A patient with primary syphilis received a single intramuscular dose of benzathine penicillin G (Bicillin) and developed a new chancre a few days later; does this indicate treatment failure and what is the appropriate management?

Development of New Chancre After Benzathine Penicillin Treatment

This does not represent treatment failure—the chancre likely reflects the natural evolution of an existing lesion that was incubating at the time of treatment, not inadequate therapy. 1

Understanding the Clinical Timeline

The appearance of a chancre a few days after treatment is expected and does not indicate treatment failure for several key reasons:

• Primary syphilis chancres typically appear 10–90 days (average 21 days) after T. pallidum exposure, meaning the lesion was already developing beneath the skin surface when treatment was administered 1, 2
• Benzathine penicillin G achieves therapeutic treponemicidal levels within hours of injection and maintains them for 2–4 weeks, effectively killing circulating spirochetes and preventing new lesion formation 1
• Existing chancres may take 1–3 weeks to fully resolve after appropriate treatment, even though the infection itself has been adequately treated 1, 2

Appropriate Management

No additional treatment is required at this time. 1 The correct approach is:

Immediate Actions

• Document the new lesion with clinical examination (size, location, characteristics) 1
• Obtain baseline quantitative RPR or VDRL titer if not already done at the time of initial treatment 1, 3
• Confirm HIV status if not previously tested, as HIV co-infection affects monitoring frequency 1, 3
• Reassure the patient that lesion appearance after treatment is common and does not indicate treatment failure 1

Follow-Up Monitoring Schedule

• Repeat quantitative nontreponemal testing (RPR or VDRL) at 6 and 12 months after the initial treatment dose 1, 3
• Treatment success is defined by a ≥4-fold decline in titer (e.g., from 1:32 to 1:8) within 6 months for primary syphilis 1, 3
• If the patient is HIV-positive, perform serologic monitoring at 3,6,9,12, and 24 months instead of the standard 6-month intervals 1, 3

When to Consider True Treatment Failure

True treatment failure is diagnosed serologically, not clinically, and requires months of follow-up. 1 Re-treatment should only be considered if:

• Nontreponemal titers fail to decline ≥4-fold within 6 months after therapy 1, 3
• A sustained 4-fold increase in titers occurs after an initial decline 1, 3
• New clinical manifestations develop months after treatment (not days), such as secondary syphilis rash, neurologic symptoms, or ocular findings 1, 3

If treatment failure is suspected based on these criteria:

• Perform CSF examination to exclude neurosyphilis 1, 3
• Re-evaluate HIV status if not previously tested 1, 3
• Re-treat with benzathine penicillin G 2.4 million units IM weekly for 3 weeks if CSF is normal 1, 3

Critical Pitfalls to Avoid

• Do not retreat based solely on the appearance of a chancre within days of treatment—this represents the natural course of an incubating lesion, not treatment failure 1
• Do not use clinical lesion resolution as the primary marker of treatment success—serologic response (4-fold titer decline) is the gold standard 1, 3
• Do not compare titers between different test methods (RPR vs. VDRL)—use the same method and ideally the same laboratory for all follow-up testing 1, 3
• Do not assume that persistent low-level positive titers (<1:8) after documented 4-fold decline indicate failure—15–25% of patients remain "serofast" indefinitely without requiring additional treatment 1, 3, 4

Special Considerations

• If the patient is pregnant, ensure treatment occurred >4 weeks before delivery for optimal prevention of congenital syphilis 1, 3
• Warn the patient about Jarisch-Herxheimer reaction (fever, headache, myalgia within 24 hours of treatment), which is common in early syphilis but does not indicate treatment failure 1, 3
• Identify and presumptively treat sexual contacts exposed within 90 days before the patient's diagnosis, even if their serology is negative 1, 3