What is the recommended treatment for a chancre caused by primary syphilis, including first‑line therapy, alternatives for penicillin‑allergic patients, and management in pregnancy?

Treatment of Chancre (Primary Syphilis)

A single intramuscular injection of benzathine penicillin G 2.4 million units is the definitive treatment for a chancre caused by primary syphilis. 1

First-Line Therapy

• Benzathine penicillin G 2.4 million units IM as a single dose achieves 90-100% treatment success and represents the gold standard based on over four decades of clinical experience. 1
• This parenteral penicillin regimen is preferred for all stages of syphilis, with the specific preparation and dosage determined by infection stage. 1
• The chancre itself is highly contagious and will resolve even without treatment, but systemic therapy is essential to prevent progression to secondary and late-stage disease. 2

Alternatives for Penicillin-Allergic Non-Pregnant Adults

• Doxycycline 100 mg orally twice daily for 14 days is the preferred alternative when penicillin cannot be used. 1, 3
• Tetracycline 500 mg orally four times daily for 14 days is an established alternative, though gastrointestinal side effects are more common and adherence is generally worse than with doxycycline. 1, 4
• Ceftriaxone 1 gram IM or IV daily for 10-14 days may be considered based on randomized trial data showing comparable efficacy to benzathine penicillin, though clinical experience remains limited. 1
• Azithromycin should NOT be used in the United States due to widespread macrolide resistance and documented treatment failures. 1
• Erythromycin 500 mg orally four times daily for 14 days is less effective than other regimens and should only be considered when compliance with therapy and follow-up can be absolutely ensured. 5, 4

Critical Caveat for Alternative Regimens

• When patient compliance with alternative therapy or follow-up cannot be guaranteed, penicillin desensitization is strongly recommended followed by standard penicillin treatment. 5, 4
• Skin testing for penicillin allergy may help clarify true allergy status before proceeding with desensitization. 5, 4

Management in Pregnancy

• All pregnant patients with penicillin allergy MUST undergo desensitization followed by penicillin treatment—no exceptions. 1
• Penicillin is the only therapy with documented efficacy for preventing maternal transmission to the fetus and treating fetal infection. 1
• Some experts recommend a second dose of benzathine penicillin 2.4 million units IM administered 1 week after the initial dose for pregnant women with primary syphilis. 1
• Tetracycline, doxycycline, erythromycin, azithromycin, and ceftriaxone are inadequate in pregnancy—erythromycin does not reliably cure fetal infection. 1

Jarisch-Herxheimer Reaction in Pregnancy

• Women treated during the second half of pregnancy are at risk for premature labor and/or fetal distress from the Jarisch-Herxheimer reaction, an acute febrile response occurring within 24 hours after therapy. 1
• Pregnant patients should seek immediate medical attention if they notice contractions or changes in fetal movements after treatment. 1

Follow-Up Protocol

• Quantitative nontreponemal serologic tests (RPR or VDRL) should be performed at 6 and 12 months after treatment for primary syphilis. 1
• A fourfold decline in nontreponemal test titers within 6 months indicates successful treatment. 1, 3
• Treatment failure is defined as failure of nontreponemal test titers to decline fourfold within 6 months, persistent or recurring signs/symptoms, or a sustained fourfold increase in titers. 1

Management of Treatment Failure

• Patients with suspected treatment failure should be re-evaluated for HIV infection and undergo CSF examination unless reinfection is likely. 1
• Re-treatment typically involves three weekly injections of benzathine penicillin G 2.4 million units IM, unless CSF examination indicates neurosyphilis. 1

Management of Sexual Partners

• Presumptive treatment of sexual partners is indicated if exposure occurred within 90 days before the diagnosis of primary syphilis, even when the partner's serology is negative. 1
• The time window for presumptive treatment is 3 months plus the duration of symptoms for primary syphilis. 1
• Partners exposed more than 90 days prior should be treated presumptively when serologic results are unavailable and reliable follow-up cannot be ensured. 1

Essential Concurrent Testing

• All individuals diagnosed with syphilis should be tested for HIV at the time of diagnosis. 1
• In regions with high HIV prevalence, patients with primary syphilis should be retested for HIV three months after the initial test. 1
• Nucleic-acid amplification testing for gonorrhea and chlamydia should be obtained when co-infection testing has not been performed. 1

Common Pitfalls to Avoid

• Do not use oral penicillin preparations for syphilis treatment as they are ineffective. 1
• Do not use single-dose ceftriaxone—it is not effective for treating syphilis and requires a full 8-10 day course. 1, 4
• Do not switch between different nontreponemal testing methods (e.g., VDRL and RPR) when monitoring serologic response, as results cannot be directly compared. 1
• Do not assume new genital lesions represent treatment failure without appropriate serologic confirmation at the required 6-month time interval. 1
• Do not retreat a patient for syphilis unless there is documented serologic failure (persistent or rising titers) or confirmed reinfection. 1