Syphilis (Lues)

Key Points

  • The treatment of syphilis is based on the duration of infection and the organ systems involved.
  • Five subtypes of syphilis can be distinguished: primary, secondary, or early syphilis of less than 1 year’s duration; infection of indeterminate length, or more than 1 year’s duration; neurosyphilis; congenital syphilis; and syphilis infection in association with HIV infection.
  • When a diagnosis of syphilis is made, evaluation for other STDs and treatment of potentially infected contacts are necessary.


Syphilis is caused by infection by the bacterial spirochete, Treponema pallidum, which is sexually and vertically transmitted. Infection rates by syphilis have been rising over the past decade. It presents across a broad clinical spectrum, including many cutaneous signs, that evolves with the duration of the infection and also correlates with the immune status of the patient.

Table 1. Cutaneous and Systemic Findings in Syphilis

Key cutaneous findings Important additional systemic findings
Primary Chancre Lymphadenopathy
Secondary Disseminated papulosquamous eruption including palms/ soles, condyloma lata, mucous patches, moth-eaten alopecia Arthralgias, myalgia, pharyngitis, ocular involvement
Tetriary Erythematous to red-brown nodules, plaques Cardiac and CNS involvement
Neurosyphilis Cranial nerve dysfunction, meningitis, stroke, altered mental status, general paresis, tabes dorsalis
Congenital syphilis Saddle nose Saber shin, Clutton’s joints, Higoumenakis sign, hepatosplenomegaly, neurosyphilis, pneumonitis, Hutchinson teeth, mulberry molars, snuffles (rhinorrhea with bloody mucus)

Neurosyphilis may occur at any time during syphilitic infection. Patients with neurosyphilis should be evaluated for co-infection with HIV. Diagnosis requires a reactive CSF with increased cell count, increased protein content, and a positive CSF VDRL. The serum FTA-ABS or MHA-TP is positive in all cases. Neurologically normal patients with early syphilis do not require CSF examination. CSF examination is required during and after treatments as an index of cure.

Infected infants may be asymptomatic at birth and have negative serologic studies. The initial evaluation requires:

  • A physical examination.
  • Maternal history to include serologic status, treatment, and response to treatment. Adequate treatment of the mother before delivery, except with erythromycin, treats the infant, although if treatment is delayed until late in gestation, stigmata may still appear.
  • CSF examination for cells, protein, and VDRL.
  • Radiographs of the long bones.
  • Examination of any lesions for spirochetes by darkfield or histologic special stains.

HIV infection may alter the natural history of syphilis in two ways: A negative VDRL or RPR can occur with active secondary syphilis; and early CNS relapse after apparently adequate therapy has been observed on multiple occasions. A CSF examination should precede and guide treatment of HIV-infected individuals with latent syphilis or syphilis present for 1 year or more, or of unknown duration. If CSF examination is not possible, treat for presumed neurosyphilis. HIV-positive persons with CNS findings should be evaluated for possible neurosyphilis.

For all patients with neurosyphilis, and infants with possible neurosyphilis, in addition, a CSF examination must be repeated 6 months following treatment. Adequate therapy is determined by a normal CSF cell count and a falling protein content. The VDRL may not return to negative. CSF examination in documented neurosyphilis (with abnormal CSF findings) is continued at 6-month intervals for 2 years. A normal CSF at 1 year is evidence of cure.

Diagnosis can be made on the basis of clinical findings, darkfield examination, nontreponemal tests (RPR or VDRL), treponemal serologies (FTA-Abs or MHA-TP).
When neurosyphilis is suspected, CSF should be examined for increased cell count, increased protein content, a positive CSF VDRL, and serum FTA-ABS or MHA-TP (both are usually positive in all cases).

The treatment of syphilis is based on the duration of infection and the organ systems involved. Five groups can be distinguished: primary, secondary, or early syphilis of less than 1 year’s duration; infection of indeterminate length, or more than 1 year’s duration; neurosyphilis; congenital syphilis; and syphilis infection in association with HIV infection. In all cases of syphilis it is important to examine for and treat other STDs, and to trace and treat all contacts. Syphilis cases should be reported to the local health department. Infected individuals may resume sexual activity after skin lesions, if present, are healed, or after therapy is complete.

Initial Evaluation

Primary syphilis

Secondary syphilis

Tertiary syphilis

Congenital syphilis

Differential diagnosis

Differential diagnosis of primary syphilis

Herpes simplex virus

Differential diagnosis of secondary syphilis

Guttate psoriasis

Pityriasis rosea

Lymphomatoid papulosis

Differential diagnosis of tertiary syphilis


Cutaneous TB

Atypical mycobacterial infection


First-line therapy: The first-line therapy for syphilis depends on the duration of infection and the immune competence of the host. Patients’ contacts should be traced and evaluated for possible syphilis infection. All documented cases of syphilis should be reported. All patients require clinical and serologic monitoring until seronegative.

