What is the treatment for syphilis?

Treatment of Syphilis

Benzathine penicillin G is the definitive 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), or 7.2 million units total (three weekly doses of 2.4 million units) for late latent, latent of unknown duration, and tertiary syphilis. 1

Treatment by Stage

Primary and Secondary Syphilis

• Benzathine penicillin G 2.4 million units IM in a single dose is the recommended treatment 1, 2
• This regimen achieves 90-100% treatment success rates 3
• All patients with syphilis should be tested for HIV 1

Early Latent Syphilis

• Benzathine penicillin G 2.4 million units IM as a single dose 1
• Early latent is defined as syphilis acquired within the preceding year, documented by seroconversion, fourfold increase in titer, history of symptoms within the past year, or having a sex partner with documented early syphilis 1

Late Latent Syphilis and Latent of Unknown Duration

• Benzathine penicillin G 7.2 million units total, administered as three doses of 2.4 million units IM at weekly intervals 1
• CSF examination is indicated before treatment if any of the following are present: neurologic or ophthalmic signs/symptoms, evidence of active tertiary syphilis, treatment failure, HIV infection with late latent syphilis, or serum nontreponemal titer ≥1:32 1

Tertiary Syphilis

• Critical first step: Perform CSF examination to exclude neurosyphilis before initiating treatment 4
• If neurosyphilis is excluded: Benzathine penicillin G 7.2 million units total (three weekly doses of 2.4 million units IM) 4
• The tertiary syphilis regimen is inadequate for CNS involvement—if neurosyphilis is present, the treatment regimen changes entirely 4

Neurosyphilis

• Aqueous crystalline penicillin G 18-24 million units per day IV (administered as 3-4 million units every 4 hours or continuous infusion) for 10-14 days 1
• This is the only appropriate regimen for documented neurosyphilis 4

Penicillin-Allergic Patients

Non-Pregnant Adults with Early Syphilis (Primary, Secondary, Early Latent)

• Doxycycline 100 mg orally twice daily for 14 days 1, 5
• Tetracycline 500 mg orally four times daily for 14 days is an alternative 1
• There is less clinical experience with doxycycline than tetracycline, but compliance is likely better 6

Non-Pregnant Adults with Late Latent Syphilis

• Doxycycline 100 mg orally twice daily for 28 days 1, 5
• Tetracycline 500 mg orally four times daily for 28 days is an alternative 1

Pregnant Women and Neurosyphilis Patients

• Penicillin desensitization is mandatory—no alternatives are acceptable 1, 4
• Only penicillin is proven effective for preventing maternal transmission and treating neurosyphilis 1
• Pregnant women with penicillin allergy MUST undergo desensitization followed by penicillin treatment 1

Special Populations

HIV-Infected Patients

• Use the same treatment regimens as HIV-negative patients 1
• No added benefit to enhanced antimicrobial therapy (e.g., multiple doses for early syphilis) 1
• Closer follow-up is mandatory to detect potential treatment failure or disease progression 1

Pregnant Women

• Screen all pregnant women for syphilis at first prenatal visit, during third trimester, and at delivery 1
• Parenteral penicillin G is the only therapy with documented efficacy for preventing maternal transmission 1
• Jarisch-Herxheimer reaction during 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

Pediatric Patients

• For early latent syphilis: Benzathine penicillin G 50,000 units/kg IM, up to adult dose of 2.4 million units, as a single dose 1
• For late latent syphilis: Benzathine penicillin G 50,000 units/kg IM, up to adult dose of 2.4 million units, for three total doses at 1-week intervals (total 150,000 units/kg up to 7.2 million units) 1
• Children require CSF examination to exclude neurosyphilis before treatment 1

Follow-Up and Monitoring

Primary and Secondary Syphilis

• Perform quantitative nontreponemal serologic tests (RPR or VDRL) at 6 and 12 months after treatment 1
• Expect a fourfold decline in titer within 6 months 1

Latent Syphilis

• Repeat quantitative nontreponemal tests at 6,12, and 24 months 1
• Expect a fourfold decline in titer within 12-24 months 1

Treatment Failure Criteria

Re-treat and evaluate for HIV if any of the following occur: 1

• Persistent or recurring signs/symptoms
• Sustained fourfold increase in nontreponemal titers
• Failure of initially high titer to decline at least fourfold within 6 months for early syphilis or 12-24 months for late syphilis

Re-Treatment Protocol

• If treatment failure occurs, re-evaluate for HIV infection and perform CSF examination 1
• Re-treat with three weekly injections of benzathine penicillin G 2.4 million units IM, unless neurosyphilis is diagnosed 6

Management of Sex Partners

• Treat sex partners presumptively if exposed within 90 days preceding diagnosis of primary, secondary, or early latent syphilis, even if seronegative 1
• Time periods for at-risk partners: 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 1

Critical Pitfalls to Avoid

• Never use oral penicillin preparations—they are completely ineffective for any stage of syphilis 4
• Never skip CSF examination before treating tertiary syphilis, as this may miss neurosyphilis requiring different treatment 4
• Never use different serologic test methods (RPR vs VDRL) when monitoring response, as results cannot be directly compared 1, 4
• Never substitute non-penicillin antibiotics in pregnancy—desensitization is mandatory 1
• Do not use azithromycin in the United States due to widespread macrolide resistance and documented treatment failures 1
• If a dose is missed during weekly therapy for late syphilis, an interval of 10-14 days between doses might be acceptable before restarting the sequence, but this is NOT acceptable for pregnant women 1

Jarisch-Herxheimer Reaction

• An acute febrile reaction with headache, myalgia, and other symptoms may occur within 24 hours after any syphilis therapy, especially in early syphilis 1, 4
• Patients should be informed about this possible adverse reaction before treatment 1
• In pregnant women during the second half of pregnancy, this reaction may precipitate premature labor or fetal distress 1