What is the recommended treatment for syphilis?

Syphilis Treatment

Benzathine penicillin G is the definitive treatment for syphilis at all stages, with dosing determined by disease stage: 2.4 million units IM as a single dose for early syphilis (primary, secondary, and early latent), or 7.2 million units total given as three weekly doses of 2.4 million units IM 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 standard treatment for adults 3, 1, 2
• This regimen has four decades of proven efficacy in achieving local cure, healing lesions, preventing sexual transmission, and preventing late sequelae 3
• For children with acquired syphilis, administer benzathine penicillin G 50,000 units/kg IM (up to adult dose of 2.4 million units) as a single dose 3, 2
• Children should have CSF examination to exclude neurosyphilis and undergo evaluation by child-protection services 3

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 syphilis acquired within the preceding year based on documented seroconversion, fourfold titer increase, history of symptoms, or sex partner with documented early syphilis 1

Late Latent 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
• This applies to both late latent syphilis (>1 year duration) and latent syphilis of unknown duration 1
• 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 is the recommended treatment (not benzathine penicillin) 1
• CSF examination is indicated for patients with neurological signs/symptoms (meningitis, cranial nerve dysfunction, auditory symptoms, ophthalmic manifestations), tertiary syphilis, or inadequate serological response 3, 1
• Routine lumbar puncture is NOT recommended for uncomplicated primary or secondary syphilis, as CSF invasion is common but rarely leads to neurosyphilis with standard treatment 3

Alternative Treatments for Penicillin Allergy

Non-Pregnant Adults

• For primary/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
• A 2005 study demonstrated that single-dose azithromycin 2g orally achieved 97.7% cure rates comparable to penicillin 4, though azithromycin resistance has emerged in the United States and ongoing monitoring is essential 4

Pregnant Women and Neurosyphilis

• Penicillin is the ONLY proven effective therapy for preventing maternal transmission and treating neurosyphilis 1, 2
• Pregnant women with penicillin allergy MUST undergo desensitization and receive penicillin 1, 2
• This is non-negotiable as no alternative has documented efficacy in pregnancy 2

Special Populations

HIV-Infected Patients

• Use the same treatment regimens as non-HIV-infected patients 1, 2
• HIV-infected patients may have atypical serologic responses but generally respond well to standard treatment 1
• Patients with primary syphilis in high HIV prevalence areas should be retested for HIV after 3 months 3

Pregnant Women

• Screen three times during pregnancy: at first prenatal visit, during third trimester, and at delivery 5
• Up to 40% of fetuses with in-utero syphilis exposure are stillborn or die in infancy, making treatment critical 5
• Only parenteral penicillin G prevents maternal transmission 1, 2

Follow-Up and Monitoring

Serologic Monitoring

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

Treatment Failure Criteria

• Failure of nontreponemal titers to decline fourfold within 6 months after therapy for primary/secondary syphilis 1, 2
• If treatment failure suspected: re-evaluate for HIV infection and perform CSF examination 1
• Re-treatment consists of weekly benzathine penicillin G 2.4 million units IM for 3 weeks 2

Management of Sexual Partners

Presumptive Treatment Indications

• Persons exposed within 90 days of diagnosis of primary, secondary, or early latent syphilis should be treated presumptively even if seronegative 3, 1, 2
• Persons exposed >90 days before diagnosis should be treated presumptively if serologic results are not immediately available and follow-up is uncertain 3, 1, 2
• Patients with syphilis of unknown duration and high nontreponemal titers (≥1:32) should be considered to have early syphilis for partner notification purposes 3

Partner Notification Time Periods

• Primary syphilis: 3 months plus duration of symptoms 3
• Secondary syphilis: 6 months plus duration of symptoms 3
• Early latent syphilis: 1 year 3
• Long-term partners of patients with late syphilis should be evaluated clinically and serologically 3, 2

Prevention Strategies

• Screen all sexually active persons aged 15-44 years at least once, and at least annually for those at increased risk 5
• Offer doxycycline postexposure prophylaxis (200 mg within 72 hours after sex) to men who have sex with men and transgender women with STI history in the past year 5
• Counsel about condom use 5

Critical Pitfalls to Avoid

Medication Errors

• Never use oral penicillin preparations—they are ineffective for syphilis treatment 1
• Administer high-dose IV penicillin G slowly (doses >10 million units) due to potassium content (1.68 mEq per million units) and risk of electrolyte imbalance 6
• Avoid intravenous or intraarterial injection of IM preparations, as this may cause neurovascular damage 6

Monitoring Errors

• Do not rely on treponemal antibody titers to assess treatment response—they correlate poorly with disease activity 1
• Do not switch between different nontreponemal tests (VDRL vs RPR) when monitoring response, as results cannot be directly compared 1
• Patients being treated for gonorrhea should have serologic testing for syphilis before receiving penicillin 7, 6

Clinical Considerations

• Warn patients about Jarisch-Herxheimer reaction: acute febrile reaction occurring within 24 hours after treatment, especially in early syphilis, with headache, myalgia, and fever 1
• All patients with syphilis should be tested for HIV 3
• Bacteriostatic antibiotics (chloramphenicol, erythromycins, sulfonamides, tetracyclines) may antagonize penicillin's bactericidal effect and should be avoided concurrently 7, 6