What is the recommended treatment for syphilis?

Treatment of Syphilis

Benzathine penicillin G remains the only proven effective treatment for all stages of syphilis, with 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 regimen applies equally to HIV-infected and HIV-uninfected patients. 1, 2

Alternative for Penicillin-Allergic Patients (Non-Pregnant)

• Doxycycline 100 mg orally twice daily for 14 days is the recommended alternative when penicillin cannot be used. 1, 2
• 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. 3
• Ceftriaxone 1 gram IV/IM daily for 10 days is a reasonable alternative based on randomized trial data showing comparable efficacy to benzathine penicillin. 3

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 syphilis acquired within the preceding year based on documented seroconversion, fourfold titer increase, symptom history, or partner with documented early syphilis. 2

Late Latent Syphilis and Latent Syphilis of Unknown Duration

Administer benzathine penicillin G 7.2 million units total, given as three doses of 2.4 million units IM at weekly intervals. 1, 2, 4

Alternative for Penicillin-Allergic Patients (Non-Pregnant)

• Doxycycline 100 mg orally twice daily for 28 days. 1, 2

Tertiary Syphilis

Critical First Step: Rule Out Neurosyphilis

Perform cerebrospinal fluid (CSF) examination before treating tertiary syphilis to exclude neurosyphilis. 4 If neurosyphilis is present, the treatment changes entirely to aqueous crystalline penicillin G 18-24 million units IV daily for 10-14 days. 4 The tertiary syphilis regimen is inadequate for CNS involvement. 4

Treatment Regimen

Benzathine penicillin G 7.2 million units total, administered as three weekly doses of 2.4 million units IM. 1, 4 This is identical to the late latent syphilis regimen. 4

Penicillin-Allergic Patients

Penicillin desensitization is strongly preferred over alternative antibiotics for tertiary disease. 4 Consult an infectious disease specialist for management. 4

Special Populations

HIV-Infected Patients

• Use the same treatment regimens as HIV-uninfected patients for all stages of syphilis. 1, 2
• Limited data suggest no benefit to multiple doses of benzathine penicillin for early syphilis in HIV-infected patients compared to a single dose. 3
• Closer follow-up is mandatory to detect potential treatment failure or disease progression. 3, 4
• The single-dose regimen for early syphilis showed 93% success rate in the per-protocol analysis of a randomized trial in HIV-infected patients. 5

Pregnant Women

Only penicillin G is proven effective for preventing maternal transmission and congenital syphilis. 1, 2

• All pregnant women with penicillin allergy MUST undergo desensitization followed by penicillin treatment. 2
• No alternative antibiotics are acceptable in pregnancy. 2, 4
• 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. 2 Women should seek immediate medical attention if they notice changes in fetal movements or contractions after treatment. 2

Follow-Up and Monitoring

Repeat quantitative nontreponemal serologic tests (RPR or VDRL) at 6,12, and 24 months. 1, 2

Expected Response

• Primary/secondary syphilis: 4-fold decline in titer within 6 months. 1, 2
• Late syphilis: 4-fold decline in titer within 12-24 months. 1, 2, 4

Indicators for CSF Examination

Perform CSF examination if: 1, 2

• Titers increase 4-fold
• Initially high titer fails to decline at least 4-fold within expected timeframes
• Neurological signs or symptoms develop

Treatment Failure Management

Treatment failure is defined as: 2

• Failure of nontreponemal test titers to decline 4-fold within 6 months after therapy for primary/secondary syphilis
• Persistent or recurring clinical signs/symptoms
• Sustained 4-fold increase in nontreponemal test titers

Re-treatment approach: 1, 2

• Re-evaluate for HIV infection
• Perform CSF examination
• Re-treat with weekly injections of benzathine penicillin G 2.4 million units IM for 3 weeks unless neurosyphilis is diagnosed

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

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

Critical Pitfalls to Avoid

• Never use oral penicillin preparations for syphilis treatment—they are completely ineffective. 2, 4
• Do not switch between different nontreponemal test methods (RPR vs VDRL) when monitoring serologic response, as results cannot be directly compared. 2, 4
• Do not rely solely on treponemal test antibody titers to assess treatment response, as they correlate poorly with disease activity. 2
• Do not skip CSF examination before treating tertiary syphilis, as this may miss neurosyphilis requiring different treatment. 4
• Never substitute non-penicillin antibiotics in pregnancy—only penicillin prevents congenital syphilis. 2

Jarisch-Herxheimer Reaction

An acute febrile reaction may occur within 24 hours after any syphilis therapy, especially in early syphilis. 2, 4 This may include headache, myalgia, fever, and other symptoms. 2 Patients should be informed about this possible adverse reaction before treatment. 2

Dosing Considerations

• If a dose is missed during weekly therapy, an interval of 10-14 days between doses might be acceptable before restarting the sequence. 2
• Benzathine penicillin G contains approximately 1.68 mEq potassium and 0.3 mEq sodium per million units. 6
• High-dose IV penicillin G (above 10 million units) should be administered slowly due to potential electrolyte imbalance from potassium content. 6, 7