What is the recommended treatment for syphilis?

Treatment of Syphilis

Benzathine penicillin G is the definitive treatment for all stages of syphilis, with dosing determined by disease stage: 2.4 million units IM as a single dose for early syphilis (primary, secondary, and early latent), or 7.2 million units total (three weekly doses of 2.4 million units) for late latent, latent of unknown duration, and tertiary syphilis. 1, 2

Stage-Specific Treatment Regimens

Early Syphilis (Primary, Secondary, and Early Latent)

• Benzathine penicillin G 2.4 million units IM as a single injection is the standard treatment for adults 1, 2, 3
• Early latent syphilis is defined as infection acquired within the preceding year, documented by seroconversion, fourfold titer increase, symptoms within the past year, or exposure to a partner with documented early syphilis 2
• For children with acquired early syphilis, administer benzathine penicillin G 50,000 units/kg IM (up to adult dose of 2.4 million units) as a single dose 1, 2

Late Latent and Tertiary Syphilis

• Benzathine penicillin G 7.2 million units total, administered as three doses of 2.4 million units IM at weekly intervals (days 0,7, and 14) 1, 2
• This regimen applies to late latent syphilis (>1 year duration), latent syphilis of unknown duration, and tertiary syphilis 1, 2
• For pediatric patients, administer benzathine penicillin G 50,000 units/kg IM (up to 2.4 million units per dose) for three total doses at weekly intervals (total 150,000 units/kg up to 7.2 million units) 2

Neurosyphilis

• 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 2, 3
• Alternative: Procaine penicillin G with probenecid, though procaine penicillin without probenecid does not achieve adequate CSF levels and is inadequate 2
• CSF examination is indicated for patients with neurologic/ophthalmic symptoms, active tertiary syphilis, treatment failure, HIV infection with late latent syphilis, or serum nontreponemal titer ≥1:32 2

Alternative Treatments for Penicillin Allergy

Non-Pregnant Adults

• Doxycycline 100 mg orally twice daily for 14 days for primary, secondary, or early latent syphilis 1, 2, 3
• Doxycycline 100 mg orally twice daily for 28 days for late latent syphilis or latent syphilis of unknown duration 1, 2
• Tetracycline 500 mg orally four times daily (14 days for early syphilis, 28 days for late latent) is an alternative, though compliance is better with doxycycline due to less frequent dosing 2, 3
• Ceftriaxone 1 gram IM/IV daily for 10 days may be considered based on randomized trial data showing comparable efficacy to benzathine penicillin 2, 3

Critical Caveat: Azithromycin

• Azithromycin should NOT be used in the United States due to widespread macrolide resistance and documented treatment failures 2

Special Populations

Pregnant Women

• All pregnant women with penicillin allergy MUST undergo desensitization followed by penicillin treatment—no exceptions 1, 2
• Penicillin is the only therapy with documented efficacy for preventing maternal transmission to the fetus and treating fetal infection 2
• Some experts recommend a second 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
• Screen all pregnant women for syphilis at first prenatal visit, during third trimester, and at delivery 2
• Jarisch-Herxheimer reaction during the second half of pregnancy may precipitate premature labor or fetal distress; women should seek immediate medical attention if they notice contractions or changes in fetal movements after treatment 2
• Tetracycline, doxycycline, erythromycin, azithromycin, and ceftriaxone are inadequate—erythromycin does not reliably cure fetal infection 2

HIV-Infected Patients

• Use the same penicillin regimens as for non-HIV-infected patients 1, 2, 3
• Limited data suggest no benefit to multiple doses of benzathine penicillin for early syphilis in HIV-infected patients compared to a single dose 2
• Closer follow-up is mandatory (every 3 months rather than every 6 months) to detect potential treatment failure or disease progression 2, 3
• Patients with penicillin allergy should undergo skin testing and desensitization, then be treated with penicillin 2

Follow-Up and Monitoring

Serologic Testing Schedule

• For primary/secondary syphilis: Quantitative nontreponemal tests (RPR or VDRL) at 6 and 12 months after treatment 2
• For latent syphilis: Repeat quantitative nontreponemal tests at 6,12, and 24 months 1, 2
• HIV-infected patients should be monitored every 3 months 2, 3

Expected Response

• A fourfold decline in titer is expected within 6 months for primary/secondary syphilis and within 12-24 months for late syphilis 1, 2
• Serologic tests may decline more slowly in patients who have had previous syphilis infections 3

Treatment Failure Criteria

• Treatment failure is defined as: persistent or recurring signs/symptoms, sustained fourfold increase in nontreponemal titers, or failure of initially high titer to decline at least fourfold within 6-12 months for early syphilis or 12-24 months for late syphilis 1, 2
• Re-treatment typically involves three weekly injections of benzathine penicillin G 2.4 million units IM, unless CSF examination indicates neurosyphilis 2
• If treatment failure is suspected, re-evaluate for HIV infection and perform lumbar puncture to evaluate for neurosyphilis 2

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 2
• 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 2
• Long-term sex partners of patients with late syphilis should be evaluated clinically and serologically 1

Critical Pitfalls to Avoid

• Do not use oral penicillin preparations for syphilis treatment—they are ineffective 1
• Do not switch between different nontreponemal testing 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
• If a dose is missed during weekly therapy, an interval of 10-14 days between doses might be acceptable before restarting the sequence 2
• Jarisch-Herxheimer reaction (fever, headache, myalgia) may occur within 24 hours after treatment, especially in early syphilis; patients should be informed about this possible adverse reaction 1, 3

Additional Considerations

• All patients with syphilis should be tested for HIV infection 2, 4
• All infections due to Group A beta-hemolytic streptococci should be treated for at least 10 days 5, 6
• Children with acquired syphilis require CSF examination to exclude neurosyphilis before treatment 2
• High-dose IV penicillin G (above 10 million units) should be administered slowly due to potential adverse effects of electrolyte imbalance from potassium content 5, 6