Syphilis is a bacterial infection caused by the spirochete Treponema pallidum pallidum (T. p. pallidum), which is usually spread through sexual contact. Syphilis has 4 clinical stages: primary, secondary, latent, and tertiary. Primary syphilis begins with a chancre, a painless ulcer on the genitals. Progression to secondary syphilis manifests as a generalized maculopapular rash, which includes the palms and soles. The development of tertiary syphilis can cause severe neurologic (neurosyphilis), cardiovascular, and/or gummatous disease. The diagnosis is through both treponemal and nontreponemal testing. Penicillin G is the antibiotic of choice. The duration of management varies based on the stage of the disease.

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  • Worldwide annual new cases: 11 million
  • Incidence in the United States is rising.
  • Men > women, particularly men who have sex with men
  • Most common age group: 20–29 years old
  • Increased prevalence in minorities


  • Causative organism:
    • Treponema pallidum pallidum (T. p. pallidum)
    • Gram-negative spirochete (spiral-shaped)
  • Transmission:
    • Human to human
    • Sexual contact
    • Direct contact with infected tissues
    • Vertical (congenital syphilis)
  • Risk factors:
    • Acquired syphilis:
      • Unprotected sexual contact
      • Multiple sex partners
      • Work in the sex trade
    • Congenital syphilis:
      • Late or no prenatal care
      • Maternal drug use
      • Inadequate treatment of syphilis during pregnancy


  • Virulence factors:
    • Hyaluronidase:
      • Allows tissue invasion
      • Facilitates dissemination
    • Corkscrew motility:
      • Able to move in thick substances (e.g., connective tissue)
      • Assists with dissemination
    • Fibronectin:
      • Protective coating
      • Comes from the host
      • Prevents phagocytosis and immune recognition
  • Pathogenesis:
    • Primary syphilis:
      • T. p. pallidum adheres to skin or mucosal membranes → hyaluronidase production → tissue invasion
      • The organism coats itself in the host’s fibronectin → prevents recognition and phagocytosis by the immune system → development of the chancre (initial ulcerative lesion)
      • Eventual local immune control → resolution of chancre
      • During the primary period, some spirochetes move into local lymph nodes.
    • Later stages:
      • Spirochetes multiply and disseminate through the bloodstream → invade other organs and tissues
      • Host immune-inflammatory response → systemic clinical manifestations

Clinical Presentation

Syphilis is a multistage disease. Patients can present at any stage and infected individuals may not exhibit symptoms for years.

Primary syphilis

  • Initial: localized infection
  • Incubation period is approximately 10–90 days.
  • Symptoms may go unnoticed.
  • Characterized by a chancre (primary lesion):
    • Painless
    • Begins as a firm, red papule
    • Becomes a firm ulcer with raised, indurated borders
    • Common locations:
      • Genitalia
      • Anus
      • Posterior pharynx
      • Lips
    • Heals spontaneously in 3–6 weeks
  •  Regional lymphadenopathy:
    • Palpable, rubbery lymph nodes
    • Usually inguinal
    • Bilateral
    • Nontender
Primary, painless chancre of syphilis

Primary, painless chancre of syphilis (T. p. pallidum infection)

Image: “Chancres on the penile shaft due to a primary syphilitic infection caused by Treponema pallidum 6803 lores” by M. Rein. License: Public Domain

