What is the recommended treatment for a patient with a positive Rapid Plasma Reagin (RPR) titer indicating syphilis infection?

Treatment of Syphilis Based on RPR Titer

Treat all patients with a positive RPR titer (confirmed by treponemal testing) with parenteral penicillin G, with the specific regimen determined by disease stage, not by the RPR titer level alone. 1

Initial Diagnostic Confirmation

• A positive RPR must be confirmed with treponemal testing (FTA-ABS, TP-PA, or MHA-TP) before initiating treatment, as RPR alone can yield false positives in 1-5% of cases 1
• Do not repeat the RPR for confirmation—treponemal testing is required to establish the diagnosis 1
• Sequential RPR tests should use the same method (VDRL or RPR) and ideally the same laboratory, as RPR titers are often slightly higher than VDRL titers and cannot be directly compared 2

Determining Disease Stage

The stage of syphilis—not the RPR titer—dictates treatment duration:

• Primary syphilis: Ulcer or chancre at infection site 1
• Secondary syphilis: Skin rash, mucocutaneous lesions, lymphadenopathy 1
• Early latent syphilis: Asymptomatic infection acquired within the previous year 1
• Late latent or unknown duration: Asymptomatic infection acquired >1 year ago or timing uncertain 1
• Neurosyphilis: Neurologic, ocular, or auditory symptoms requiring CSF evaluation 1

Critical caveat: An RPR titer ≥1:32 suggests early syphilis for purposes of partner notification, but serologic titers alone should not determine treatment duration 1

Treatment Regimens by Stage

Primary, Secondary, or Early Latent Syphilis

• Benzathine penicillin G 2.4 million units IM as a single dose 1
• Cure rate: 90-95% for primary/secondary, 85-90% for early latent 1
• Alternative for non-pregnant penicillin-allergic patients: Doxycycline 100 mg orally twice daily for 14 days 1, 3

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
• Cure rate: 80-85% 1
• Before treatment, evaluate for neurologic or ocular symptoms; if present, perform CSF analysis and slit-lamp examination 1
• Routine CSF examination is not required in asymptomatic patients 1

Neurosyphilis, Ocular Syphilis, or Otic Syphilis

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

Special Populations

HIV-Infected Patients

• Use the same penicillin regimens as for HIV-negative patients—a single dose of benzathine penicillin G for early syphilis is adequate 1, 4
• A randomized trial found no benefit of 3 doses versus 1 dose in HIV-infected patients with early syphilis (success rates 93% vs 100%, P=0.49) 4
• More intensive monitoring is required: Clinical and serological evaluation at 3,6,9,12, and 24 months 1
• Consider CSF examination for late latent syphilis in HIV-infected patients to exclude neurosyphilis, particularly if CD4 <350 cells/mm³ or RPR ≥1:32 1, 5
• HIV-infected patients may have atypical serologic responses (unusually high, low, or fluctuating titers), but this does not change treatment 2

Pregnant Women

• Treat with the penicillin regimen appropriate for the stage of syphilis; treatment must occur >4 weeks before delivery for optimal outcomes 1
• 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 1
• Pregnant women with penicillin allergy must be desensitized and treated with penicillin—it is the only therapy with documented efficacy for preventing congenital syphilis 2, 1

Follow-Up and Treatment Success

Monitoring Schedule

• Primary and secondary syphilis: Clinical and serological evaluation at 6 and 12 months 1
• Latent syphilis: Clinical and serological evaluation at 6,12,18, and 24 months 1
• Neurosyphilis: If CSF pleocytosis was present initially, repeat CSF examination every 6 months until cell count normalizes 1

Defining Treatment Success

• A fourfold decrease in RPR titer (equivalent to a 2-dilution drop, e.g., from 1:16 to 1:4) indicates successful treatment 1
• For HIV-infected patients with primary/secondary syphilis, failure to achieve a fourfold decrease by 3 months indicates treatment failure 1

Managing Treatment Failure

• Re-treat if: Clinical symptoms persist or recur, RPR titers increase fourfold, or titers fail to decline appropriately 1
• Perform CSF examination before retreatment 1
• If CSF is normal, re-treat with benzathine penicillin G 7.2 million units (3 weekly doses of 2.4 million units each) 1

Important Warnings and Pitfalls

Jarisch-Herxheimer Reaction

• Warn all patients about this acute febrile reaction with headache and myalgia that may occur within 24 hours of treatment 2, 1
• Antipyretics may be recommended, but there are no proven prevention methods 2
• In pregnant women, this reaction may induce early labor or fetal distress, but this should not delay therapy 2

Partner Management

• Presumptively treat sexual partners exposed within 90 days preceding diagnosis, even if seronegative 2, 1
• Partners exposed >90 days before diagnosis should be treated presumptively if serologic results are not immediately available and follow-up is uncertain 2

Common Pitfalls to Avoid

• Do not use azithromycin—widespread resistance makes it unreliable despite older studies suggesting efficacy 1, 6
• Do not use RPR titer level alone to determine treatment duration; stage of disease is what matters 1
• Do not fail to test all syphilis patients for HIV if status is unknown 1
• Do not assume that a low RPR titer (e.g., 1:1) in a previously treated patient requires retreatment—this likely represents a "serologic scar" and is expected in 15-25% of treated patients 1, 7

Serofast Patients

• Patients with persistently low RPR titers (1:1 to 1:4) after appropriate treatment are "serofast" and do not require additional therapy in the absence of clinical findings or new exposures 7
• Repeat RPR testing only if new symptoms develop or new sexual exposure occurs 7