What are the recommended treatments for syphilis?

Syphilis Testing and Treatment

Diagnostic Testing

Syphilis diagnosis relies on serologic testing combined with clinical presentation consistent with active or latent infection. 1

• Nontreponemal tests (RPR or VDRL) should be used for initial screening and monitoring treatment response 2
• Treponemal tests confirm the diagnosis but correlate poorly with disease activity and should not be used to assess treatment response 2
• Do not switch between different nontreponemal test methods (e.g., RPR and VDRL) when monitoring serologic response, as results cannot be directly compared 2
• CSF examination is indicated for patients with neurological signs/symptoms, tertiary syphilis, ophthalmic disease, or those whose serologic titers fail to decline appropriately 2, 3
• HIV testing should be performed in all patients diagnosed with syphilis 4
• Dark field microscopy can confirm primary syphilis when mucocutaneous lesions are present 5

Treatment by Stage

Primary and Secondary Syphilis

Benzathine penicillin G 2.4 million units IM as a single dose is the definitive treatment for primary and secondary syphilis. 2, 3, 6

• This regimen has four decades of proven efficacy in achieving local cure, preventing sexual transmission, and preventing late sequelae 4
• For children: Benzathine penicillin G 50,000 units/kg IM (up to adult dose of 2.4 million units) as a single dose 4, 3
• Children should have CSF examination to exclude neurosyphilis and evaluation by child-protection services 4

Early Latent Syphilis

Benzathine penicillin G 2.4 million units IM as a single dose 2, 3

• Early latent syphilis is defined as infection acquired within the preceding year based on documented seroconversion, fourfold increase in titer, history of symptoms, or having a sex partner with documented early syphilis 2

Late Latent Syphilis and Tertiary Syphilis

Benzathine penicillin G 7.2 million units total, administered as 3 doses of 2.4 million units IM at weekly intervals 2, 3, 6

• If a dose is missed, an interval of 10-14 days between doses may be acceptable before restarting the sequence 2
• Late latent syphilis is defined as infection of more than one year duration or unknown duration 6

Neurosyphilis

Aqueous crystalline penicillin G 18-24 million units daily, administered as 3-4 million units IV every 4 hours for 10-14 days 6

• High-dose IV penicillin G (above 10 million units) should be administered slowly due to potential electrolyte imbalance from potassium content 7, 8
• Penicillin G contains approximately 1.68 mEq potassium per million units 7

Alternative Treatments for Penicillin-Allergic Patients

Non-Pregnant Adults

For primary and secondary syphilis: Doxycycline 100 mg orally twice daily for 14 days 2, 3, 6

For late latent syphilis: Doxycycline 100 mg orally twice daily for 28 days 2, 3

• Tetracycline 500 mg orally four times daily is an alternative, though compliance is better with doxycycline due to less frequent dosing 6
• Ceftriaxone 1 g daily (IM or IV) for 8-10 days may be considered, though optimal dosing is not well established 6
• Azithromycin should not be used due to widespread macrolide resistance in T. pallidum in the United States 6

Pregnant Women and Neurosyphilis

Penicillin is the only proven effective therapy for preventing maternal transmission and treating neurosyphilis. 2, 3, 6

• Pregnant women with penicillin allergy must undergo desensitization and be treated with penicillin 2, 3, 6
• Alternative regimens are not adequately studied in pregnancy 6

Special Populations

HIV-Infected Patients

HIV-infected patients should receive the same penicillin regimens as non-HIV-infected patients 2, 3, 6

• HIV-infected patients may have atypical serologic responses but generally respond well to standard treatment 2
• More frequent monitoring is recommended: every 3 months rather than every 6 months 6
• Recent evidence suggests that single-dose BPG plus 7-day doxycycline achieves higher serologic response rates (79.5% vs 70.3%) compared to BPG alone in PWH 9

Pregnant Women

All pregnant patients should be screened for syphilis three times: at the first prenatal visit, during the third trimester, and at delivery 1

• Parenteral penicillin G is the only therapy with documented efficacy for preventing maternal transmission 2, 3
• Up to 40% of fetuses with in-utero exposure to syphilis are stillborn or die from infection during infancy 1

Follow-Up and Monitoring

Quantitative nontreponemal serologic tests should be repeated at 3,6,12, and 24 months after treatment 2, 3

• Expected serologic response: A fourfold decline in titer within 6 months for primary/secondary syphilis and within 12-24 months for late syphilis 2, 3
• Treatment failure is defined as: Failure of nontreponemal test titers to decline fourfold within 6 months after therapy for primary or secondary syphilis 2, 3
• If treatment failure is suspected, patients should be re-evaluated for HIV infection and undergo CSF examination 2
• Serologic tests may decline more slowly in patients who have had previous syphilis infections 6

Management of Sexual Partners

Persons exposed within 90 days preceding diagnosis of primary, secondary, or early latent syphilis should be treated presumptively, even if seronegative 4, 2, 3

• Persons exposed >90 days before diagnosis should be treated presumptively if serologic test results are not immediately available and follow-up is uncertain 4, 2
• Patients with syphilis of unknown duration and high nontreponemal titers (≥1:32) may be considered infected with early syphilis for partner notification purposes 4
• Long-term sex partners of patients with late syphilis should be evaluated clinically and serologically 4, 3

Time periods for identifying at-risk sex partners:

• Primary syphilis: 3 months plus duration of symptoms 4
• Secondary syphilis: 6 months plus duration of symptoms 4
• Early latent syphilis: 1 year 4

Important Clinical Considerations

Jarisch-Herxheimer Reaction

An acute febrile reaction may occur within 24 hours after any syphilis therapy, especially in early syphilis 2, 6

• Symptoms include fever, headache, myalgia, and other constitutional symptoms 2, 6
• Patients should be informed about this possible adverse reaction before treatment 2

Critical Pitfalls to Avoid

• Do not use oral penicillin preparations for syphilis treatment as they are ineffective 2
• Do not rely solely on treponemal test antibody titers to assess treatment response 2
• Avoid bacteriostatic antibiotics (chloramphenicol, erythromycins, sulfonamides, tetracyclines) concurrently with penicillin, as they may antagonize the bactericidal effect 7, 8
• Do not perform routine lumbar puncture for primary or secondary syphilis unless clinical signs or symptoms of neurologic or ophthalmic involvement are present 4
• Be aware that false-positive glucose reactions may occur with Benedict's solution, Fehling's solution, or Clinitest tablets after penicillin G treatment 7, 8

Prevention Strategies

Routine screening of sexually active people aged 15-44 years at least once, and at least annually for those at increased risk 1

• Men who have sex with men (MSM) comprised 32.7% of all males with primary and secondary syphilis in 2023 1
• Doxycycline postexposure prophylaxis: 200 mg doxycycline taken within 72 hours after sex is recommended for MSM and transgender women with a history of sexually transmitted infection in the past year 1
• Counseling about condom use should be provided 1