What is the treatment for primary syphilis (Treponema pallidum infection) in a patient with an indurated painless sore on the penis?

Treatment for Primary Syphilis in a 23-Year-Old Male

Treat this patient with a single intramuscular injection of benzathine penicillin G 2.4 million units immediately. This is the definitive treatment for primary syphilis confirmed by darkfield microscopy, supported by over 40 years of clinical experience and recent high-quality randomized controlled trials 1, 2.

Primary Treatment Regimen

• Benzathine penicillin G 2.4 million units IM as a single dose is the standard of care for primary syphilis 1.
• A recent 2025 multicenter randomized controlled trial (N=249) demonstrated that a single dose was noninferior to three weekly doses, with 76% achieving serologic response at 6 months in both groups 2.
• This single-dose regimen has been validated across multiple CDC guidelines spanning decades and remains the gold standard 1.

Essential Concurrent Testing

• Test for HIV infection immediately - all patients with syphilis must be screened for HIV, as coinfection affects monitoring frequency and may increase risk for neurologic complications 1, 3.
• If HIV-positive, the same single-dose treatment is still recommended, but follow-up intervals change from 6-month to 3-month intervals 1, 3.

Alternative Treatment (Penicillin Allergy Only)

If the patient has a documented penicillin allergy:

• Doxycycline 100 mg orally twice daily for 14 days is the preferred alternative 1, 4.
• Tetracycline 500 mg orally four times daily for 14 days is an option, but compliance is typically worse due to gastrointestinal side effects 1.
• Critical caveat: These alternatives have limited supporting data compared to penicillin, and close follow-up is essential 1.
• If compliance cannot be ensured, the patient should undergo penicillin desensitization and receive benzathine penicillin 1.

Follow-Up Protocol

• Clinical and serologic evaluation at 6 and 12 months after treatment using nontreponemal tests (RPR or VDRL) 1, 3.
• A successful response is defined as a fourfold decline in nontreponemal titer (equivalent to a two-dilution decrease) within 6-12 months 1, 3.
• If HIV-positive, evaluate at 3,6,9, and 12 months instead 1, 3.
• Use the same testing method (RPR or VDRL) at the same laboratory for all follow-up tests to ensure accurate comparison 3.

Treatment Failure Criteria

Treatment failure should be suspected if:

• Nontreponemal titers fail to decline fourfold within 6 months after therapy 1.
• Clinical signs or symptoms persist or recur 1.
• A sustained fourfold increase in titer occurs compared to baseline 1.

If treatment failure occurs:

• Re-evaluate for HIV infection 1.
• Consider CSF examination to exclude neurosyphilis 1.
• Re-treat with benzathine penicillin G 2.4 million units IM weekly for 3 weeks unless neurosyphilis is confirmed 1.

Partner Management

• All sexual contacts from the past 3 months (for primary syphilis) should be evaluated and treated presumptively 1.
• Partners should receive the same treatment regimen even if asymptomatic 1.

Common Pitfalls to Avoid

• Do not use treponemal tests (FTA-ABS, TP-PA) to monitor treatment response - these remain positive for life and do not correlate with disease activity 3.
• Do not compare titers between different test types (VDRL vs RPR) - they are not directly comparable 3.
• Do not assume persistent low-titer reactivity indicates treatment failure - approximately 15-25% of patients remain "serofast" with low unchanging titers despite cure 1, 3.
• Do not perform routine lumbar puncture in primary syphilis without neurologic or ophthalmic symptoms - CSF invasion is common but rarely leads to neurosyphilis with appropriate treatment 1.