Treatment of Early Primary Syphilis
The most appropriate treatment is benzathine penicillin 2.4 million units intramuscular injection as a single dose (Option A). This patient has primary syphilis confirmed by dark-field microscopy showing Treponema pallidum, with exposure occurring 7 days prior and symptom onset 2 days ago, clearly placing him in the early primary syphilis category.
Rationale for Single-Dose Benzathine Penicillin
Benzathine penicillin G 2.4 million units IM as a single dose is the CDC-recommended first-line treatment for primary, secondary, and early latent syphilis 1, 2.
This regimen is supported by over 50 years of clinical experience with treatment success rates of 90-100% in early syphilis 3.
A recent 2025 randomized controlled trial definitively demonstrated that one dose of 2.4 million units was noninferior to three weekly doses, with 76% achieving serologic response at 6 months in both groups, and importantly, no clinical relapses or treatment failures occurred in either arm 4.
Long-acting benzathine penicillin preparations remain the treatment of choice for all stages of syphilis, with primary, secondary, and early latent syphilis effectively treated with a single dose 1.
Why Not Three Doses?
Three weekly doses (Option B) are reserved for late latent syphilis, latent syphilis of unknown duration, or tertiary syphilis 1, 2.
This patient's exposure was only 7 days ago with a 2-day history of symptoms—this is definitively early primary syphilis, not late-stage disease 1.
Multiple studies, including a 2017 trial in HIV-infected patients, showed no benefit of three doses over single-dose therapy for early syphilis, with success rates of 93% versus 100% respectively (not statistically significant) 5.
Why Not Doxycycline?
Doxycycline is only recommended for penicillin-allergic patients 1, 6, 2.
There is no indication this patient has a penicillin allergy, making doxycycline inappropriate as first-line therapy 1.
For penicillin-allergic patients with primary/secondary syphilis, the alternative would be doxycycline 100mg orally twice daily for 14 days (Option C), not 21 days 1, 6, 7.
The 21-day duration (Option D) is not a standard CDC-recommended regimen for any stage of syphilis 6, 7.
Doxycycline 100mg twice daily for 28 days (not 21 days) is reserved for late latent syphilis or syphilis of unknown duration in penicillin-allergic patients 1, 6.
Critical Clinical Considerations
Counsel the patient about Jarisch-Herxheimer reaction, which occurs in the first 24 hours after treatment and is most common in early syphilis, presenting with fever, headache, and myalgia 1, 2.
Follow-up with quantitative nontreponemal tests (RPR or VDRL) at 6 and 12 months to confirm treatment success, defined as a fourfold (two-dilution) decline in titers 1, 2.
Evaluate and presumptively treat sexual partners exposed within 90 days of diagnosis, even if seronegative, as they may be in the incubation period 1, 2.
Test for HIV infection, as syphilis and HIV coinfection is common, though treatment regimens remain the same 1, 2, 5.
Common Pitfalls to Avoid
Do not over-treat early syphilis with three doses when one dose is sufficient and equally effective 4.
Do not use oral penicillin preparations—they are ineffective for syphilis treatment 1.
Do not use doxycycline as first-line therapy when penicillin is available and the patient has no allergy 1, 2.
Do not confuse the 14-day doxycycline regimen for early syphilis with the 28-day regimen for late latent disease 6, 7.