What is the recommended treatment for syphilis?

Recommended Treatment for Syphilis

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 each for late latent, latent of unknown duration, and tertiary syphilis. 1, 2, 3

Primary and Secondary Syphilis

• Administer benzathine penicillin G 2.4 million units IM as a single injection for all patients with primary or secondary syphilis, regardless of HIV status 1, 2, 3
• This single-dose regimen is equally effective in HIV-infected patients—recent randomized trial data show no benefit to multiple doses over single-dose therapy in terms of serologic outcomes 4, 5
• Some specialists historically recommended three weekly doses for HIV-infected patients, but this approach lacks evidence of improved efficacy and is not necessary 4

Early Latent Syphilis

• Use the same single-dose regimen as primary/secondary syphilis: benzathine penicillin G 2.4 million units IM once 1, 2
• 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 and Tertiary Syphilis

• Administer benzathine penicillin G 7.2 million units total: three doses of 2.4 million units IM given at weekly intervals 1, 2
• This regimen applies to late latent syphilis (>1 year duration), latent syphilis of unknown duration, and tertiary syphilis 1, 2
• Before initiating treatment, perform CSF examination if neurological signs/symptoms are present, if serological titers fail to decline appropriately, or in tertiary syphilis to exclude neurosyphilis 2

Neurosyphilis

• Treat with 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 for diagnosis in patients with neurological manifestations, tertiary syphilis, or treatment failure 2
• HIV infection itself can cause mild CSF pleocytosis (5-15 cells/µL), making neurosyphilis diagnosis more challenging; if neurosyphilis cannot be excluded, treat as neurosyphilis 4

Alternative Regimens for Penicillin-Allergic Patients

Non-Pregnant Adults

• For primary and secondary syphilis: doxycycline 100 mg orally twice daily for 14 days 1, 3
• For late latent syphilis: doxycycline 100 mg orally twice daily for 28 days 1, 2
• Tetracycline 500 mg orally four times daily (14 days for early syphilis, 28 days for late latent) is an alternative, though compliance is better with doxycycline due to less frequent dosing 3
• Ceftriaxone 1 g daily (IM or IV) for 10 days is a reasonable alternative for early syphilis based on randomized trial data showing comparable efficacy to benzathine penicillin 4, 3
• Do NOT use azithromycin in the United States—despite some evidence of efficacy with a single 2-gram oral dose, widespread macrolide resistance in Treponema pallidum and documented treatment failures make this unacceptable 4, 3

Pregnant Patients

• All pregnant women with penicillin allergy MUST undergo desensitization followed by penicillin treatment 1, 2, 3
• Penicillin is the only therapy proven effective for preventing maternal transmission and congenital syphilis 1, 2
• Alternative regimens are inadequate and should never be substituted in pregnancy 2
• Screen all pregnant women for syphilis at first prenatal visit, during third trimester, and at delivery 2

Special Populations

HIV-Infected Patients

• Use identical treatment regimens as HIV-negative patients for all stages of syphilis 1, 2, 3
• HIV-infected patients generally respond well to standard benzathine penicillin therapy 2
• Implement closer follow-up: evaluate clinically and serologically every 3 months (rather than every 6 months) to detect potential treatment failure or disease progression 4, 3
• Screen sexually active HIV-infected persons for syphilis at least annually, with more frequent screening (every 3-6 months) for those with multiple partners, unprotected intercourse, or methamphetamine use 4

Pediatric Patients

• For children with 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
• Monitor all newborns treated with penicillins closely for clinical and laboratory evidence of toxic or adverse effects due to incompletely developed renal function 6

Follow-Up and Monitoring

• Perform quantitative nontreponemal serologic tests (RPR or VDRL) at 6,12, and 24 months after treatment 1, 3
• HIV-infected patients require more frequent monitoring at 3,6,9,12, and 24 months 3
• Expect a fourfold (2-dilution) decline in titer within 6 months for primary/secondary syphilis and within 12-24 months for late syphilis 1, 2
• Do not switch between different nontreponemal test methods (RPR vs. VDRL) when monitoring response, as results cannot be directly compared 2

Defining Treatment Failure

• Treatment failure occurs when nontreponemal test titers fail to decline fourfold within 6 months after therapy for primary or secondary syphilis, or when titers increase fourfold at any time 1, 2
• If treatment failure is suspected: re-evaluate for HIV infection, perform CSF examination to exclude neurosyphilis, and re-treat with weekly injections of benzathine penicillin G 2.4 million units IM for 3 weeks 1, 2

Management of Sexual Partners

• Treat persons exposed within 90 days preceding diagnosis of primary, secondary, or early latent syphilis presumptively, even if seronegative 1, 2
• Persons exposed >90 days before diagnosis should be treated presumptively if serologic results are not immediately available and follow-up is uncertain 2
• Long-term sexual 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
• Do not rely on treponemal test antibody titers (e.g., FTA-ABS, TP-PA) to assess treatment response, as they correlate poorly with disease activity and typically remain positive for life 2
• Be aware of the Jarisch-Herxheimer reaction: an acute febrile reaction with headache, myalgia, and other symptoms that may occur within 24 hours after any syphilis therapy, especially in early syphilis 2, 3
• In pregnant women, Jarisch-Herxheimer reaction during the second half of pregnancy may precipitate premature labor or fetal distress; counsel women to seek immediate medical attention if they notice changes in fetal movements or contractions after treatment 2
• If a dose is missed during weekly therapy for late latent syphilis, an interval of 10-14 days between doses might be acceptable before restarting the sequence 2
• Patients with histories of significant allergies or asthma should use penicillin with caution; consider desensitization if penicillin is essential 6
• When administering high-dose intravenous penicillin G (>10 million units), administer slowly due to potential electrolyte imbalance from potassium content (1.7 mEq potassium per million units) 6

Additional Considerations

• All patients treated for gonococcal infection should have serologic testing for syphilis before receiving penicillin 6
• All cases of penicillin-treated syphilis require adequate follow-up including clinical and serological examinations, with follow-up intervals varying by stage of syphilis 6
• Probenecid blocks renal tubular secretion of penicillins and may prolong penicillin blood levels; other drugs that compete for renal tubular secretion include aspirin, phenylbutazone, sulfonamides, indomethacin, thiazide diuretics, furosemide, and ethacrynic acid 6
• False-positive glucose reactions in urine may occur with Benedict's solution, Fehling's solution, or Clinitest tablets after penicillin G treatment, but not with enzyme-based tests like Clinistix 6