In a patient previously treated for syphilis whose rapid plasma reagin (RPR) titre decreased and now is increasing, what does this indicate?

Rising RPR Titer After Initial Decline Following Syphilis Treatment

A fourfold increase in RPR titer after an initial decline following treatment indicates either treatment failure or reinfection, and mandates immediate CSF examination followed by retreatment. 1

Clinical Significance of Rising Titers

The pattern you describe—RPR declining after treatment, then subsequently rising—meets the CDC's definition of treatment failure or reinfection. Specifically:

• A sustained fourfold increase in nontreponemal titers above the post-treatment nadir is the threshold for intervention 1
• This fourfold rise represents a change of two dilutions (e.g., from 1:4 to 1:16, or from 1:8 to 1:32) 2
• The increase must be "sustained" rather than transient fluctuation, as RPR titers can vary by one dilution due to technical factors 3, 4

Important distinction: This is different from the "serofast" state, where titers remain stable at low levels (typically <1:8) after treatment. Serofast status does not represent treatment failure, but a rising titer does. 1

Mandatory Next Steps

1. CSF Examination is Required

You must perform lumbar puncture before retreatment to rule out neurosyphilis. 1, 5

The rationale is critical:

• Rising titers may indicate CNS involvement that requires IV penicillin rather than IM benzathine penicillin 1
• HIV-infected patients have increased risk for neurosyphilis and poorer CSF responses 1, 5
• Treatment decisions depend entirely on CSF results 5

Do not skip this step—it is guideline-mandated regardless of whether the patient has neurologic symptoms. 5

2. Assess HIV Status

• Test for HIV if status is unknown, as HIV infection significantly affects management 1, 2
• HIV-infected patients require more intensive monitoring (every 3 months vs. every 6 months) 1
• HIV patients may have atypical serologic responses with unusually high, low, or fluctuating titers 1

3. Evaluate for Clinical Signs

Look specifically for:

• New chancre or genital ulcer 1
• Rash (particularly palms/soles) or mucocutaneous lesions 1
• Neurologic symptoms: headache, confusion, cranial nerve palsies, vision changes 1
• Ocular symptoms: uveitis, vision loss 1

Retreatment Algorithm Based on CSF Results

If CSF is Normal (No Neurosyphilis)

Treat with benzathine penicillin G 2.4 million units IM weekly for 3 weeks (total 7.2 million units). 1, 5

• This is the standard retreatment regimen for early-stage syphilis treatment failure without CNS involvement 1, 5
• Some specialists also recommend adding a neurosyphilis regimen even with normal CSF, though data supporting this are limited 1

If CSF Shows Neurosyphilis

Treat with aqueous crystalline penicillin G 18-24 million units daily IV (administered as 3-4 million units every 4 hours or continuous infusion) for 10-14 days. 1, 5

Alternative if IV access is problematic:

• Procaine penicillin 2.4 million units IM once daily PLUS probenecid 500 mg orally four times daily, both for 10-14 days 1

If Penicillin Allergy

Penicillin desensitization followed by penicillin therapy is strongly preferred over alternative antibiotics. 1, 5

• Ceftriaxone 1-2 g IV daily for 10-14 days is a potential alternative for neurosyphilis, but has limited data 1
• Doxycycline and other alternatives are inadequate for neurosyphilis 1

Follow-Up Monitoring After Retreatment

Standard Monitoring Schedule

Repeat RPR at 3,6,9,12, and 24 months after retreatment. 1

• Expect a fourfold decline in titer within 6-12 months if retreatment is successful 1, 5
• Use the same testing method (RPR vs. VDRL) and preferably the same laboratory for all follow-up tests 1, 2

If CSF Was Abnormal

Repeat CSF examination at 3 and 6 months after completing neurosyphilis therapy, then every 6 months until CSF white blood cell count normalizes and CSF-VDRL becomes nonreactive. 1, 5

• The earliest CSF indicator of response is decline in lymphocytosis 1
• CSF-VDRL may respond more slowly 1

Distinguishing Treatment Failure from Reinfection

While both require the same initial workup (CSF examination), consider reinfection more likely if:

• The patient has ongoing high-risk sexual exposures 1
• There are new clinical signs of early syphilis (chancre, rash) 1
• The titer rise occurs after a period of documented serologic cure 1

However, do not assume reinfection without investigation—both scenarios require CSF examination before retreatment. 5

Common Pitfalls to Avoid

1. Do not retreat without CSF examination in patients with rising titers—this is a guideline violation 5
2. Do not use single-dose benzathine penicillin for retreatment—the 3-week regimen is required 1, 5
3. Do not compare titers between different test methods (RPR vs. VDRL)—they are not directly interchangeable 2, 6
4. Do not ignore small titer fluctuations of one dilution—these can represent technical variation rather than true biologic change 3, 4, 6
5. Do not delay treatment while awaiting CSF results if the patient has concerning neurologic or ocular symptoms—empiric neurosyphilis treatment may be warranted 1

Special Consideration: Spontaneous Titer Fluctuation

Recent research shows that RPR titers can fluctuate spontaneously:

• About 20% of patients show at least one dilution increase in the first 14 days after treatment 3
• Up to 26% show fourfold changes when diagnosis and treatment are separated by 10-14 days 4
• Pre-treatment spontaneous decreases are associated with slower post-treatment declines 7

However, a sustained fourfold increase after an initial documented decline still requires full evaluation and retreatment per guidelines. 1, 5