After a recent exposure (within 90 days) to a partner with primary, secondary, or early latent syphilis, should I begin empiric benzathine penicillin G treatment now or wait for serologic testing, especially if the patient is pregnant, immunocompromised, or symptomatic?

Empiric Treatment for Recent Syphilis Exposure

If a patient was exposed to a partner with primary, secondary, or early latent syphilis within the past 90 days, start benzathine penicillin G 2.4 million units IM immediately—do not wait for serologic test results, even if the patient is seronegative. 1

Treatment Algorithm Based on Exposure Timing

Exposure ≤90 Days: Immediate Presumptive Treatment

• Administer benzathine penicillin G 2.4 million units IM as a single dose immediately, regardless of serologic test results. 1, 2
• This recommendation applies even when initial RPR/VDRL tests are negative, because early infection may not yet produce detectable antibodies. 1, 3
• The rationale is that persons exposed within 90 days might be infected but seronegative during the window period, and early treatment prevents progression to symptomatic disease. 1, 2

Exposure >90 Days: Conditional Approach

• If serologic results are unavailable immediately AND follow-up is uncertain, treat presumptively with the same single-dose benzathine penicillin G regimen. 1, 3
• If reliable serologic testing and assured follow-up are available, you may base treatment decisions on the partner's test results rather than treating empirically. 3

Special Population Considerations

Pregnant Patients

• Pregnant women exposed to syphilis require immediate presumptive treatment with benzathine penicillin G 2.4 million units IM—never delay therapy. 1, 2
• Some experts recommend an additional dose of benzathine penicillin G 2.4 million units IM one week after the initial dose for pregnant women with documented exposure to primary, secondary, or early latent syphilis, particularly in the third trimester. 2
• Treatment must be completed at least 4 weeks before delivery to achieve optimal prevention of congenital syphilis. 2
• If the patient has a documented penicillin allergy, desensitization is mandatory—there are no acceptable alternatives in pregnancy because only penicillin reliably prevents congenital infection. 1, 2, 4
• Warn pregnant patients about the Jarisch-Herxheimer reaction, which can precipitate preterm labor or fetal distress, but never delay treatment because untreated syphilis poses far greater fetal risk. 1, 2, 4

Immunocompromised/HIV-Infected Patients

• Use the same single-dose benzathine penicillin G 2.4 million units IM regimen for HIV-infected patients exposed within 90 days. 1, 4
• Some experts recommend three weekly doses of benzathine penicillin G 2.4 million units IM (instead of a single dose) for HIV-infected persons with documented early syphilis, though this is not universally required for exposure prophylaxis. 1, 4
• HIV-infected patients require more intensive serologic monitoring at 3,6,9,12, and 24 months after treatment (rather than the standard 6 and 12 months). 1, 2, 4
• HIV co-infection increases the risk of treatment failure and atypical serologic responses, but does not change the initial empiric treatment regimen. 1, 4

Symptomatic Patients

• If the exposed patient already has symptoms suggestive of primary or secondary syphilis (painless ulcer, diffuse rash, mucocutaneous lesions, lymphadenopathy), treat immediately with benzathine penicillin G 2.4 million units IM. 1, 2, 5
• Do not perform routine CSF examination unless neurologic or ophthalmic signs are present (meningismus, cranial nerve deficits, uveitis, vision changes). 1, 2, 4

Penicillin-Allergic Patients (Non-Pregnant)

• For non-pregnant, penicillin-allergic patients, the alternative is doxycycline 100 mg orally twice daily for 14 days. 2, 4, 3
• Tetracycline 500 mg orally four times daily for 14 days is an alternative, but adherence is typically lower. 4, 3
• Close clinical and serologic follow-up is essential when using non-penicillin regimens because efficacy data are less robust than for penicillin. 4
• Azithromycin is not recommended due to widespread resistance. 2

Critical Follow-Up Requirements

• All treated contacts must have repeat serologic testing (RPR or VDRL) at 6,12, and 24 weeks after exposure, because an initial negative test does not exclude early infection. 3
• Test all patients for HIV at the time of syphilis exposure evaluation, as co-infection is common and influences management. 1, 2, 4, 3
• Treatment success is defined by a fourfold (two-dilution) decline in nontreponemal titers within 6 months for early syphilis. 2, 4

Partner Identification Time Frames

• Primary syphilis: Identify partners from 3 months before symptom onset. 1, 3
• Secondary syphilis: Identify partners from 6 months before symptom onset. 1, 3
• Early latent syphilis: Identify partners from 1 year before diagnosis. 1, 3

Common Pitfalls to Avoid

• Never wait for serologic confirmation in patients exposed within 90 days—early infection is often seronegative. 1, 3
• Never substitute erythromycin, azithromycin, or ceftriaxone for penicillin in pregnant patients—these do not reliably prevent congenital syphilis. 2, 4
• Do not use serologic titers alone to differentiate early from late latent syphilis when determining treatment duration. 1, 2
• Counsel all patients about the Jarisch-Herxheimer reaction (acute fever, headache, myalgia within 24 hours), but emphasize that this should not delay treatment. 1, 2, 4, 3