What is the diagnosis and treatment for syphilis?

Diagnosis and Treatment of Syphilis

Diagnostic Approach

Syphilis diagnosis requires both direct detection methods for early disease and a two-test serologic algorithm combining nontreponemal and treponemal tests—using one test type alone is insufficient for diagnosis. 1

Direct Detection Methods (Early Syphilis)

• Darkfield microscopy and direct fluorescent antibody tests of lesion exudate or tissue are the definitive diagnostic methods for early syphilis (primary and secondary stages). 1, 2
• These direct visualization techniques should be performed on mucocutaneous lesions when present, as they provide immediate confirmation of Treponema pallidum infection. 1

Serologic Testing Algorithm

• Two types of serologic tests must be used together: nontreponemal tests (VDRL or RPR) and treponemal tests (FTA-ABS or MHA-TP). 1, 2
• Nontreponemal test titers correlate with disease activity and should be reported quantitatively—a fourfold change in titer (two dilution difference, e.g., 1:16 to 1:4) represents clinically significant change. 1, 2
• Treponemal tests remain reactive for life in most patients regardless of treatment (15-25% treated during primary stage may revert to nonreactive after 2-3 years), making them unsuitable for monitoring treatment response. 1

Critical pitfall: Sequential serologic tests must use the same testing method (VDRL or RPR) and preferably the same laboratory, as VDRL and RPR titers cannot be directly compared—RPR titers are often slightly higher than VDRL titers. 1

Special Diagnostic Considerations

• HIV-infected patients may have atypical serologic responses (unusually high, low, or fluctuating titers), but serologic tests remain accurate and reliable for most HIV-infected patients. 1
• For HIV-infected patients with clinical syndromes suggestive of early syphilis but atypical serology, consider biopsy and direct microscopy. 1
• All patients diagnosed with syphilis should be tested for HIV. 2

Neurosyphilis Diagnosis

• No single test diagnoses neurosyphilis—diagnosis requires combinations of reactive serologic tests, CSF abnormalities (elevated protein, leukocyte count >5 WBC/mm³), and/or reactive VDRL-CSF with or without clinical manifestations. 1
• VDRL-CSF (not RPR) is the standard CSF test—when reactive without substantial blood contamination, it is diagnostic of neurosyphilis, though it may be nonreactive when neurosyphilis is present. 1
• CSF FTA-ABS is more sensitive but less specific than VDRL-CSF; some experts use a negative CSF FTA-ABS to exclude neurosyphilis. 1
• CSF examination is recommended for patients with neurologic signs/symptoms, tertiary syphilis, or those whose serologic titers fail to decline appropriately after treatment. 3

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Treatment Regimens

Parenteral penicillin G is the preferred drug for all stages of syphilis and the only therapy with documented efficacy for neurosyphilis and syphilis during pregnancy. 1, 3, 4

Primary and Secondary Syphilis

• Benzathine penicillin G 2.4 million units IM as a single dose. 3, 2
• For penicillin-allergic non-pregnant adults: Doxycycline 100 mg orally twice daily for 14 days. 3, 2, 5

Early Latent Syphilis

• Benzathine penicillin G 2.4 million units IM as a single dose. 3
• Early latent syphilis is defined as documented seroconversion, fourfold titer increase, history of symptoms, or sex partner with documented early syphilis within the preceding year. 3

Late Latent Syphilis or Latent Syphilis of Unknown Duration

• Benzathine penicillin G 7.2 million units total, administered as three doses of 2.4 million units IM at 1-week intervals. 3, 2
• For penicillin-allergic non-pregnant adults: Doxycycline 100 mg orally twice daily for 28 days. 3, 5

Tertiary Syphilis

• Benzathine penicillin G 7.2 million units total, administered as three doses of 2.4 million units IM at 1-week intervals. 3, 2

Neurosyphilis

• Aqueous crystalline penicillin G 18-24 million units per day IV, administered as 3-4 million units IV every 4 hours or by continuous infusion for 10-14 days. 3, 6, 2
• Alternative regimen: Aqueous procaine penicillin G 2.4 million units IM once daily plus probenecid 500 mg orally four times daily for 10-14 days. 6
• Penicillin-allergic patients must undergo desensitization, as penicillin is the only proven effective therapy for neurosyphilis. 3, 6

Critical pitfall: Do not use oral penicillin preparations for any stage of syphilis—they are ineffective. 3

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Special Populations

Pregnancy

• Parenteral penicillin G is the only therapy with documented efficacy for preventing maternal transmission to the fetus. 1, 3
• Pregnant women with penicillin allergy must undergo desensitization before treatment, as alternative antibiotics are not effective for preventing congenital syphilis. 1, 3
• Pregnant patients should be screened three times: at first prenatal visit, during third trimester, and at delivery. 7

HIV-Infected Patients

• HIV-infected patients receive the same treatment regimens as non-HIV-infected patients. 3, 6
• HIV-infected patients may have atypical serologic responses but generally respond well to standard treatment. 1, 3, 6
• Closer follow-up is recommended to detect treatment failure or disease progression. 6

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Follow-Up and Monitoring

• Quantitative nontreponemal serologic tests (VDRL or RPR) should be repeated at 3,6,12, and 24 months after treatment. 3, 6, 2
• Expected response: Fourfold decline in titer within 6 months for primary/secondary syphilis and within 12-24 months for late syphilis. 3, 6, 2
• Treatment failure is defined as: Failure of nontreponemal test titers to decline fourfold within 6 months after therapy for primary or secondary syphilis. 3, 2
• If treatment failure is suspected, re-evaluate for HIV infection and perform CSF examination. 3
• For neurosyphilis, CSF leukocyte count is a sensitive measure of treatment effectiveness and should be monitored serially. 1

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Management of Sexual Partners

• Persons exposed within 90 days preceding diagnosis of primary, secondary, or early latent syphilis should be treated presumptively even if seronegative. 1, 3, 2
• Persons exposed >90 days before diagnosis should be treated presumptively if serologic results are not immediately available and follow-up is uncertain. 1, 3, 2

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Important Clinical Considerations

Jarisch-Herxheimer Reaction

• An acute febrile reaction may occur within 24 hours after any syphilis therapy, especially in early syphilis, often accompanied by headache, myalgia, and other symptoms. 1, 3, 6
• Patients should be informed about this possible adverse reaction; antipyretics may be recommended, but no proven methods prevent it. 1
• In pregnant women, this reaction may induce early labor or fetal distress but should not prevent or delay therapy. 1

Dosing Considerations

• If a dose is missed during weekly benzathine penicillin therapy, an interval of 10-14 days between doses might be acceptable before restarting the sequence. 3
• Doxycycline should be administered with adequate fluid to reduce risk of esophageal irritation and ulceration; if gastric irritation occurs, give with food or milk. 5