzathine penicillin for early syphilis in HIV-infected patients compared to a single dose 1
• Patients with penicillin allergy should undergo skin testing and desensitization, then be treated with penicillin 1

Follow-Up Protocol

Perform quantitative nontreponemal serologic tests (RPR or VDRL) at 6 and 12 months after treatment for primary/secondary syphilis. 1, 2, 5

• For latent syphilis, repeat quantitative nontreponemal tests at 6,12, and 24 months 1, 2, 5
• A fourfold decline in titer is expected within 6 months for primary/secondary syphilis and within 12-24 months for late syphilis 1, 3
• Treatment failure is defined by persistent or recurring signs/symptoms, sustained fourfold increase in nontreponemal titers, or failure of initially high titer to decline fourfold within 6-12 months 1, 2, 5

Management of Treatment Failure

• Re-treat and evaluate for HIV if treatment failure is suspected 1, 2
• Unless reinfection is likely, lumbar puncture should be performed 8
• Re-treatment typically involves three weekly injections of benzathine penicillin G 2.4 million units IM, unless CSF examination indicates neurosyphilis 8

Partner Management

Persons exposed within 90 days preceding diagnosis of primary, secondary, or early latent syphilis should be treated presumptively with benzathine penicillin G 2.4 million units IM, even if seronegative. 1, 5

• 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
• Persons exposed >90 days before diagnosis should be treated presumptively if serologic test results are not immediately available and follow-up is uncertain 1

Important Clinical Considerations

• All patients with syphilis should be tested for HIV infection at the time of diagnosis 1, 5, 9
• The Jarisch-Herxheimer reaction is an acute febrile reaction that may occur within 24 hours after any syphilis therapy, especially in early syphilis 1, 5
• Patients should be informed about this possible adverse reaction, which may include headache, myalgia, fever, and other symptoms 1, 5

Critical Pitfalls to Avoid

• Do not use oral penicillin preparations for syphilis treatment as they are ineffective 1
• Do not rely solely on treponemal test antibody titers to assess treatment response, as they correlate poorly with disease activity 1
• Do not use different testing methods (e.g., switching between VDRL and RPR) when monitoring serologic response, as results cannot be directly compared 1
• Do not substitute inadequate alternatives in pregnancy—only penicillin prevents congenital syphilis 1