Treatment of Syphilis
Benzathine penicillin G is the recommended first-line treatment for all stages of syphilis, with dosing regimens varying based on the stage of infection. 1
Treatment Recommendations by Stage
Early Syphilis (Primary, Secondary, and Early Latent)
- Recommended treatment: Benzathine penicillin G 2.4 million units IM in a single dose 1
- This regimen has demonstrated 90-100% treatment success rates 2
Late Latent Syphilis or Latent Syphilis of Unknown Duration
- Recommended treatment: Benzathine penicillin G 7.2 million units total, administered as 3 doses of 2.4 million units IM at 1-week intervals 1
- For children: 50,000 units/kg IM (up to adult dose of 2.4 million units) as three weekly doses 1
Neurosyphilis
- Recommended treatment: Penicillin G aqueous 18-24 million units IV daily, administered as 3-4 million units every 4 hours for 10-14 days 1
- Careful administration is required due to potential electrolyte imbalances from the potassium content in high doses (above 10 million units) 3
Alternative Treatments for Penicillin-Allergic Patients (Non-Pregnant)
For patients with penicillin allergy and no evidence of neurosyphilis:
- Doxycycline: 100 mg orally twice daily for 14 days (early syphilis) or 28 days (late latent syphilis) 1
- Ceftriaxone: 1 g IV/IM daily for 10 days 1
- Tetracycline: 500 mg orally four times daily for 14 days (early) or 28 days (late) 1
Doxycycline is preferred over tetracycline due to better compliance and fewer gastrointestinal side effects 1
Special Considerations
Pregnant Women
- Only penicillin has been proven effective for treating syphilis during pregnancy 1
- If allergic to penicillin, desensitization is required before treatment 1, 4
- Missed doses are never acceptable in pregnancy; the full course must be repeated if any dose is missed 1
HIV-Infected Patients
- Same treatment regimens as HIV-negative patients, but with closer follow-up 1
- There is no proven benefit to enhanced antimicrobial therapy for HIV-infected persons with syphilis 5
Missed Doses
- For non-pregnant patients, an interval of 10-14 days between doses might be acceptable before restarting the sequence 1
- Pharmacologic considerations suggest that an interval of 7-9 days between doses may be more optimal 5
Monitoring and Follow-up
CSF examination is recommended before treatment if any of the following are present:
- Neurologic or ophthalmic signs/symptoms
- Evidence of active tertiary syphilis
- Treatment failure
- HIV infection with late latent syphilis or syphilis of unknown duration
- Nontreponemal serologic test titers >1:32 1
Serologic monitoring:
- Quantitative nontreponemal tests (RPR or VDRL) should be repeated at 6,12, and 24 months 1
- Treatment success is indicated by a fourfold decline in titers within 12-24 months 1
- Response should be evident by 6 months in early syphilis but is generally slower (12-24 months) for latent syphilis 2
- Approximately 15% of patients may not meet standard criteria for serological cure 12 months after adequate treatment ("serofast state") 1, 2
Partner Management
- All sexual partners should be evaluated clinically and serologically for syphilis 1
- Partners exposed within 90 days of diagnosis should be treated presumptively even if seronegative 1
- Partners exposed >90 days before diagnosis should be treated based on clinical and serological evaluation 1
Common Pitfalls and Caveats
- Jarisch-Herxheimer reaction: A self-limited reaction that can occur within 24 hours of treatment, particularly in early syphilis
- Serofast state: Persistent low-level positive nontreponemal tests despite adequate treatment
- Treatment failure vs. reinfection: Important to distinguish between the two when titers fail to decline appropriately
- Drug interactions: Bacteriostatic antibiotics (chloramphenicol, erythromycins, sulfonamides, tetracyclines) may antagonize the bactericidal effect of penicillin 3, 6
- Laboratory interference: Penicillin G may cause false-positive reactions for glucose in urine with certain tests and pseudoproteinuria 3, 6