What is the treatment for a positive Rapid Plasma Reagin (RPR) test indicating syphilis infection?

Treatment for Positive RPR

Treat with benzathine penicillin G 2.4 million units IM as a single dose for early syphilis (primary, secondary, or early latent), or 2.4 million units IM weekly for 3 weeks for late latent or unknown duration syphilis, after confirming the diagnosis with a treponemal test and determining the stage of infection. 1

Diagnostic Confirmation Required First

Before initiating treatment, you must confirm the positive RPR with a treponemal test (FTA-ABS, TP-PA, or MHA-TP), as RPR alone is insufficient for diagnosis 1. False-positive RPR results can occur at low titers (<1:8) in conditions like injection drug use, autoimmune diseases, and pregnancy 1.

Stage-Based Treatment Algorithm

Primary and Secondary Syphilis

• Single dose of benzathine penicillin G 2.4 million units IM 1, 2
• Primary syphilis presents with painless anogenital ulcers (chancres) 1, 2
• Secondary syphilis manifests with diffuse rash, mucocutaneous lesions, and lymphadenopathy 1, 2
• Cure rate: 90-95% 1

Early Latent Syphilis

• Single dose of benzathine penicillin G 2.4 million units IM 1
• Defined as asymptomatic infection acquired within the previous year 1
• Cure rate: 85-90% 1

Late Latent or Unknown Duration Syphilis

• Benzathine penicillin G 2.4 million units IM weekly for 3 weeks (total 7.2 million units) 1, 2
• Applies when infection occurred >1 year ago or timing is uncertain 1
• Cure rate: 80-85% 1

Neurosyphilis

• Aqueous crystalline penicillin G 18-24 million units per day IV (administered as 3-4 million units every 4 hours) for 10-14 days 1, 3
• Consider neurosyphilis if neurologic symptoms, ocular symptoms, or auditory symptoms are present 3
• Cure rate: 90-95% 1

Critical Special Populations

HIV-Infected Patients

• Use the same penicillin regimen as HIV-negative patients 1, 3
• HIV infection does NOT change the treatment regimen itself 1
• However, HIV-infected patients require more intensive monitoring at 3,6,9,12, and 24 months (rather than standard 6 and 12 months) 1
• Consider CSF examination for late-latent syphilis in HIV-infected patients to exclude neurosyphilis 3
• Patients with CD4 count <350 cells/mm³ have higher risk of serologic failure and require closer monitoring 4

Important caveat: A 2024 study found that adding doxycycline 100 mg orally twice daily for 7 days to single-dose benzathine penicillin G improved serologic response rates in HIV-infected patients with early syphilis (79.5% vs 70.3%) 5. However, this is not yet incorporated into CDC guidelines, so standard single-dose benzathine penicillin G remains the official recommendation 1.

Pregnant Women

• Treat with the penicillin regimen appropriate for the stage of syphilis 1, 6
• 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 6
• Treatment must occur >4 weeks before delivery for optimal outcomes 7
• Up to 40% of fetuses with in-utero syphilis exposure are stillborn or die in infancy if untreated 2

Penicillin Allergy

• For early syphilis: Doxycycline 100 mg orally twice daily for 14 days 6, 3
• For late latent syphilis or pregnancy: Penicillin desensitization is preferred over alternative antibiotics 6, 3
• Critical warning: Azithromycin is NOT recommended due to widespread resistance 1, 8

Post-Treatment Monitoring

Early Syphilis (Primary, Secondary, Early Latent)

• Clinical and serologic evaluation at 6 and 12 months after treatment 1, 3
• For HIV-infected patients: evaluate at 3,6,9,12, and 24 months 1

Late Latent Syphilis

• Clinical and serologic evaluation at 6,12,18, and 24 months after treatment 1, 3

Defining Treatment Success

• A fourfold decrease in RPR titer (equivalent to 2 dilutions, e.g., 1:32 to 1:8) by 6-12 months 1, 3
• Use the same testing method (RPR or VDRL) from the same laboratory for serial monitoring 3
• 15-25% of patients remain "serofast" with persistent low-level titers (<1:8) despite successful treatment—this does NOT indicate treatment failure 6, 3

Treatment Failure Indicators

• No fourfold decrease in titer by 6-12 months for early syphilis 1, 3
• Clinical symptoms persist or recur 3
• Sustained fourfold increase in titer 3
• Action required: Perform lumbar puncture to evaluate for neurosyphilis and retreat with benzathine penicillin G 7.2 million units (3 weekly doses) if CSF is normal 1

Common Pitfalls to Avoid

• Do not treat based on RPR alone—always confirm with treponemal testing first 1
• Do not use treponemal tests to monitor treatment response—they 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 titers indicate treatment failure—serofast state is common and does not require retreatment 6, 3
• Do not use azithromycin—resistance is widespread 1
• Do not forget HIV testing—all patients diagnosed with syphilis should be tested for HIV 1, 3

Additional Considerations

All sexual contacts should be evaluated and treated if necessary to prevent reinfection 3. Patients with baseline RPR titer ≤1:16 or previous history of syphilis have higher risk of serologic failure and require closer monitoring 4.