What is the recommended treatment for syphilis?

Syphilis Management

First-Line Treatment: Benzathine Penicillin G

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

Primary and Secondary Syphilis

• Benzathine penicillin G 2.4 million units IM as a single dose is the definitive treatment 1, 2, 3
• This regimen applies to both primary chancres and secondary manifestations (rash, mucocutaneous lesions, lymphadenopathy) 4
• Treatment success is verified by a fourfold decline in nontreponemal titers within 6 months 1, 2

Early Latent Syphilis

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

Late Latent, Latent of Unknown Duration, and Tertiary Syphilis

• Benzathine penicillin G 7.2 million units total: three doses of 2.4 million units IM given at weekly intervals 1, 2, 3
• If a dose is missed, an interval of 10-14 days between doses is acceptable before restarting the sequence 2
• This extended regimen is necessary because late-stage disease requires prolonged treponemacidal levels 5

Neurosyphilis

• 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 mandatory before diagnosing neurosyphilis in patients with neurological signs/symptoms, tertiary syphilis, or treatment failure 2, 3

Alternative Treatment for Penicillin-Allergic Patients

Non-Pregnant Adults Only

• Primary/secondary syphilis: Doxycycline 100 mg orally twice daily for 14 days 1, 2, 3
• Late latent syphilis: Doxycycline 100 mg orally twice daily for 28 days 1, 2

Critical Caveat: Pregnant Women and Neurosyphilis

• Penicillin is the ONLY proven effective therapy for preventing maternal-fetal transmission and treating neurosyphilis 1, 2
• All pregnant women with penicillin allergy MUST undergo desensitization followed by penicillin treatment 6, 1, 2
• Erythromycin and tetracyclines are contraindicated—erythromycin cannot reliably cure fetal infection, and tetracyclines are teratogenic 6
• Skin testing may help confirm true penicillin allergy before desensitization 6, 7

Special Populations

HIV-Infected Patients

• Use the same treatment regimens as non-HIV-infected patients 1, 2
• HIV patients may have atypical serologic responses but generally respond well to standard penicillin therapy 2
• For late latent syphilis with HIV and normal CSF: benzathine penicillin G 7.2 million units (three weekly doses of 2.4 million units each) 6
• All syphilis patients should be tested for HIV 6, 3

Pregnant Women

• Screen all pregnant women for syphilis at first prenatal visit, during third trimester, and at delivery 6, 4
• Treat with the penicillin regimen appropriate for disease stage 6, 3
• Some experts recommend an additional dose of benzathine penicillin 2.4 million units IM one week after initial treatment for women in third trimester or with secondary syphilis 6
• Warning: Jarisch-Herxheimer reaction during second half of pregnancy may precipitate premature labor or fetal distress 6
• Women should seek immediate medical attention if they notice changes in fetal movements or contractions after treatment 6

Pediatric Patients

• Children with acquired primary/secondary syphilis: Benzathine penicillin G 50,000 units/kg IM, up to adult dose of 2.4 million units single dose 1
• Newborns have incompletely developed renal function that may delay penicillin elimination, requiring dosage adjustments 7

Follow-Up and Monitoring

Serologic Monitoring

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

Treatment Failure Criteria

• Failure of nontreponemal titers to decline fourfold within 6 months after therapy for primary/secondary syphilis 1, 2, 3
• Fourfold increase in titers at any point 1
• Development of neurological signs or symptoms 1

Management of Treatment Failure

• Re-treat with weekly injections of benzathine penicillin G 2.4 million units IM for 3 weeks 1
• Perform CSF examination to rule out neurosyphilis 1, 2
• Re-evaluate for HIV infection 2

Management of Sex Partners

Recent Exposure (≤90 Days)

• Treat presumptively with benzathine penicillin G 2.4 million units IM single dose, even if seronegative 1, 2
• This applies to partners of patients with primary, secondary, or early latent syphilis 1, 2

Exposure >90 Days

• Treat presumptively if serologic results are not immediately available and follow-up is uncertain 2
• Otherwise, evaluate clinically and serologically before deciding on treatment 1

Long-Term Partners of Late Syphilis

• Evaluate clinically and serologically rather than treating presumptively 1

Critical Pitfalls to Avoid

Medication Errors

• Never use oral penicillin preparations—they are completely ineffective for syphilis 2
• Do not substitute different penicillin formulations; benzathine penicillin G provides the prolonged treponemacidal levels required 1, 2

Monitoring Errors

• Do not switch between different nontreponemal tests (VDRL vs RPR) when monitoring response—results cannot be directly compared 2
• Do not use treponemal test titers (FTA-ABS, MHA-TP) to assess treatment response—they correlate poorly with disease activity and often remain positive for life 2
• A fourfold change means a two-dilution change (e.g., 1:32 to 1:8), not a simple multiplication 3

Drug Interactions

• Avoid concurrent use of bacteriostatic antibiotics (tetracyclines, erythromycins, chloramphenicol, sulfonamides) with penicillin—they may antagonize penicillin's bactericidal effect 7
• Probenecid, aspirin, phenylbutazone, sulfonamides, indomethacin, and thiazide diuretics prolong penicillin half-life by competing for renal tubular secretion 7

Jarisch-Herxheimer Reaction

• Inform all patients about this acute febrile reaction that may occur within 24 hours of treatment, especially in early syphilis 2
• Symptoms include fever, headache, myalgia, and temporary worsening of skin lesions 2
• This is not an allergic reaction and does not contraindicate future penicillin use 2

Addressing Benzathine Penicillin G Shortages

When benzathine penicillin G is unavailable:

• For non-pregnant adults with early syphilis: doxycycline 100 mg orally twice daily for 14 days is acceptable 1, 8
• For pregnant women: exhaust all efforts to locate benzathine penicillin G, including contacting multiple facilities and pharmacies 8
• Contact local health departments and CDC for assistance in locating supply 8
• Never substitute with inadequate alternatives in pregnancy—only penicillin prevents congenital syphilis 6, 1