What is the recommended treatment for syphilis?

Syphilis Treatment Recommendations

First-Line Treatment: Parenteral Penicillin G

Parenteral penicillin G is the preferred and only fully proven treatment for all stages of syphilis, with specific dosing determined by disease stage. 1, 2

Primary and Secondary Syphilis

• Administer benzathine penicillin G 2.4 million units intramuscularly as a single dose. 1, 2
• This single-dose regimen is highly effective and remains the gold standard for early symptomatic disease 1
• Expect a fourfold decline in nontreponemal titers (RPR/VDRL) within 6 months 1, 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 is defined as asymptomatic infection acquired within the preceding year, documented by seroconversion, fourfold titer increase, history of symptoms, or exposure to a partner with documented early syphilis 1

Late Latent Syphilis and Latent Syphilis of Unknown Duration

• Administer benzathine penicillin G 7.2 million units total: three doses of 2.4 million units IM given at weekly intervals. 1, 2
• If a dose is missed, an interval of 10-14 days between doses may be acceptable before restarting the sequence 1
• Expect a fourfold decline in titers within 12-24 months 1, 2

Tertiary Syphilis

• Before treating tertiary syphilis, perform cerebrospinal fluid (CSF) examination to exclude neurosyphilis. 3
• If CSF is normal, administer benzathine penicillin G 7.2 million units total as three weekly doses of 2.4 million units IM 2, 3
• The tertiary syphilis regimen is completely inadequate for CNS involvement; if neurosyphilis is present, switch to aqueous crystalline penicillin G 18-24 million units IV daily for 10-14 days 3
• Some specialists treat all cardiovascular syphilis cases with neurosyphilis regimens due to concern about CNS involvement 3

Neurosyphilis

• Administer aqueous crystalline penicillin G 18-24 million units IV daily for 10-14 days. 1, 3
• CSF examination is recommended for patients with neurological signs/symptoms, tertiary syphilis, or those whose serological titers fail to decline appropriately 1

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Alternative Treatments for Penicillin-Allergic Patients

Non-Pregnant Adults

• For primary and secondary syphilis: doxycycline 100 mg orally twice daily for 14 days. 1, 2
• For late latent syphilis: doxycycline 100 mg orally twice daily for 28 days. 1, 2
• 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
• Do NOT use azithromycin in the United States due to widespread macrolide resistance and documented treatment failures. 1

Pregnant Women and Neurosyphilis Patients

• Penicillin is the only proven effective therapy; patients with penicillin allergy MUST undergo desensitization followed by penicillin treatment. 1, 2, 3
• Only penicillin prevents congenital syphilis—never substitute with inadequate alternatives in pregnancy 1
• Pregnant women should be screened for syphilis at first prenatal visit, during third trimester, and at delivery 1

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Special Populations

HIV-Infected Patients

• Use the same treatment regimens as 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 1, 4
• However, closer follow-up is mandatory to detect potential treatment failure or disease progression 1, 3
• HIV-infected patients may have atypical serologic responses but generally respond well to standard treatment 1

Pediatric Patients

• For children with acquired primary or secondary syphilis, administer benzathine penicillin G 50,000 units/kg IM, up to the adult dose of 2.4 million units in a single dose 2
• Monitor all newborns treated with penicillins closely for clinical and laboratory evidence of toxic or adverse effects 5

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Follow-Up and Monitoring

Serologic Testing Schedule

• Repeat quantitative nontreponemal serologic tests (RPR or VDRL) at 3,6,12, 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

Treatment Failure Criteria

• Treatment failure is defined as: 1, 2
  • Failure of nontreponemal test titers to decline fourfold within 6 months after therapy for primary or secondary syphilis
  • Fourfold increase in titers
  • Persistent or recurring clinical signs/symptoms
• If treatment failure is suspected, re-evaluate for HIV infection and perform CSF examination 1, 2
• Retreat with weekly injections of benzathine penicillin G 2.4 million units IM for 3 weeks unless neurosyphilis is diagnosed 2, 3

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

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Critical Pitfalls to Avoid

• Do NOT use oral penicillin preparations for syphilis treatment—they are completely ineffective. 1, 3
• 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, 3
• Do NOT skip CSF examination before treating tertiary syphilis, as this may miss neurosyphilis requiring different treatment. 3
• Do NOT substitute non-penicillin antibiotics in pregnant women or neurosyphilis patients without desensitization. 1, 2, 3

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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, 3
• Patients should be informed about this possible adverse reaction, which may include headache, myalgia, and other symptoms 1
• During the second half of pregnancy, this reaction may precipitate premature labor or fetal distress; women should seek immediate medical attention if they notice changes in fetal movements or contractions after treatment 1