What are the stages of syphilis and how are they determined, and what are the treatment options for each stage?

Staging and Treatment of Syphilis

Stages of Syphilis and How They Are Determined

Syphilis progresses through distinct clinical stages that are determined by the timing of infection, clinical manifestations, and serologic testing results. 1

Primary Syphilis

• Characterized by a single painless chancre (ulcer) at the site of inoculation, typically appearing 10-90 days after exposure, accompanied by regional lymphadenopathy 2, 3
• HIV-infected individuals may present with multiple or atypical chancres, and primary lesions may be absent or missed 2, 3
• Diagnosis is confirmed by darkfield microscopy of lesion exudate or direct fluorescent antibody testing, along with reactive serologic tests 2, 3

Secondary Syphilis

• Develops 2-8 weeks after primary inoculation and presents with disseminated manifestations 2
• Classic presentation includes macular, maculopapular, papulosquamous, or pustular rash beginning on the trunk and spreading peripherally to involve palms and soles 2
• Accompanied by generalized lymphadenopathy, fever, malaise, anorexia, arthralgias, and headache 2
• Condyloma lata (moist, flat papular lesions in warm intertriginous regions) may occur 2
• Can mimic acute HIV infection with constitutional symptoms and CSF abnormalities 2, 3

Latent Syphilis

• Defined by positive serologic tests without any clinical manifestations 3
• Early latent syphilis: infection acquired within the preceding year, documented by seroconversion, fourfold increase in titer, history of symptoms within the past year, or having a sex partner with documented early syphilis 1
• Late latent syphilis: infection present for more than one year or of unknown duration 1
• Relapses of secondary manifestations can occur, most commonly during the first 1-4 years following infection 2

Tertiary (Late) Syphilis

• Occurs in approximately 25% of untreated patients after 3-12 years of latency 3
• Manifestations include gummatous lesions (granulomatous lesions affecting skin, bones, or organs), cardiovascular syphilis (aortitis, aortic regurgitation), and late neurologic involvement 2, 3

Neurosyphilis

• Can occur at any stage of syphilis 2, 1
• Asymptomatic neurosyphilis is defined by one or more CSF abnormalities (elevated protein, lymphocytic pleocytosis >5 WBCs/mm³, or positive VDRL-CSF) without symptoms 2
• Symptomatic neurosyphilis presents as meningitis, meningovascular disease, or parenchymatous disease 2
• HIV-infected persons may have more common manifestations such as concomitant uveitis and meningitis 2

Diagnostic Approach

Serologic Testing Algorithm

• Screen with nontreponemal tests (VDRL or RPR), then confirm reactive results with treponemal tests (FTA-ABS or TP-PA) 2, 3
• Nontreponemal test titers correlate with disease activity and should be reported quantitatively 2
• A fourfold change in titer (two dilutions, e.g., 1:16 to 1:4) is clinically significant 2
• Sequential tests must use the same method (VDRL or RPR) and preferably the same laboratory 2
• Treponemal tests remain reactive for life in most patients regardless of treatment and should not be used to assess treatment response 2

CSF Examination Indications

• Perform lumbar puncture for: neurologic or ophthalmic signs/symptoms, evidence of active tertiary syphilis, treatment failure, HIV infection with late latent syphilis or syphilis of unknown duration, or serum nontreponemal titer ≥1:32 1
• VDRL-CSF is highly specific but insensitive; when reactive without substantial blood contamination, it is diagnostic of neurosyphilis 2
• CSF leukocyte count >5 WBCs/mm³ is a sensitive measure of neurosyphilis and treatment effectiveness 2

Treatment Regimens

Primary and Secondary Syphilis

• Benzathine penicillin G 2.4 million units IM as a single dose 1, 3
• For penicillin-allergic non-pregnant adults: doxycycline 100 mg orally twice daily for 14 days 1, 3, 4
• Alternative: ceftriaxone 1 gram IM/IV daily for 10 days (based on randomized trial data showing comparable efficacy) 1

Early Latent Syphilis

• Benzathine penicillin G 2.4 million units IM as a single dose 1
• For penicillin-allergic non-pregnant adults: doxycycline 100 mg orally twice daily for 14 days 1, 4

Late Latent Syphilis or Latent Syphilis of Unknown Duration

• Benzathine penicillin G 7.2 million units total, administered as 3 doses of 2.4 million units IM at 1-week intervals 1, 3
• For penicillin-allergic non-pregnant adults: doxycycline 100 mg orally twice daily for 28 days 1, 3, 4

Tertiary Syphilis (Non-Neurosyphilis)

