What are the next steps for a patient with suspected syphilis (sexually transmitted infection) treatment failure?

Management of Suspected Syphilis Treatment Failure

For patients with suspected syphilis treatment failure, perform a thorough evaluation including HIV testing, CSF examination (unless reinfection is certain), and re-treatment with three weekly injections of benzathine penicillin G 2.4 million units IM. 1

Defining Treatment Failure

Treatment failure in syphilis can be identified by:

• Persistence or recurrence of clinical signs and symptoms after appropriate treatment 1
• Sustained fourfold increase in nontreponemal test titer compared to baseline or subsequent results 1
• Failure of nontreponemal test titers to decline fourfold within 6 months after therapy for primary or secondary syphilis 1

Evaluation Algorithm for Suspected Treatment Failure

1. Rule out reinfection

   • Detailed sexual history to determine possibility of reexposure 1
   • If reinfection is certain, standard treatment for the appropriate stage can be administered 1

2. HIV testing

   • All patients with suspected treatment failure should be evaluated or re-evaluated for HIV infection 1
   • HIV-infected patients may have slower serologic responses and require more frequent monitoring 1

3. CSF examination

   • Unless reinfection is certain, perform lumbar puncture to evaluate for neurosyphilis 1
   • Look for CSF abnormalities including elevated protein, pleocytosis, or positive VDRL test 1

4. Serologic monitoring

   • A recent clinical trial showed that 15% of patients with early syphilis treated with recommended therapy will not achieve the expected two-dilution decline in nontreponemal titer at 1 year 1
   • More frequent serologic testing (every 3 months) is recommended for HIV-infected patients 1

Re-treatment Recommendations

Standard re-treatment regimen:

• Three weekly injections of benzathine penicillin G 2.4 million units IM 1
• This regimen should be used unless CSF examination indicates neurosyphilis is present 1

For neurosyphilis:

• If CSF examination confirms neurosyphilis, treat according to neurosyphilis protocols 1
• This typically involves aqueous crystalline penicillin G or procaine penicillin with probenecid 2

For penicillin-allergic patients:

• Desensitization and treatment with penicillin is preferred, especially if:

  • Patient is pregnant 1
  • Patient has neurosyphilis 1
  • Patient's compliance with therapy or follow-up cannot be assured 1

• Alternative regimens for non-pregnant patients without neurosyphilis:

  • Doxycycline 100 mg orally twice daily for 2 weeks 1
  • Tetracycline 500 mg orally four times daily for 2 weeks 1
  • Ceftriaxone 1g daily IM or IV for 8-10 days (limited data) 1

Follow-Up After Re-treatment

• Clinical and serologic follow-up at 3-month intervals 1
• HIV-infected patients should be evaluated more frequently (every 3 months instead of every 6 months) 1
• In rare instances, serologic titers may not decline despite appropriate therapy and negative CSF examination 1
• Additional therapy or repeated CSF examinations are not warranted in these circumstances 1

Important Considerations

• Treatment failure is difficult to distinguish from reinfection 1, 3
• Recent research suggests that penicillin resistance-related gene mutations of Treponema pallidum may be associated with treatment failure in 10-20% of patients with early syphilis 3
• Enhanced therapy with additional antibiotics (e.g., amoxicillin and probenecid) has not been shown to improve outcomes compared to standard benzathine penicillin G therapy, even in HIV-infected patients 4
• Management of sex partners should be addressed according to standard guidelines for syphilis 1