What is the recommended treatment for syphilis?

Syphilis Treatment

Benzathine penicillin G remains 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 given as three weekly doses of 2.4 million units IM for late latent, latent of unknown duration, and tertiary syphilis. 1, 2

Treatment by Stage

Early Syphilis (Primary, Secondary, and Early Latent)

• Administer benzathine penicillin G 2.4 million units IM as a single injection 1, 3
• This single-dose regimen is effective regardless of HIV status 4, 1
• Early latent syphilis is defined as infection acquired within the preceding year, documented by seroconversion, fourfold titer increase, history of symptoms, or exposure to a partner with documented early syphilis 2

Late Latent, Unknown Duration, and Tertiary Syphilis

• Give benzathine penicillin G 7.2 million units total: three doses of 2.4 million units IM at weekly intervals 1, 2
• CSF examination should be performed before treatment to exclude neurosyphilis in patients with neurological signs/symptoms, tertiary syphilis, or inadequate serologic response 2

Neurosyphilis

• Treat with aqueous crystalline penicillin G 18-24 million units daily IV (administered as 3-4 million units every 4 hours) for 10-14 days 3
• This is the only proven effective regimen for neurosyphilis 2

Alternative Treatments for Penicillin Allergy

Doxycycline is the preferred alternative when penicillin cannot be used, but only in non-pregnant patients. 1, 3

For Early Syphilis

• Doxycycline 100 mg orally twice daily for 14 days 1, 3
• Tetracycline 500 mg orally four times daily for 14 days is another option, though compliance is better with doxycycline due to less frequent dosing 3
• Ceftriaxone 1 g daily (IM or IV) for 8-10 days may be considered, with one randomized trial showing comparable efficacy to benzathine penicillin for early syphilis 4, 3

For Late Latent Syphilis

• Doxycycline 100 mg orally twice daily for 28 days 1, 2
• Limited retrospective data provide reassurance about tetracycline efficacy for late latent syphilis 4

Critical Caveat: Azithromycin Should NOT Be Used

• Despite some evidence of efficacy, azithromycin is not recommended in the United States due to widespread macrolide resistance in T. pallidum and documented treatment failures 4, 3
• Molecular resistance mutations are highly prevalent in the U.S., making this previously promising single-dose option unsuitable 4

Special Populations

HIV-Infected Patients

• Use the same treatment regimens as HIV-negative patients 4, 1, 2
• Limited data suggest no benefit in serologic outcomes from multiple doses versus single-dose benzathine penicillin for early syphilis in HIV-infected patients 4
• Implement closer follow-up: evaluate every 3 months rather than every 6 months 3
• Some specialists recommend three weekly doses even for early syphilis in HIV patients, though data do not support significant benefit 3

Pregnant Women

• Penicillin is the ONLY proven effective therapy for preventing maternal-fetal transmission 1, 2, 3
• Pregnant women with penicillin allergy MUST undergo desensitization and be treated with penicillin 1, 3
• Alternative agents are not adequately studied in pregnancy and cannot be relied upon to prevent congenital syphilis 3

Pediatric Patients

• For acquired primary or secondary syphilis: benzathine penicillin G 50,000 units/kg IM, up to the adult dose of 2.4 million units as a single dose 1
• Incompletely developed renal function in newborns may delay penicillin elimination, requiring dosage adjustments 5, 6

Follow-Up and Monitoring

Serologic Testing Schedule

• Repeat quantitative nontreponemal tests (RPR or VDRL) at 6,12, and 24 months after treatment 1
• For HIV-infected patients: evaluate at 3,6,9, and 12 months 3
• Expected response: fourfold decline in titer within 6 months for primary/secondary syphilis and within 12-24 months for late syphilis 1, 2

Treatment Failure Criteria

• Failure is defined as persistent/recurring signs or symptoms, OR failure of nontreponemal titers to decline fourfold within 6 months for early syphilis 3
• Sustained fourfold increase in titers also indicates treatment failure 3
• When treatment failure is suspected: re-evaluate for HIV infection and perform CSF examination 2

Re-Treatment Protocol

• Give benzathine penicillin G 2.4 million units IM weekly for 3 weeks 1

Management of Sexual Partners

Exposure Within 90 Days

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

Exposure Beyond 90 Days

• Treat presumptively if serologic results are not immediately available and follow-up is uncertain 2
• Long-term partners of patients with late syphilis should be evaluated clinically and serologically 1

Critical Pitfalls to Avoid

Jarisch-Herxheimer Reaction

• Expect an acute febrile reaction within 24 hours after treatment, especially in early syphilis 2, 3
• Symptoms include fever, headache, myalgia, and may be more pronounced in secondary syphilis 2
• This is NOT an allergic reaction and does not contraindicate future penicillin use 2
• Inform patients in advance about this expected reaction 2

Monitoring Errors

• Never switch between different nontreponemal tests (RPR vs. VDRL) when monitoring treatment response—results cannot be directly compared 2
• Do not rely on treponemal antibody titers (FTA-ABS, TP-PA) to assess treatment response, as they correlate poorly with disease activity and often remain positive for life 2

Dosing Considerations

• Oral penicillin preparations are completely ineffective for syphilis treatment and should never be used 2
• If a weekly dose is missed during the three-dose regimen, an interval of 10-14 days between doses may be acceptable before restarting the sequence 2
• High-dose IV penicillin (>10 million units) must be administered slowly due to potassium content (1.68 mEq per million units) and risk of electrolyte imbalance 6

Penicillin Allergy Assessment

• For patients whose compliance or follow-up cannot be ensured, desensitization and penicillin treatment is preferred over alternative agents 3
• This is particularly critical in pregnancy where alternatives are unproven 3