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

Neurosyphilis

• Aqueous crystalline penicillin G 18-24 million units per day IV (administered as 3-4 million units every 4 hours or continuous infusion) for 10-14 days 1, 3
• Alternative: procaine penicillin G with probenecid (though procaine penicillin without probenecid does not achieve adequate CSF levels) 1
• Ceftriaxone 2 grams daily IV for 10-14 days may be considered, but data are limited 1

Special Populations

Pregnant Women

• Parenteral penicillin G is the only therapy with documented efficacy for preventing maternal transmission and treating fetal infection 1, 5
• All pregnant women with penicillin allergy MUST undergo desensitization followed by penicillin treatment—no exceptions 1, 5
• Some experts recommend a second dose of benzathine penicillin 2.4 million units IM one week after the initial dose for primary, secondary, or early latent syphilis 1
• Screen all pregnant women at first prenatal visit, during third trimester, and at delivery 1
• 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 treatment regimens as non-HIV-infected patients 1
• HIV-infected patients may have atypical serologic responses (unusually high, low, or fluctuating titers) but generally respond well to standard treatment 2, 1
• Closer follow-up is mandatory to detect potential treatment failure or disease progression 1
• For late latent syphilis with HIV and normal CSF, use benzathine penicillin G 7.2 million units (three weekly doses) 1

Pediatric Patients

• For acquired syphilis: benzathine penicillin G 50,000 units/kg IM (up to adult dose of 2.4 million units) as a single dose for early syphilis 1
• For late latent syphilis: benzathine penicillin G 50,000 units/kg IM for three doses at 1-week intervals (total 150,000 units/kg up to 7.2 million units) 1
• Children require CSF examination to exclude neurosyphilis before treatment 1

Follow-Up and Monitoring

Serologic Follow-Up

• Perform quantitative nontreponemal tests (RPR or VDRL) at 3,6,12, and 24 months after treatment 1
• Expected response: fourfold decline in titer within 6 months for primary/secondary syphilis and within 12-24 months for late syphilis 1, 3
• Use the same nontreponemal test method throughout follow-up; VDRL and RPR titers cannot be directly compared 2, 1

Treatment Failure Criteria

• Persistent or recurring signs/symptoms, sustained fourfold increase in nontreponemal titers, or failure of initially high titer to decline at least fourfold within 6-12 months for early syphilis or 12-24 months for late syphilis 1
• If treatment failure is suspected: re-evaluate for HIV infection and perform CSF examination 1
• Re-treatment typically involves three weekly injections of benzathine penicillin G 2.4 million units IM, unless CSF examination indicates neurosyphilis 1

Neurosyphilis Follow-Up

• CSF leukocyte count is a sensitive measure of treatment effectiveness 2
• Serial CSF examinations are necessary to ensure adequate treatment 6

Management of Sex Partners

• Treat sex partners presumptively if exposed within 90 days preceding diagnosis of primary, secondary, or early latent syphilis, even if seronegative 1
• Time periods for at-risk partners: 3 months plus duration of symptoms for primary syphilis, 6 months plus duration of symptoms for secondary syphilis, and 1 year for early latent syphilis 1
• Persons exposed >90 days before diagnosis should be treated presumptively if serologic test results are not immediately available and follow-up is uncertain 1

Critical Pitfalls to Avoid

• Do NOT use oral penicillin preparations for syphilis treatment—they are ineffective 1
• Do NOT use azithromycin in the United States due to widespread macrolide resistance and documented treatment failures 1
• Do NOT rely solely on treponemal test antibody titers to assess treatment response, as they correlate poorly with disease activity 2, 1
• Do NOT switch between different nontreponemal testing methods (VDRL vs. RPR) when monitoring serologic response 2, 1
• Do NOT substitute inadequate alternatives for penicillin in pregnancy—only penicillin prevents congenital syphilis 1
• Procaine penicillin without probenecid does not achieve adequate CSF levels and is inadequate for neurosyphilis treatment 1
• All patients with syphilis should be tested for HIV 1, 3

Important Clinical Considerations

Jarisch-Herxheimer Reaction

• An acute febrile reaction that may occur within 24 hours after any syphilis therapy, especially in early syphilis 1, 3
• Symptoms include fever, headache, myalgia, and other constitutional symptoms 1
• Patients should be informed about this possible adverse reaction before treatment 1

Serofast Reaction

• 15-25% of successfully treated patients remain "serofast" with persistent low titers (<1:8) that do not indicate treatment failure 1
• Nontreponemal tests usually become nonreactive with time after treatment, but some patients maintain low titers for life 2