What are the current guidelines for treating syphilis?

Current Guidelines for Syphilis Treatment

Benzathine penicillin G remains the preferred 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) and 7.2 million units total (three weekly doses of 2.4 million units) for late latent or tertiary syphilis. 1, 2

Treatment by Stage

Primary and Secondary Syphilis

• Benzathine penicillin G 2.4 million units IM in a single dose is the recommended regimen for adults 3, 1, 2
• For children with acquired syphilis, administer benzathine penicillin G 50,000 units/kg IM, up to the adult dose of 2.4 million units in a single dose 3, 2
• This single-dose regimen achieves clinical resolution, prevents sexual transmission, and prevents late sequelae 3

Early Latent Syphilis

• Benzathine penicillin G 2.4 million units IM in a single dose (same as primary/secondary) 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 and Tertiary Syphilis

• Benzathine penicillin G 7.2 million units total, administered as three doses of 2.4 million units IM at 1-week intervals 1, 2
• This applies to both late latent syphilis (asymptomatic infection >1 year duration) and tertiary syphilis (gummatous, cardiovascular, or late neurologic manifestations) 1, 2
• If a dose is missed, an interval of 10-14 days between doses may be acceptable before restarting the sequence 1

Neurosyphilis

• Aqueous crystalline penicillin G 18-24 million units per day IV (administered as 3-4 million units every 4 hours) for 10-14 days 4
• CSF examination is recommended for patients with neurological signs/symptoms, tertiary syphilis, or those whose serological titers fail to decline appropriately 1
• CSF examination should be performed in all persons with serologic evidence of syphilis and neurologic symptoms 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, 6
• For late latent syphilis: Doxycycline 100 mg orally twice daily for 28 days 1, 2, 6
• 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

Critical Caveat: Azithromycin Should NOT Be Used

• Azithromycin should NOT be used in the United States due to widespread macrolide resistance and documented treatment failures, despite some evidence of efficacy in low-resistance areas 1

Pregnant Women and Neurosyphilis Patients

• Penicillin remains the only proven effective therapy for preventing maternal transmission and treating neurosyphilis 1, 2
• All pregnant women with penicillin allergy MUST undergo desensitization followed by penicillin treatment 1, 2
• Only penicillin prevents congenital syphilis; never substitute with inadequate alternatives in pregnancy 1

Special Populations

HIV-Infected Patients

• Treatment regimens are the same as for non-HIV-infected patients 1, 2
• HIV-infected patients may have atypical serologic responses but generally respond well to standard treatment 1
• 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
• HIV-infected persons with RPR titers ≥1:32 and/or CD4 counts <350 cells/mm³ may be at increased risk for asymptomatic neurosyphilis 5

Pregnant Women

• Screen all pregnant women for syphilis at first prenatal visit, during third trimester, and at delivery 1
• The Jarisch-Herxheimer reaction during the second half of pregnancy may precipitate premature labor or fetal distress 1
• Women should seek immediate medical attention if they notice changes in fetal movements or contractions after treatment 1
• Up to 40% of fetuses with in-utero exposure to syphilis are stillborn or die from their infection during infancy 7

Follow-Up and Monitoring

Serologic Monitoring

• Quantitative nontreponemal serologic tests (RPR or VDRL) should be repeated at 6,12, and 24 months 1, 2
• A fourfold decline in titer is expected within 6 months for primary/secondary syphilis and within 12-24 months for late syphilis 1, 2
• Patients should be reexamined clinically and serologically at these intervals 3

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, 2
• Patients with signs/symptoms that persist or recur, or who have a sustained fourfold increase in nontreponemal test titer, probably failed treatment or were reinfected 3
• These patients should be re-treated, reevaluated for HIV infection, and undergo CSF examination 3

CSF Monitoring for Neurosyphilis

• If CSF pleocytosis is evident at initial CSF examination, repeat examinations every 6 months until the cell count is normal 5

Management of Sex Partners

• Persons exposed within 90 days preceding the 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
• For identification of at-risk partners, the time periods before treatment are: 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 3
• Long-term sex partners of patients with late syphilis should be evaluated clinically and serologically 3, 2

Important Clinical Considerations

HIV Testing

• All patients with syphilis should be tested for HIV 3, 2
• In geographic areas with high HIV prevalence, patients with primary syphilis should be retested for HIV after 3 months if the first test was negative 3

Jarisch-Herxheimer Reaction

• The Jarisch-Herxheimer reaction is 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, fever, and other symptoms 1

Neurologic and Ophthalmic Involvement

• Patients with symptoms or signs suggesting neurologic disease (meningitis) or ophthalmic disease (uveitis) should have an evaluation that includes CSF analysis and ocular slit-lamp examination 3
• Treatment should be guided by the results of this evaluation 3

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 (switching between VDRL and RPR) when monitoring serologic response, as results cannot be directly compared 1
• Do not perform routine CSF analysis for patients with primary or secondary syphilis unless clinical signs or symptoms of neurologic or ophthalmic involvement are present 3