Last updated: September 11, 2023

Summarytoggle arrow icon

Syphilis is a predominantly sexually transmitted bacterial infection caused by the spirochete Treponema pallidum. The disease presentation consists of four distinct, successive clinical stages if left untreated. Primary syphilis manifests with a painless chancre (primary lesion), typically on the genitals. Secondary syphilis is characterized by a polymorphic, maculopapular rash that appears on the palms and soles. The first two stages are followed by an asymptomatic phase (latent syphilis), which may last indefinitely or progress to tertiary syphilis. During the tertiary stage, characteristic granulomas (gumma) may appear, which can cause irreversible organ damage, particularly in the cardiovascular system (e.g., syphilitic aortic aneurysm). Neurosyphilis, ocular syphilis, and otosyphilis are serious manifestations that can occur at any stage of infection. Treponemal or nontreponemal serological studies are used for screening, and diagnosis is typically made based on clinical assessment and the interpretation of the syphilis serologies. Alternatively, the diagnosis can be made using tests that directly detect T. pallidum (e.g., darkfield microscopy, PCR) if a specimen of infected tissue is obtainable. First-line treatment for syphilis is penicillin G; allergen sensitization should be initiated in patients with a penicillin allergy.

Epidemiologytoggle arrow icon


Epidemiological data refers to the US, unless otherwise specified.

Etiologytoggle arrow icon

Treponema bacteria (particularly during stages I and II) are highly contagious.

Pathophysiologytoggle arrow icon

  • Spirochetes invade the body → disseminate systemically within hours → bind to endothelial cells → inflammatory reaction → endarteritis and perivascular inflammatory infiltrates [2]

Clinical featurestoggle arrow icon

See “Subtypes and variants” for details on neurosyphilis, ocular syphilis, and otosyphilis, which can occur at any stage of infection.

Incubation period [4]

  • 10–90 days
  • On average 21 days

Primary syphilis

Secondary syphilis

Remember that Secondary Syphilis causes Systemic Symptoms.

Latent syphilis

  • No clinical symptoms, despite seropositivity
  • May last months, years, or even for the entire life of the patient
  • Disease may resolve, reactivate, or progress to tertiary syphilis
  • Early latent: acquired within the last year
  • Late latent: acquired > 1 year ago

Tertiary syphilis


  • Chronic, destructive granulomatous lesions with a necrotic center that tend to ulcerate
  • May affect any organ, e.g., skin, internal organs, bones

Cardiovascular syphilis

Subtypes and variantstoggle arrow icon

Neurosyphilis [6][7]

Patients with syphilis but without neurosyphilis can have unexplained CSF abnormalities. In patients with clinical features of neurosyphilis, a reactive CSF-VDRL strongly supports the diagnosis. [6]

Other [6]

Diagnosticstoggle arrow icon


Clinical evaluation [6]

A detailed assessment of exposure history is essential for distinguishing early latent syphilis (infected ≤ 1 year) versus late latent syphilis (infected > 1 year) in asymptomatic seropositive patients. [6]

Serological studies [7]

Nontreponemal tests (NTT) [6][11]

False-Positive results on VDRL with Pregnancy, Viral infection (e.g., EBV, hepatitis), Drugs (e.g., chlorpromazine, procainamide), Rheumatic fever (rare), Lupus, and Leprosy

Treponemal tests (TT) [11][13]

  • Indications
  • Mechanism: : qualitative detection of antibodies to treponemal antigens
  • Types: Many TTs exist; examples of common types are listed here.
    • Fluorescent treponemal antibody absorption test (FTA-ABS)
    • Treponema pallidum particle agglutination (TPPA)
    • IgG/IgM immunoassay (enzyme or chemiluminescence)
  • Accuracy
  • Important considerations: After infection, TT titer typically stays positive indefinitely.

Testing algorithms [13]

Standard and reverse testing algorithms involve both NTT and TT to reduce the chance of false-positive and false-negative results. [6]

  • Standard algorithm
  • Reverse algorithm [13]
    • TT first
    • If positive, perform an NTT
    • If NTT is negative, perform a second TT.


  • Interpret serology results based on the clinical context (i.e., clinical features, risk factors, treatment history).
  • Consider consulting an infectious disease specialist for assistance with interpreting serology results.

Interpretation of syphilis serologies for diagnosis


Nontreponemal test
Reactive Nonreactive
Treponemal test Reactive
  • Infected if supported by clinical context, or
  • Not infected
    • Serofast state: previously treated syphilis with persistent TT and NTT reactivity
    • False-positive TT and NTT due to a non-venereal treponematoses (e.g., yaws)

Serologic tests may be negative in early syphilis. If there is high clinical suspicion, repeat serologic testing after 2–4 weeks. Alternatively, if a suitable lesion exists, order a direct pathogen test (e.g., darkfield microscopy, PCR) to establish the diagnosis. [7][18]

Direct detection [11]

Additional studies [6]

After confirming syphilis infection, order the following studies based on the clinical scenario.

No single finding can establish a diagnosis of neurosyphilis, ocular syphilis, or otosyphilis. These diagnoses can occur at any stage of infection and, if suspected, require prompt evaluation by a specialist. [6]

Imaging [20]

Intimal calcifications of the aorta may have a tree bark appearance on CT or MRI. [22]

Treatmenttoggle arrow icon

General principles [6]

  • Initiate antibiotic treatment in patients with:
    • Confirmed syphilis infection
    • Suspected early infection (prior to seroconversion, history of sexual contact with an infected person)
  • Inform patients about the possibility of a Jarisch-Herxheimer reaction to treatment.
  • Assess for treatment response with NTT titer.
  • Consult infectious disease for assistance with complex cases , and specialists for affected organs (e.g., ophthalmology for ocular syphilis).

All sexual contacts of a patient with syphilis should be identified, evaluated, and treated.

Antibiotic therapy [6]

Antibiotic therapy for syphilis infection [6]
Stage or subtype Penicillin regimens (first-line) Alternative regimens (if nonpregnant)
Primary, secondary, or early latent syphilis
Tertiary or late latent syphilis
Neurosyphilis, ocular syphilis, or otosyphilis
  • Intravenous penicillin G for 10–14 days [6]
  • OR intramuscular penicillin G for 10–14 days PLUS probenecid for 10–14 days if IV therapy is not preferred and adherence can be ensured [6]

If neurosyphilis is suspected, perform a lumbar puncture and CSF analysis before starting treatment.

Posttreatment assessment [6]

  • Perform a clinical evaluation and measure NTT titers at 6 and 12 months after treatment. [6]
  • Compare NTT titers to pretreatment results.
    • NTT titer decreased by ≥ fourfold: successful treatment response
    • Unchanged NTT titers within 12 months: treatment failure or serofast state
    • NTT titer increased by ≥ fourfold after successful treatment: reinfection

Either type of NTT (i.e., RPR or VDRL) may be used to assess treatment response, but do not compare across types when assessing the trend in titers. For example, a titer for RPR can only be compared to prior titers of RPR.

Complicationstoggle arrow icon

We list the most important complications. The selection is not exhaustive.

Preventiontoggle arrow icon

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Referencestoggle arrow icon

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