First steps

Table 2. Syphilis and Treatment Options

First-line treatment Alternative treatment Treatment options for penicillin-allergic patients Treatment options for pregnant individuals Monitoring
Primary, secondary, or early syphilis Intramuscular benzathine penicillin G 2.4 x 106 U as a single dose A single 2 g dose of azithromycin may be considered as a second choice treatment; azithromycin-resistant strains are common. Azithromycin should not be used in men who have sex with men or in pregnant women. IM Ceftriaxone 1 g daily for 10 days Doxycycline 100 mg b.i.d. for 14 days If penicillin allergic: strongly consider penicillin desensitization or consider oral erythromycin 500 mg q.i.d. for 15 days; erythromycin may not adequately treat the fetus.Give additional penicillin therapy as for congenital syphilis (see below) to the baby at birth. 3, 6, 9, 12 and 24 months
Indeterminate length, > 1 year duration Intramuscular benzathine penicillin G 2.4 x 106 U weekly for 3 successive weeks Azithromycin 2 g single dose, doxycycline 100 mg b.i.d. for 28 days, IM Ceftriaxone 1 g daily for 10 days Doxycycline 100 mg b.i.d. for 28 days If penicillin-allergic: oral erythromycin 500 mg q.i.d. for 30 days 6, 12 and 24 months
Neurosyphilis Intravenous aqueous penicillin G 4 x 106 U q4 hours or continuous infusion for 10-14 days Procaine penicillin G 2.4 X 106 U daily with oral probenecid 500 mg q.i.d. for 10-14 days. Another option is ceftriaxone 2 g IM or IV daily for 10-14 days Doxycycline 200 mg b.i.d. for 28 days or Oral erythromycin 500 mg q.i.d. for 30 days
Congenital A positive CSF VDRL in the asymptomatic infant requires treatment for possible CNS involvement(a) Infants with normal CSF: Intramuscular benzathine penicillin G 50,000 U/kg in a single dose.(b) Infants with abnormal CSF and those in whom CNS involvement cannot be ruled out: Intramuscular aqueous procaine penicillin G 50,000 U/kg/day for 10 days(c) For older children the dosage of penicillin is as noted above, but should not exceed that recommended for adults with syphilis of more than 1 year’s duration 3, 6, 9, 12 and 24 months
Syphilis in HIV-infected individual Intramuscular benzathine penicillin G 2.4 x 106 U as a single dose Efficacy of alternative regimens is not well established


  • Compliance with long courses of oral antibiotics is a concern. Parenteral treatment is preferred. If oral therapy is given, compliance must be stressed, and careful follow-up is essential to document cure.
  • Tetracycline is contraindicated in the second and third trimesters of pregnancy and in children less than 8 years of age.
  • A Jarisch-Herxheimer reaction may occur in the first 24 hours after treating any patient, resulting from inflammatory cytokines triggered by antigens elaborated by dying spirochetes. Patients should be warned before therapy. Anti-inflammatory treatment, including aspirin (and prednisone in rare cases), is helpful. Patients may need additional monitoring for hemodynamic instability.

When to refer to a dermatologist

  • If the diagnosis is not clear.
  • If a skin or mucosal biopsy is needed.
  • For co-management of cutaneous manifestations of the disease.

Clinical Case

Case 1

  • 21-year-old male who has sex with men
  • Past medical history notable for HIV infection; he is currently not taking antiretroviral medications and his CD4+ count is 43
  • Review of systems is notable only for recent fevers in association with a new painless ulcer on the penis after a recent sexual encounter without barrier protection

Initial evaluation

  • Tired-appearing, slightly cachectic male
  • Fever is noted
  • 1 cm well marginated ulcer with clean base and raised indurated border on the penile shaft with palpable inguinal lymphadenopathy
  • Diagnosis: favor syphilitic chancre
  • Ulcer fluid is evaluated by darkfield testing
  • RPR, VDRL are tested
  • Follow-up evaluation 3 days later

Follow-up evaluation

  • The ulcer fluid reveals presence of spirochetes by darkfield microscopy and the RPR and VDRL are also both elevated.
  • A complete physical, including neurologic evaluation, is performed (normal). Notably, no additional cutaneous signs of syphilis are found.
  • A detailed sexual history is performed and his case (and contacts) are reported to the public health department.
  • The patient is given an intramuscular dose of penicillin G benzathine 2.4 x 106 U.
  • Follow-up evaluation in two weeks (ulcer healed) and he is also referred to primary care physician for ongoing management of his HIV disease. The patient is followed clinically and serologically three months later and every three months following for the first year, and then one year afterwards. Over this monitoring period, his serologic titers were reduced to undetectable levels and he exhibited no additional signs of syphilis infection.


Read PJ and Donovan B (2012) Clinical aspects of adult syphilis, Int Med Journal, 42: 614-619.

Mattei, PL et al (2012) Syphilis: an emerging infection, AFP, 86: 433-440.

Roett MA, Mayor MT, Uduhiri KA (2012) Diagnosis and management of genital ulcers, AFP, 85: 255-262.