What are the stages of syphilis and their corresponding treatments?

Syphilis Staging and Treatment

Syphilis progresses through distinct stages (primary, secondary, latent, and tertiary), each requiring specific treatment regimens based on benzathine penicillin G as the first-line therapy for all stages. 1

Stages of Syphilis and Corresponding Treatments

Primary Syphilis

• Clinical presentation: Solitary, painless chancre at site of infection
• Diagnosis: Dark-field microscopy or direct fluorescent antibody tests of lesion exudate; serologic testing (nontreponemal and treponemal tests)
• Treatment:
  • Recommended: Benzathine penicillin G, 2.4 million units IM in a single dose 1
  • Alternative (for non-pregnant, penicillin-allergic patients): Doxycycline 100 mg orally twice daily for 14 days 2

Secondary Syphilis

• Clinical presentation: Disseminated skin eruptions, mucocutaneous lesions, generalized lymphadenopathy, fever
• Diagnosis: Same as primary syphilis
• Treatment:
  • Recommended: Benzathine penicillin G, 2.4 million units IM in a single dose 1
  • Alternative: Same as for primary syphilis

Latent Syphilis

• Early latent (acquired within preceding year):

  • Treatment: Benzathine penicillin G, 2.4 million units IM in a single dose 1
  • Alternative: Doxycycline 100 mg orally twice daily for 14 days 2

• Late latent (>1 year or unknown duration):

  • Treatment: Benzathine penicillin G, 7.2 million units total, administered as 3 doses of 2.4 million units IM each at 1-week intervals 1
  • Alternative: Doxycycline 100 mg orally twice daily for 28 days 1, 2

Tertiary Syphilis

• Clinical presentation: Gummatous disease, cardiovascular syphilis (not including neurosyphilis)
• Treatment:
  • Recommended: Benzathine penicillin G, 7.2 million units total, administered as 3 doses of 2.4 million units IM each at 1-week intervals 1
  • CSF examination should be performed before initiating therapy 1

Neurosyphilis (can occur at any stage)

• Clinical presentation: Cognitive dysfunction, motor/sensory deficits, ophthalmic/auditory symptoms, cranial nerve palsies, meningitis
• Treatment:
  • Recommended: Aqueous crystalline penicillin G 18–24 million units per day, administered as 3–4 million units IV every 4 hours or continuous infusion, for 10–14 days 1
  • Alternative: Procaine penicillin 2.4 million units IM once daily PLUS probenecid 500 mg orally four times a day, both for 10–14 days 1

Special Considerations

HIV Co-infection

• HIV-infected patients with early syphilis may be at increased risk for neurologic complications and treatment failure 1
• CSF examination before therapy may be recommended by some experts 1
• For latent syphilis in HIV-infected patients, CSF examination is recommended before treatment 1
• Treatment: Benzathine penicillin G 7.2 million units (as 3 weekly doses of 2.4 million units) if CSF examination is normal 1

Pregnancy

• Penicillin is the only proven effective treatment during pregnancy 1, 3
• Pregnant women allergic to penicillin should be desensitized and then treated with penicillin 1

Follow-up

• Primary and Secondary Syphilis: Clinical and serologic evaluation at 3 and 6 months 1
• Latent Syphilis: Quantitative nontreponemal tests at 6,12, and 24 months 1
• Treatment failure is indicated by:
  • Persistent or recurring signs/symptoms
  • Sustained fourfold increase in nontreponemal test titer
  • Failure of initially high titers (≥1:32) to decline fourfold within 12-24 months 1

Common Pitfalls to Avoid

1. Inadequate serologic testing: Always use both nontreponemal (VDRL, RPR) and treponemal-specific tests (FTA-ABS, MHA-TP) for diagnosis 1

2. Missing neurosyphilis: Consider CSF examination in patients with neurologic, ophthalmic, or auditory symptoms regardless of syphilis stage 1

3. Improper follow-up: Failure to monitor serologic response can miss treatment failures; quantitative nontreponemal tests should show a fourfold decline in titer within appropriate timeframes 1

4. Using macrolides empirically: Emergence of macrolide-resistant T. pallidum has limited the use of azithromycin as a second-line treatment 4

5. Inadequate treatment of partners: Sexual contacts within appropriate time periods should be evaluated and treated presumptively 1

The most recent evidence confirms that benzathine penicillin G remains the cornerstone of syphilis treatment across all stages, with specific dosing regimens based on disease stage and duration 5.