What is the recommended treatment regimen for syphilis?

Syphilis Treatment Guidelines

Primary and Secondary Syphilis

For adults with primary or secondary syphilis, administer benzathine penicillin G 2.4 million units intramuscularly as a single dose. 1, 2, 3

• This single-dose regimen achieves 90-100% treatment success rates and has been the standard of care for over 50 years 4
• The same regimen applies regardless of HIV status, though HIV-infected patients require closer monitoring 2
• For children with acquired primary or secondary syphilis, give benzathine penicillin G 50,000 units/kg IM (up to the adult dose of 2.4 million units) as a single dose 5

Alternative Regimens for Penicillin Allergy

For non-pregnant adults with penicillin allergy, doxycycline 100 mg orally twice daily for 14 days is the preferred alternative. 1, 2, 6

• Tetracycline 500 mg orally four times daily for 14 days is another option, though compliance is better with doxycycline due to less frequent dosing 2
• Ceftriaxone 1 g daily (IM or IV) for 8-10 days may be considered, though optimal dosing remains uncertain 2
• Pregnant women with penicillin allergy must undergo desensitization and receive penicillin, as no alternative has proven efficacy for preventing maternal transmission 1, 2

Early Latent Syphilis

Treat early latent syphilis (acquired within the preceding year) with benzathine penicillin G 2.4 million units IM as a single dose. 1

• 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
• For penicillin-allergic non-pregnant adults, use doxycycline 100 mg orally twice daily for 14 days 1

Late Latent and Tertiary Syphilis

For late latent syphilis, latent syphilis of unknown duration, or tertiary syphilis, administer benzathine penicillin G 7.2 million units total as three doses of 2.4 million units IM at weekly intervals. 1, 3

• If a dose is missed, an interval of 10-14 days between doses may be acceptable before restarting the sequence 1
• For penicillin-allergic non-pregnant adults with late latent syphilis, use doxycycline 100 mg orally twice daily for 28 days 1, 6
• Serologic response is slower for late syphilis (12-24 months) compared to early syphilis (6 months) 4

Neurosyphilis

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

• CSF examination is indicated for patients with neurological signs/symptoms, tertiary syphilis, or those whose serologic titers fail to decline appropriately 1
• Penicillin remains the only proven effective therapy for neurosyphilis; desensitization is required for penicillin-allergic patients 1
• Routine CSF analysis is not recommended for primary or secondary syphilis unless clinical signs of neurologic or ophthalmic involvement are present 5

Special Populations

HIV-Infected Patients

• HIV-infected patients receive the same treatment regimens as non-HIV-infected patients 1, 2
• Monitor HIV-infected patients more frequently: every 3 months rather than every 6 months 2
• Although some specialists recommend additional doses for HIV-infected patients with early syphilis, data show no significant benefit of multiple doses over a single dose 2

Pregnant Women

• Parenteral penicillin G is the only therapy with documented efficacy for preventing maternal transmission 1
• Up to 40% of fetuses with in-utero exposure to syphilis are stillborn or die from infection during infancy 7
• Screen pregnant individuals three times: at the first prenatal visit, during the third trimester, and at delivery 7

Management of Sexual Partners

Treat sex partners exposed within 90 days preceding diagnosis of primary, secondary, or early latent syphilis presumptively, even if seronegative. 5, 1

• Partners exposed >90 days before diagnosis should be treated presumptively if serologic results are not immediately available and follow-up is uncertain 5, 1
• Time periods for identifying 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 5
• Patients with syphilis of unknown duration and high nontreponemal titers (≥1:32) can be assumed to have early syphilis for partner notification purposes 5

Follow-Up and Monitoring

Perform quantitative nontreponemal serologic tests 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, 3
• 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
• Do not switch between different nontreponemal test methods (VDRL vs RPR) when monitoring response, as results cannot be directly compared 1

Important Clinical Considerations

Jarisch-Herxheimer Reaction

• An acute febrile reaction may occur within 24 hours after any syphilis therapy, especially in early syphilis 1, 2
• Symptoms include fever, headache, and myalgia 1, 2
• Inform patients about this possible adverse reaction before treatment 1

Testing Recommendations

• All patients with syphilis should be tested for HIV infection 5, 3
• In high HIV prevalence areas, retest patients with primary syphilis for HIV after 3 months if initially negative 5
• Patients with symptoms suggesting neurologic disease (meningitis) or ophthalmic disease (uveitis) require CSF analysis and ocular slit-lamp examination 5

Critical Pitfalls to Avoid

• Do not use oral penicillin preparations for syphilis treatment—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
• Macrolide resistance in T. pallidum is widespread in the United States, making azithromycin unsuitable despite some evidence of efficacy 2
• Serologic tests may decline more slowly in patients who have had previous syphilis infections 5, 2
• A significant proportion of patients may remain seropositive after successful treatment (the "serofast state"), which does not necessarily indicate treatment failure 4