Secondary syphilis

  • Develops 2–12 weeks after the primary infection
  • Lasts 4–8 weeks
  • Constitutional symptoms:
    • Fever
    • Malaise
    • Myalgias
    • Headaches
    • Anorexia
    • Weight loss
    • Nausea
  • Generalized lymphadenopathy:
    • Firm
    • Tender
    • Rubbery
  • Mucocutaneous features (all are highly contagious):
    • Generalized rash 
      • Nonpruritic
      • Macular, papular, or nodular
      • Scaly or smooth
      • Red, reddish-brown, or copper color
      • Involves the trunk, extremities, palms, and soles
    • Condylomata lata:
      • Grayish-white color
      • Wart-like lesions
      • Mostly seen around the anus and vagina (near the location of the primary chancre)
    • Lues maligna:
      • More severe, ulcerating skin lesions
      • Seen in immunocompromised patients (e.g., HIV)
    • Alopecia (hair loss)
  • Systemic manifestations:
    • GI involvement:
      • Hepatitis
      • GI infiltration and/or ulcerations
      • Proctitis
    • Musculoskeletal involvement:
      • Periostitis
      • Synovitis
      • Osteitis
    • Renal involvement:
      • Nephrotic syndrome
      • Acute nephritis
      • Renal failure
    • Ocular involvement:
      • Keratitis
      • Anterior uveitis
      • Posterior uveitis
      • Optic neuritis
    • Ear involvement:
      • Hearing loss
      • Tinnitus
      • Vertigo

Latent syphilis

  • Period between secondary and tertiary syphilis where the disease lays dormant
  • Classified based on the duration since initial infection:
    • Early: < 1 year after initial infection
    • Late: > 1 year after initial infection
  • May last months to years (often decades)
  • The disease can resolve, relapse with skin/mucosal lesions, or progress to tertiary syphilis.

Tertiary syphilis

  • Seen in 33% of untreated cases
  • Occurs 1–30 years after the initial infection
  • Neurosyphilis:
    • Meningitis:
      • Headache
      • Nausea and vomiting
      • Neck stiffness
      • Photophobia
      • Focal neurologic deficits
      • Cranial nerve deficits
      • Seizures
    • Meningovascular disease:
      • Endarteritis → stroke
      • Meningomyelitis → spastic weakness, paresthesia, muscular atrophy
    • Paretic neurosyphilis: 
      • Chronic progressive meningoencephalitis → cerebral atrophy
      • Mood disturbances
      • Psychiatric disease (e.g., depression, mania, psychosis)
      • Memory impairment
      • Tremors
      • Dysarthria
      • Seizure
      • Pupillary abnormalities can occur but are rare.
    • Tabes dorsalis (locomotor ataxia): 
      • Demyelination of the dorsal columns and the dorsal roots
      • Ataxia
      • Stabbing (“lightning-like”) pain in the back and legs
      • Loss of vibratory sense and proprioception
      • Loss of reflexes
      • Paresthesia
      • Charcot joints
      • Urine retention and incontinence
      • Argyll Robertson pupils (pupils accommodate but do not react)
  • Cardiovascular syphilis:
    • A consequence of vasculitis in the vasa vasorum
    • Findings:
      • Aortitis
      • Aortic aneurysm and aortic root dilation → aortic regurgitation
      • Coronary artery narrowing
  • Benign tertiary gummatous syphilis:
    • Gummas:
      • Soft, solitary, granulomatous lesions with central necrosis
      • Variable in size
      • Destructive (leaves scars)
    • Occurs on skin, bones, or organs
    • Bone involvement may cause deep, boring pain (worse at night).
Tertiary syphilis gumma

A gumma on the palate of a patient with tertiary syphilis

Image: “16762” by CDC. License: Public Domain


General approach

It is difficult to diagnose syphilis. However, specific labs and the correlation of history and examination results can lead to a diagnosis.

  • Patients with suspected T. p. pallidum infection should be screened with a nontreponemal test 1st.
  • A positive nontreponemal test should be followed by a confirmatory treponemal test.
  • Patients should also be tested for other STIs.

