What is the recommended treatment for an adult patient with a positive syphilis serology?

Treatment for Positive Syphilis Serology

For adults with positive syphilis serology, benzathine penicillin G 2.4 million units intramuscularly as a single dose is the definitive treatment for primary, secondary, and early latent syphilis, while late latent or unknown duration syphilis requires three weekly doses of 2.4 million units IM (total 7.2 million units). 1, 2

Determining Stage of Syphilis Before Treatment

Before initiating treatment, you must determine the stage of syphilis to select the appropriate regimen:

• Primary syphilis: Painless anogenital ulcer or chancre at infection site 3
• Secondary syphilis: Diffuse rash, mucocutaneous lesions, lymphadenopathy 3
• Early latent syphilis: Asymptomatic infection acquired within the preceding year, documented by seroconversion, fourfold increase in titer, history of symptoms within past year, or sex partner with documented early syphilis 1
• Late latent syphilis: Asymptomatic infection acquired more than one year ago or of unknown duration 1
• Tertiary syphilis: Cardiac, ophthalmic, auditory, or gummatous manifestations 4

Critical evaluation: Assess for neurologic symptoms (meningitis, cranial nerve dysfunction, auditory changes) or ophthalmic symptoms (uveitis) before treatment, as these require CSF examination and different treatment regimens 1, 4

Treatment Regimens by Stage

Early Syphilis (Primary, Secondary, Early Latent)

• Benzathine penicillin G 2.4 million units IM as a single dose 5, 1, 2
• This achieves 90-95% cure rates for primary/secondary syphilis and 85-90% for early latent 4

Late Latent or Unknown Duration Syphilis

• Benzathine penicillin G 2.4 million units IM weekly for 3 consecutive weeks (total 7.2 million units) 1, 2
• Achieves 80-85% cure rates 4

Neurosyphilis (Any Stage with Neurologic/Ophthalmic Involvement)

• Aqueous crystalline penicillin G 18-24 million units IV daily (administered as 3-4 million units every 4 hours or continuous infusion) for 10-14 days 1, 2
• Alternative: Procaine penicillin 2.4 million units IM once daily PLUS probenecid 500 mg orally four times daily, both for 10-14 days 2
• Consider adding benzathine penicillin G 2.4 million units IM weekly for up to 3 weeks after completing neurosyphilis treatment 2

Penicillin Allergy Alternatives (Non-Pregnant Adults Only)

For non-pregnant penicillin-allergic patients:

• Primary, secondary, or early latent syphilis: Doxycycline 100 mg orally twice daily for 14 days 1, 2, 6
• Late latent syphilis: Doxycycline 100 mg orally twice daily for 28 days 1, 6
• Alternative: Tetracycline 500 mg orally four times daily (14 days for early, 28 days for late latent) 1

Critical caveat: Ceftriaxone 1 gram IM/IV daily for 10-14 days is a reasonable alternative based on randomized trial data showing comparable efficacy to benzathine penicillin, but patients with severe penicillin allergy may also react to ceftriaxone as both are beta-lactam antibiotics 1

Never use azithromycin in the United States due to widespread macrolide resistance and documented treatment failures 1

Special Populations

Pregnant Women

• Use the same stage-appropriate penicillin regimens as non-pregnant patients 4, 2
• Pregnant women with penicillin allergy MUST undergo desensitization followed by penicillin treatment—no exceptions, as penicillin is the only therapy with documented efficacy for preventing congenital syphilis 1, 4, 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 primary, secondary, or early latent syphilis 4
• Screen all pregnant women for syphilis at first prenatal visit, during third trimester, and at delivery 1, 2
• Warning: Jarisch-Herxheimer reaction during second half of pregnancy may precipitate premature labor or fetal distress; women should seek immediate medical attention if they notice contractions or changes in fetal movements 1

HIV-Infected Patients

• Use the same penicillin regimens as HIV-negative patients for all stages 1, 2
• No benefit to multiple doses of benzathine penicillin for early syphilis in HIV-infected patients compared to single dose 1, 7
• Consider CSF examination for late latent syphilis in HIV-infected patients to exclude neurosyphilis 2
• Require more intensive monitoring at 3,6,9,12, and 24 months (instead of 6 and 12 months) 4, 2

Mandatory Concurrent Testing and Follow-Up

• Test all patients with syphilis for HIV infection at diagnosis 5, 1, 2
• Follow-up schedule for primary/secondary syphilis: Clinical and serological evaluation at 6 and 12 months 1, 2
• Follow-up schedule for latent syphilis: Clinical and serological evaluation at 6,12,18, and 24 months 4
• Treatment success: Expect a fourfold decline (2 dilutions) in nontreponemal test titers within 6 months for early syphilis 1, 2

Treatment Failure Indicators

• Persistent or recurring signs/symptoms 5
• Sustained fourfold increase in nontreponemal titers 5
• Failure of nontreponemal test titers to decline fourfold within 6 months for primary/secondary syphilis 5, 1

Management of treatment failure: Re-evaluate for HIV infection, perform lumbar puncture unless reinfection is certain, and re-treat with three weekly injections of benzathine penicillin G 2.4 million units IM unless CSF indicates neurosyphilis 5, 1

Partner Management

• Presumptively treat sexual partners exposed within 90 days preceding diagnosis of primary, secondary, or early latent syphilis with benzathine penicillin G 2.4 million units IM, even if seronegative 1, 2
• Partners exposed >90 days before diagnosis should be treated presumptively if serologic results are not immediately available and follow-up is uncertain 1

Critical Warnings and Pitfalls

• Jarisch-Herxheimer reaction: Inform all patients about this acute febrile reaction with headache, myalgia, chills, and weakness that occurs in approximately 24% of patients within 4-12 hours after treatment (median onset 4.9 hours, median duration 12.8 hours) 1, 8
• The reaction is more common in secondary syphilis and associated with successful treatment outcomes 8
• Never use oral penicillin preparations for syphilis treatment as they are ineffective 1
• Do not switch testing methods (e.g., between VDRL and RPR) when monitoring serologic response, as results cannot be directly compared 1, 4
• Use the same laboratory and same method for sequential RPR tests 4
• Remember that 15-25% of successfully treated patients remain "serofast" with persistent low titers (<1:8) that do not indicate treatment failure 1