Last updated: September 29, 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 (primary, secondary, latent, and tertiary) 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 the diagnosis is typically made based on clinical assessment and the interpretation of syphilis serologies. Alternatively, the diagnosis can be made using studies 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. Prevention of syphilis includes providing counseling on safe sex practices to all individuals and offering syphilis screening to individuals with indications.

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]

Direct detection [9]

Serological studies [6][7][11]

  • Serological studies can miss early primary syphilis, as antibodies do not develop until 1–4 weeks after lesions appear. [11]
  • Syphilis testing algorithms, which combine nontreponemal and treponemal tests, are used to confirm a diagnosis.
  • When interpreting results:
    • Consider clinical context (i.e., clinical features, risk factors, treatment history)
    • Be aware that serologic testing may remain positive in patients previously treated for syphilis.
    • Consider consulting an infectious disease specialist for assistance.

Nontreponemal tests (NTT) [6][9]

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) [9][11]

  • 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.

Syphilis testing algorithms [6][11]

Overview of syphilis testing algorithms [6][11]

  • Either the standard algorithm or reverse algorithm can be used to diagnose syphilis.
  • If the initial test is positive, both algorithms require an additional test to confirm the diagnosis.
    • Both tests positive: A current or past infection is likely.
    • Second test negative: Next steps vary based on the testing algorithm used.
  • If the initial test in either algorithm is negative
    • Low-risk patients: Syphilis is unlikely; no further testing is necessary.
    • High-risk patients
      • Early primary syphilis cannot be excluded.
      • Offer presumptive treatment; if declined, repeat testing.

Standard algorithm [6][11]

Reverse algorithm [6][11]

Serologic tests may be negative in early syphilis. If there is high clinical suspicion, offer presumptive treatment. Alternatively, if a suitable lesion exists, order a direct pathogen test (e.g., darkfield microscopy, PCR) to establish the diagnosis. [7][11][17]

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 [18]

Intimal calcifications of the aorta may have a tree bark appearance on CT or MRI. [20]

Treatmenttoggle arrow icon

Approach [6]

  • Initiate antibiotic treatment in patients with:
    • Confirmed syphilis infection
    • Suspected early infection (prior to seroconversion, history of sexual contact with a person with syphilis)
  • Inform patients about the possibility of a Jarisch-Herxheimer reaction to treatment.
  • Screen for and treat any coinfections with other STIs. (see “Diagnostics of syphilis”).
  • Evaluate and treat sexual partners.
    • Initiate presumptive treatment for:
      • All sexual partners from the 90 days before diagnosis
      • Sexual partners from > 90 days before diagnosis if there is concern for loss to follow-up
    • The trace-back period for testing depends on the stage of syphilis.
  • Advise patients to:
    • Abstain from all sexual contact until all of the following criteria are met: [11]
      • Symptoms have resolved
      • 7 days have passed since the treatment course was completed
      • Sexual partners have been treated and meet the above criteria
    • Use barrier contraception until treatment response has been confirmed with NTT titers.
  • Offer counseling on STI prevention, including HIV PrEP if appropriate. [6]
  • Consult infectious diseases for complex cases and specialists for affected organs (e.g., ophthalmology for ocular syphilis).
  • For further information on management in pregnancy, see “Syphilis in pregnancy.”

All sexual contacts of patients 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 for syphilis [6]

  • Perform a clinical evaluation and measure NTT titers at:
  • Compare NTT titers to pretreatment results.
    • NTT titer decreased by ≥ fourfold: successful treatment response
    • NTT titer increased by ≥ fourfold: treatment failure or reinfection
    • NTT titer unchanged or changed by < fourfold within 12 months: serofast state or treatment failure
  • If NTT titers have not decreased by ≥ fourfold, determine whether this is due to a serofast state, reinfection, or treatment failure.
    • Factors suggestive of a serofast state
    • Factors suggestive of reinfection or treatment failure
      • A fourfold increase in titers for > 2 weeks
      • Persistent or recurrent symptoms
    • Consult a specialist if the diagnosis is uncertain.
  • If a serofast state is suspected:
    • Assess for HIV.
    • Perform additional neurological examinations.
    • Reassess clinically every year and perform serology.
    • If there is concern for loss to follow-up, re-treat.
  • If reinfection or treatment failure is suspected: Re-treat patients with weekly IM penicillin G for 3 weeks (see “Antibiotic therapy for syphilis infection”).

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

Primary prevention

Some clinicians are providing MSM and transgender women with doxycycline as postexposure prophylaxis for bacterial STIs (including syphilis) after unprotected anal sex. The CDC is assessing the efficacy of this practice but currently does not routinely recommend it. [6]

Screening for syphilis [6][27][28]

Screening is performed on a blood sample using the standard or reverse syphilis testing algorithm.

Overview of syphilis screening [6][27]
Indications for initial screening Indications and frequency of repeat screening
Screening for adolescents and adults
Prenatal screening for syphilis [28][29]

Check local guidance; some states require syphilis screening for all women at the time of delivery. [30]

Further management

Special patient groupstoggle arrow icon

Syphilis in pregnancy

Diagnostics for syphilis in pregnancy [6]

Screen patients with syphilis for coinfection with other STIs, including HIV. [6]

Treatment of syphilis in pregnancy [6]

Antibiotic therapy

Obstetric management

For patients diagnosed at ≥ 20 weeks' gestation:


  • Repeat NTT titers.
    • Diagnosis at ≤ 24 weeks' gestation: Repeat after 8 weeks and at delivery.
    • Diagnosis at > 24 weeks' gestation: Repeat at delivery.
  • If there is a fourfold or greater increase in titers for > 2 weeks: Repeat treatment.
  • For management of neonates, see “Congenital syphilis.”

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Referencestoggle arrow icon

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