What is the recommended treatment for syphilis?

Treatment for Syphilis

Benzathine penicillin G is the preferred treatment for all stages of syphilis, with dosing and duration determined by the stage of infection. 1, 2

Primary and Secondary Syphilis

Administer benzathine penicillin G 2.4 million units intramuscularly as a single dose. 1, 2, 3

• This single injection is highly effective for early-stage disease and remains the gold standard treatment 1
• Expect a fourfold decline in nontreponemal titers within 6 months 1, 2
• For children with acquired primary or secondary syphilis, dose is 50,000 units/kg IM (up to adult dose of 2.4 million units) 1

Early Latent Syphilis

Use the same regimen as primary/secondary syphilis: benzathine penicillin G 2.4 million units IM as a single dose. 1, 2

• Early latent is defined as infection acquired within the preceding year, documented by seroconversion, fourfold titer increase, recent symptoms, or partner with documented early syphilis 2

Late Latent Syphilis and Latent Syphilis of Unknown Duration

Administer benzathine penicillin G 7.2 million units total, given as three doses of 2.4 million units IM at weekly intervals. 1, 2

• This extended regimen is necessary due to longer infection duration 1
• Expect a fourfold decline in titers within 12-24 months 1, 2
• If a dose is missed, an interval of 10-14 days between doses may be acceptable before restarting the sequence, though 7-9 days is more optimal 4
• Missed doses are NOT acceptable for pregnant women 4

Tertiary Syphilis

Before treating tertiary syphilis, perform CSF examination to exclude neurosyphilis. 5

• If neurosyphilis is ruled out, treat with benzathine penicillin G 7.2 million units total (three weekly doses of 2.4 million units IM) 5
• If neurosyphilis is present, the treatment changes entirely to aqueous crystalline penicillin G 18-24 million units IV daily for 10-14 days 2, 5
• The tertiary syphilis regimen is inadequate for CNS involvement 5
• Some specialists treat all cardiovascular syphilis cases with neurosyphilis regimens due to concern for CNS involvement 5

Neurosyphilis

Administer aqueous crystalline penicillin G 18-24 million units per day IV (given as 3-4 million units every 4 hours or continuous infusion) for 10-14 days. 2

• An alternative is procaine penicillin G with probenecid, though procaine penicillin without probenecid does not achieve adequate CSF levels 2
• CSF examination is indicated for patients with neurologic/ophthalmic symptoms, tertiary syphilis, treatment failure, HIV with late latent syphilis, or nontreponemal titer ≥1:32 2

Penicillin-Allergic Patients (Non-Pregnant)

For primary, secondary, or early latent syphilis: doxycycline 100 mg orally twice daily for 14 days. 1, 2

For late latent syphilis or latent syphilis of unknown duration: doxycycline 100 mg orally twice daily for 28 days. 1, 2

• Tetracycline 500 mg orally four times daily is an alternative (14 days for early, 28 days for late) 2
• Ceftriaxone 1 gram IM/IV daily for 10-14 days may be considered based on randomized trial data showing comparable efficacy to benzathine penicillin 2, 4
• However, ceftriaxone has limited data for late latent and tertiary syphilis, and patients with severe penicillin allergy may also react to ceftriaxone 2
• Do NOT use azithromycin in the United States due to widespread macrolide resistance and documented treatment failures 2, 4

Special Populations

Pregnant Women

All pregnant women with penicillin allergy MUST undergo desensitization followed by penicillin treatment—no exceptions. 1, 2, 5

• Penicillin is the only therapy proven effective for preventing maternal transmission and treating fetal infection 2, 5
• Some experts recommend a second dose of benzathine penicillin 2.4 million units IM one week after the initial dose for primary, secondary, or early latent syphilis in pregnancy 2
• Screen all pregnant women at first prenatal visit, during third trimester, and at delivery 2
• Jarisch-Herxheimer reaction during the second half of pregnancy may precipitate premature labor or fetal distress 2
• Women should seek immediate medical attention if they notice contractions or changes in fetal movements after treatment 2
• Tetracycline, doxycycline, erythromycin, azithromycin, and ceftriaxone are inadequate—erythromycin does not reliably cure fetal infection 2

HIV-Infected Patients

Use the same penicillin regimens as HIV-negative patients for all stages of syphilis. 1, 2, 5

• HIV-infected patients may have atypical serologic responses but generally respond well to standard treatment 2
• Closer follow-up is mandatory to detect treatment failure or disease progression 2, 5
• Limited data suggest no benefit to multiple doses of benzathine penicillin for early syphilis in HIV-infected patients compared to a single dose 2, 6
• Patients with penicillin allergy should undergo skin testing and desensitization, then be treated with penicillin 2

Pediatric Patients

For children with acquired primary or secondary syphilis: benzathine penicillin G 50,000 units/kg IM (up to adult dose of 2.4 million units) as a single dose. 1, 2

For late latent syphilis: benzathine penicillin G 50,000 units/kg IM for three doses at weekly intervals (total 150,000 units/kg up to 7.2 million units). 2

• Children require CSF examination to exclude neurosyphilis before treatment 2
• Incompletely developed renal function in newborns may delay penicillin elimination; appropriate dose reductions should be made 7, 8

Follow-Up and Monitoring

Repeat quantitative nontreponemal serologic tests (RPR or VDRL) at 6,12, and 24 months. 1, 2, 5

• For primary/secondary syphilis, expect a fourfold decline in titer within 6 months 1, 2
• For late syphilis, expect a fourfold decline within 12-24 months 1, 2
• Perform CSF examination if titers increase fourfold, fail to decline appropriately, or neurological symptoms develop 1, 2
• 15-25% of successfully treated patients remain "serofast" with persistent low titers (<1:8) that do not indicate treatment failure 2

Treatment Failure

Treatment failure is defined as persistent/recurring symptoms, sustained fourfold increase in titers, or failure of titers to decline fourfold within expected timeframes. 1, 2, 5

• Re-evaluate for HIV infection and perform CSF examination 2
• Re-treat with benzathine penicillin G 2.4 million units IM weekly for 3 weeks unless neurosyphilis is diagnosed 2

Management of Sex Partners

Persons exposed within 90 days preceding diagnosis of primary, secondary, or early latent syphilis should be treated presumptively, even if seronegative. 1, 2

• 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 2
• Long-term sex partners of patients with late syphilis should be evaluated clinically and serologically 1

Critical Pitfalls to Avoid

• Never use oral penicillin preparations—they are completely ineffective for syphilis 2, 5
• Do not use different serologic test methods (RPR vs VDRL) when monitoring response, as results cannot be directly compared 2, 5
• Do not rely solely on treponemal test antibody titers to assess treatment response, as they correlate poorly with disease activity 2
• Administer high-dose IV penicillin G (above 10 million units) slowly due to potential electrolyte imbalance from potassium content 7, 8
• Warn patients about Jarisch-Herxheimer reaction, an acute febrile reaction with headache and myalgia that may occur within 24 hours of treatment 2, 5
• All patients with syphilis should be tested for HIV infection 2