What is the recommended treatment regimen for syphilis?

Syphilis Treatment Recommendations

The recommended treatment for syphilis is benzathine penicillin G, with the dosage regimen determined by the stage of infection: 2.4 million units IM as a single dose for primary, secondary, and early latent syphilis, or 7.2 million units total (administered as three weekly doses of 2.4 million units IM) for late latent syphilis or latent syphilis of unknown duration. 1

Treatment Regimens by Stage

Early Syphilis (Primary, Secondary, Early Latent < 1 year)

• First-line: Benzathine penicillin G 2.4 million units IM in a single dose 1
• Alternative (for penicillin-allergic patients): Doxycycline 100 mg orally twice daily for 14 days 1, 2

Late Latent Syphilis or Latent Syphilis of Unknown Duration

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

Neurosyphilis

• First-line: Penicillin G aqueous 18-24 million units IV daily, administered as 3-4 million units every 4 hours for 10-14 days 1, 3

Special Populations

Pregnant Women

• Penicillin is the only proven effective treatment for syphilis during pregnancy 1
• Pregnant women with penicillin allergy should undergo desensitization followed by appropriate penicillin therapy 1
• Doxycycline is contraindicated in pregnancy

HIV-Infected Patients

• Same treatment regimens as HIV-negative patients, but with closer follow-up 1
• More frequent clinical and serologic evaluation recommended (at 3,6,9,12, and 24 months)

Follow-up and Monitoring

1. Obtain quantitative non-treponemal test titers (RPR or VDRL) at baseline
2. Follow-up titers at 6,12, and 24 months after treatment 1
3. Successful treatment should show:
   • Fourfold decline in titers within 6 months for primary/secondary syphilis
   • Fourfold decline in titers within 12-24 months for latent/late syphilis 1

Partner Management

• Sexual contacts within 90 days of diagnosis should be treated presumptively, even if seronegative 1
• Contacts from >90 days should be treated presumptively if follow-up is uncertain 1
• Long-term contacts of patients with late latent syphilis should be evaluated clinically and serologically

Important Clinical Considerations

Penicillin Allergy Management

• Patients with documented penicillin allergy should undergo desensitization when possible, as penicillin remains the most effective therapy 1
• While doxycycline is an acceptable alternative for non-pregnant patients, its efficacy is supported by less robust evidence than penicillin 1, 4

Medication Administration Notes

• For benzathine penicillin G, single or divided doses (splitting the 2.4 million units into two 1.2 million unit injections) are equally well-tolerated 5
• When administering IV penicillin G for neurosyphilis, monitor for electrolyte imbalance due to potassium content 3

Potential Pitfalls to Avoid

1. Inadequate follow-up: Failure to monitor serologic response can miss treatment failure 1
2. Incomplete treatment: Missing doses in multi-dose regimens for late syphilis can lead to treatment failure; if a dose is missed, clinical experience suggests that an interval of 10-14 days between doses might be acceptable before restarting the sequence 4
3. Azithromycin resistance: Despite some evidence of efficacy 6, azithromycin is not recommended due to emerging resistance 1
4. Benzathine penicillin G shortages: Recent shortages have been reported 7; have contingency plans ready (doxycycline) if BPG is unavailable

Treatment Challenges

• Approximately 15% of patients may not meet standard criteria for serological cure 12 months after adequate treatment 1
• Recent benzathine penicillin G shortages have complicated treatment in some regions 7
• For patients who fail to achieve a fourfold decline in non-treponemal titers within the expected timeframe, consider CSF examination to rule out neurosyphilis 1, 4