What is the recommended treatment for secondary syphilis?

Treatment of Secondary Syphilis

Benzathine penicillin G 2.4 million units IM in a single dose is the recommended first-line treatment for secondary syphilis. 1, 2

First-Line Treatment

• Adults: Benzathine penicillin G 2.4 million units IM as a single dose 1
• Children: Benzathine penicillin G 50,000 units/kg IM (maximum 2.4 million units) as a single dose 1

Parenteral penicillin G has been the gold standard treatment for syphilis for decades, with extensive clinical experience supporting its efficacy in achieving clinical resolution and preventing late sequelae 1.

Alternative Regimens for Penicillin-Allergic Patients

For non-pregnant patients with documented penicillin allergy:

• Doxycycline: 100 mg orally twice daily for 14 days 1, 3
• Tetracycline: 500 mg orally four times daily for 14 days 1

Doxycycline is preferred over tetracycline due to better compliance with the twice-daily dosing schedule and fewer gastrointestinal side effects 1. The FDA label specifically indicates doxycycline for early syphilis in penicillin-allergic patients at a dose of 100 mg twice daily for 2 weeks 3.

Special Populations

Pregnant Women

• All pregnant women with penicillin allergy should undergo desensitization and then receive penicillin 1, 2
• Doxycycline and tetracycline are contraindicated in pregnancy

HIV-Infected Patients

• Same treatment regimen as HIV-negative patients (benzathine penicillin G 2.4 million units IM) 1
• More frequent clinical and serological follow-up (every 3 months rather than every 6 months) 1

Follow-Up Evaluation

• Clinical and serological evaluation at 6 and 12 months after treatment 1
• Treatment success is defined as:
  • Resolution of clinical symptoms
  • Four-fold (2 dilution) decrease in nontreponemal test titers by 6 months 1

Treatment Failure

Consider treatment failure or reinfection if:

• Clinical signs/symptoms persist or recur
• Sustained four-fold increase in nontreponemal test titer compared to baseline
• Failure of nontreponemal test titers to decline four-fold within 6 months 1

For suspected treatment failure:

1. Re-evaluate for HIV infection
2. Perform CSF examination to rule out neurosyphilis
3. Re-treat with three weekly injections of benzathine penicillin G 2.4 million units IM 1

Emerging Treatments

While azithromycin (2.0 g as a single oral dose) has shown promise in limited studies 4, it is not currently recommended in guidelines due to concerns about resistance and limited long-term efficacy data.

Important Considerations

• Jarisch-Herxheimer reaction: Patients should be warned about this potential reaction within 24 hours after treatment, characterized by fever, headache, myalgia, and worsening of cutaneous lesions 2
• Partner notification: Sexual contacts within 90 days of diagnosis should be treated presumptively even if seronegative 1, 2
• HIV testing: All patients with secondary syphilis should be tested for HIV infection 1

Common Pitfalls

1. Inadequate follow-up: Ensure patients return for serological monitoring at 6 and 12 months
2. Misinterpreting serological response: A four-fold decline in nontreponemal titers by 6 months indicates treatment success
3. Overlooking neurosyphilis: Consider CSF examination in patients with neurological symptoms or persistent high titers despite treatment
4. Benzathine penicillin shortages: Be aware of potential supply issues that may necessitate alternative treatments 5

While some older studies suggested two weekly doses of benzathine penicillin G for secondary syphilis 6, current guidelines consistently recommend a single dose of 2.4 million units IM as sufficient for early syphilis, including secondary syphilis 1, 2.