Nontreponemal testing

  • Use for screening purposes since the tests are sensitive, but not specific.
  • Detects anticardiolipin antibodies
  • Options:
    • Rapid plasma reagin test: 1st choice
    • VDRL: 
      • Best initial test for CSF analysis
      • Test of choice for neurosyphilis
  • False-positive results can occur with: 
    • Pregnancy
    • Viral infections
    • Rheumatic fever
    • Systemic lupus erythematosus
    • Drugs

Treponemal testing

  • Confirmatory tests that detect antibodies to Treponema antigens
  • Even after treatment, treponemal antibody titers are positive for life.
  • Options:
    • Fluorescent treponemal antibody absorption test:
      • Can be done on CSF to evaluate for neurosyphilis
      • Less specific than the CSF-VDRL test
    • Microhemagglutination assay for T. p. pallidum (MHA-TP)
    • T. p. pallidum particle agglutination test (TPPA)
    • T. p. pallidum enzyme immunoassay (TP-EIA)
    • Chemiluminescence immunoassay (CIA)

Direct methods

Definitive tests using obtained specimens (such as mucosal lesions). However, use is limited since the tests are not routinely available.

  • Darkfield microscopy: 
    • A microscopy technique illuminating specimens against a dark background.
    • Motile spirochetes are seen.
  • Direct fluorescent antibody (DFA) testing
  • PCR to detect T. p. pallidum DNA.
Darkfield microscopy of T. pallidum

Darkfield microscopy of T. p. pallidum:
Corkscrew-shaped bacteria are seen.

Image: “20488” by Richard O. Deitrick. License: Public Domain


Early syphilis management

For primary, secondary, or early-latent syphilis, the following antibiotics can be used:

  • Preferred: IM penicillin G (single dose)
  • Alternative regimens: 
    • Doxycycline
    • Ceftriaxone
    • Tetracycline
    • Amoxicillin + probenecid
    • Azithromycin

Late syphilis management

For late-latent syphilis, tertiary syphilis, or syphilis of unknown duration, the following regimen is used:

  • Preferred: IM penicillin G (3 weeks)
  • Alternative regimen: 
    • Doxycycline
    • Ceftriaxone


  • Preferred: IV penicillin G
  • Alternative regimen: ceftriaxone

Jarisch–Herxheimer reaction

  • Caused by an immune response to the antigens released by dying spirochetes
  • Symptoms:
    • Rigors
    • Myalgias
    • Rise in temperature
    • Increased respiratory rate
    • Hypotension
  • All patients should be monitored after therapy is initiated:
    • Occurs within 24 hours
    • Resolves within 12–24 hours
    • Seen in 10%–35% of cases
  • Supportive care may be given:
    • Antipyretics (e.g., acetaminophen, aspirin, ibuprofen)
    • IV fluids

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Differential Diagnosis

  • Chancroid: STI caused by Haemophilus ducreyi. Patients develop painful, necrotizing genital ulcers, and inguinal lymphadenopathy. Diagnosis is usually clinical, but PCR and cultures can help to confirm. Management is with macrolide antibiotics.
  • Donovanosis: STI caused by Klebsiella granulomatis. Donovanosis is also known as granuloma inguinale. The progressive, nodular genital lesions can form into painless ulcerations and cause tissue damage. Lymphadenopathy is uncommon. Diagnosis is confirmed with microscopic findings of Donovan bodies from the lesion. Management involves antibiotics, such as macrolides, tetracyclines, and trimethoprim-sulfamethoxazole.
  • Lymphogranuloma venereum: STI caused by 3 strains of Chlamydia trachomatis. Patients may have a small, transient, painless genital ulcer, followed by lymphadenopathy (bubo). Diagnosis is clinical, though PCR testing can help with confirmation. Management involves tetracyclines or erythromycin.
  • Genital herpes: a common STI caused by HSV type 1 or 2. Prodromal symptoms often precede clusters of painful, fluid-filled vesicles on an erythematous base, which eventually form ulcers that can coalesce. Lymphadenopathy, dysuria, and severe neuralgia can occur. The diagnosis is generally clinical but confirmed with PCR and serologic testing. Management includes antiviral therapy.
  • Genital warts (also called condylomata acuminata): a human papillomavirus (HPV) infection causing a range of mucocutaneous findings, including broad-based smooth or velvety papules, or rough verrucous or fungating plaques, in the anogenital region. The diagnosis is clinical. Management may include cytodestructive therapy (podophyllotoxin), immune-mediated therapy (imiquimod), or surgical therapy.


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