What is the recommended treatment for syphilis?

Syphilis Treatment Guidelines

The recommended first-line treatment for syphilis is parenteral penicillin G, with the specific preparation, dosage, and duration determined by the stage of infection. 1

Treatment by Stage of Infection

Primary and Secondary Syphilis

• For adults with primary or secondary syphilis, the recommended regimen is benzathine penicillin G, 2.4 million units IM in a single dose 1, 2
• For children with acquired primary or secondary syphilis, the recommended regimen is benzathine penicillin G, 50,000 units/kg IM, up to the adult dose of 2.4 million units in a single dose 2

Early Latent Syphilis

• Early latent syphilis (acquired within the preceding year) should be treated with benzathine penicillin G, 2.4 million units IM in a single dose 1
• Early latent syphilis is defined based on documented seroconversion, fourfold increase in titer, history of symptoms, or having a sex partner with documented early syphilis 1

Late Latent Syphilis or Latent Syphilis of Unknown Duration

• The recommended regimen is benzathine penicillin G, 7.2 million units total, administered as 3 doses of 2.4 million units IM each at 1-week intervals 1, 2
• This extended regimen is necessary to ensure adequate treatment of potentially longer-standing infection 2

Tertiary Syphilis

• Treatment consists of benzathine penicillin G, 7.2 million units total, administered as 3 doses of 2.4 million units IM each at 1-week intervals 1, 2

Neurosyphilis

• Aqueous crystalline penicillin G is recommended for neurosyphilis treatment 1
• The regimen is 18-24 million units a day, administered as 3-4 million units IV every 4 hours for 10-14 days 3
• CSF examination is recommended for diagnosing neurosyphilis in patients with neurological signs/symptoms, tertiary syphilis, or those whose serological titers fail to decline appropriately 1

Alternative Treatments for Penicillin-Allergic Patients

• For non-pregnant adults with primary and secondary syphilis who are allergic to penicillin, doxycycline 100 mg orally twice daily for 14 days is recommended 1, 2
• For late latent syphilis or latent syphilis of unknown duration, doxycycline 100 mg orally twice daily for 28 days is the alternative treatment 1, 2
• For pregnant women and neurosyphilis patients, penicillin remains the only proven effective therapy, and patients should undergo desensitization if they report penicillin allergy 1, 2

Special Populations

HIV-Infected Patients

• HIV-infected patients receive 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
• All patients with syphilis should be tested for HIV 3

Pregnant Women

• Parenteral penicillin G is the only therapy with documented efficacy for preventing maternal transmission 1, 2
• Pregnant women with penicillin allergy should undergo desensitization and be treated with penicillin 2

Follow-Up and Monitoring

• Quantitative nontreponemal serologic tests should be repeated at regular intervals (3,6,12, and 24 months) 1, 2
• A fourfold decline in titer is expected within 6 months for primary/secondary syphilis and within 12-24 months for late syphilis 1, 2
• Treatment failure is defined as failure of nontreponemal test titers to decline fourfold within 6 months after therapy for primary or secondary syphilis 1, 3
• If treatment failure is suspected, patients should be re-evaluated for HIV infection and undergo CSF examination 4

Management of Sex Partners

• Persons exposed within 90 days preceding the diagnosis of primary, secondary, or early latent syphilis should be treated presumptively even if seronegative 1, 2
• Persons exposed >90 days before diagnosis should be treated presumptively if serologic test results are not immediately available and follow-up is uncertain 1, 2
• Long-term sex partners of patients with late syphilis should be evaluated clinically and serologically for syphilis 2

Important Clinical Considerations and Pitfalls

• Do not use oral penicillin preparations for syphilis treatment as they are ineffective 1
• The Jarisch-Herxheimer reaction is an acute febrile reaction that may occur within 24 hours after any syphilis therapy, especially in early syphilis 1
• Bacteriostatic antibacterials (chloramphenicol, erythromycins, sulfonamides, tetracyclines) may antagonize the bactericidal effect of penicillin, and concurrent use should be avoided 5
• Do not rely solely on treponemal test antibody titers to assess treatment response, as they correlate poorly with disease activity 1
• Do not use different testing methods (e.g., switching between VDRL and RPR) when monitoring serologic response, as results cannot be directly compared 1
• Recent studies have reported treatment failures in 10-20% of patients with early syphilis, potentially related to penicillin resistance-related gene mutations of Treponema pallidum 6
• Benzathine penicillin G shortages have been reported, which may necessitate the use of alternative treatments in some cases 7