What is the recommended treatment for syphilis?

Syphilis Treatment Recommendations

First-Line Treatment: Parenteral Penicillin G

Benzathine penicillin G is the definitive treatment for all stages of syphilis, with dosing and duration determined by disease stage. 1, 2

Primary and Secondary Syphilis

• Administer benzathine penicillin G 2.4 million units IM as a single dose 1, 2, 3
• This regimen achieves 90-100% treatment success rates 4
• For children with acquired primary or secondary syphilis, dose is 50,000 units/kg IM, up to the adult dose of 2.4 million units 2

Early Latent Syphilis

• Use the same regimen as primary/secondary syphilis: benzathine penicillin G 2.4 million units IM as a single dose 1, 2
• Early latent syphilis is defined as infection acquired within the preceding year, based on documented seroconversion, fourfold titer increase, symptom history, or exposure to a partner with documented early syphilis 1

Late Latent Syphilis and Tertiary Syphilis

• Administer benzathine penicillin G 7.2 million units total, given as 3 doses of 2.4 million units IM at weekly intervals 1, 2, 3
• If a dose is missed, an interval of 10-14 days between doses may be acceptable before restarting the sequence 1

Neurosyphilis

• Use aqueous crystalline penicillin G 18-24 million units daily, administered as 3-4 million units IV every 4 hours for 10-14 days 3
• CSF examination is recommended for patients with neurological signs/symptoms, tertiary syphilis, or those whose serological titers fail to decline appropriately 1
• High-dose IV penicillin G (above 10 million units) should be administered slowly due to potential electrolyte imbalance from potassium content (65.8 mg potassium per million units) 5

Alternative Regimens for Penicillin-Allergic Patients

Non-Pregnant Adults

• For primary and secondary 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
• Note that tetracycline requires multiple daily dosing, has relatively frequent adverse effects, and has unproven efficacy for CNS involvement 6

Pregnant Women and Neurosyphilis Patients

• Penicillin remains the only proven effective therapy for preventing maternal transmission and treating neurosyphilis 1, 2
• Patients with penicillin allergy must undergo desensitization and be treated with penicillin 1, 2
• This is non-negotiable as no alternative has documented efficacy in these populations 1

Special Populations

HIV-Infected Patients

• Use the same treatment regimens as non-HIV-infected patients 1, 2
• HIV-infected patients may have atypical serologic responses but generally respond well to standard treatment 1
• All patients with syphilis should be tested for HIV 3
• The value of multiple-dose treatment for early syphilis in HIV-infected individuals remains uncertain 4

Pregnant Women

• Screen 3 times during pregnancy: at first prenatal visit, during third trimester, and at delivery 7
• Up to 40% of fetuses with in-utero syphilis exposure are stillborn or die during infancy 7
• Only parenteral penicillin G has documented efficacy for preventing maternal transmission 1, 2

Follow-Up and Monitoring

Serologic Testing Schedule

• Repeat quantitative nontreponemal serologic tests (RPR or VDRL) at 3,6,12, and 24 months 1, 3
• A fourfold decline in titer is expected within 6 months for primary/secondary syphilis 1, 2, 3
• For late syphilis, expect fourfold decline within 12-24 months 1

Treatment Failure Criteria

• Treatment failure is defined as failure of nontreponemal test titers to decline fourfold within 6 months after therapy for primary or secondary syphilis 1, 3
• If treatment failure is suspected, re-evaluate for HIV infection and perform CSF examination 1
• Re-treat with weekly injections of benzathine penicillin G 2.4 million units IM for 3 weeks 2

Important Monitoring Considerations

• Do not switch between different nontreponemal test methods (VDRL vs RPR) when monitoring response, as results cannot be directly compared 1
• Do not rely on treponemal test antibody titers to assess treatment response, as they correlate poorly with disease activity 1
• A significant proportion of patients may remain seropositive (the "serofast state") despite adequate treatment—44% of late latent syphilis patients became seronegative within 5 years, while 56% had persistently positive tests 8

Management of Sexual 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 results are not immediately available and follow-up is uncertain 1
• Long-term sex partners of patients with late syphilis should be evaluated clinically and serologically 2

Critical Pitfalls to Avoid

• Do not use oral penicillin preparations for syphilis treatment—they are ineffective 1
• Benzathine penicillin provides prolonged treponemicidal serum levels but does not reliably produce adequate CNS levels 6
• Be aware of the Jarisch-Herxheimer reaction, an acute febrile reaction that may occur within 24 hours after any syphilis therapy, especially in early syphilis 1
• Patients should be informed about this possible adverse reaction, which may include headache, myalgia, and fever 1
• Be aware of ongoing benzathine penicillin G shortages that may require searching multiple facilities or using alternative regimens 9

Prevention Strategies

• Screen sexually active people aged 15-44 years at least once, and at least annually for those at increased risk 7
• Counsel about condom use 7
• Offer doxycycline postexposure prophylaxis (200 mg within 72 hours after sex) to men who have sex with men and transgender women with a history of sexually transmitted infection in the past year 7