I. What every physician needs to know.

Syphilis, caused by the bacterium Treponema pallidum, is primarily transmitted through sexual contact and is often known as “the great imitator” because it can manifest itself in so many different ways. It is important to accurately classify this disease into early (within first year after acquisition of infection) or late (more than a year after transmission) syphilis as it impacts risk of transmission and duration of treatment. Stages of this disease are primary, secondary, latent and tertiary. Syphilis is a reportable disease. In 2008, health officials reported over 117,000 cases of syphilis; almost 19,999 cases of primary and secondary syphilis have been documented in 2014. Over half of these cases were reported from only 70 counties in the United States and occurred predominantly in men who have sex with men, between 20 and 29 years of age. The incidence of syphilis has increased among women also, which is of particular concern as that heralds a rise in congenital syphilis. Between 2013-2014, the number of syphilis cases increased by 15.1%.

T. pallidum is transmitted by contact of infectious lesions with small breaks in the skin. Incubation period is about 10-60 days.

II. Diagnostic Confirmation: Are you sure your patient has syphilis?

The diagnosis of syphilis depends on clinical findings, examination of lesions for treponemes and/or serologic tests. Dark field microscopy is the main diagnostic method for diagnosing primary syphilis.

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A. History Part I: Pattern Recognition:

  • Primary syphilis – painless chancre develops at the site of infection about 1-3 weeks after exposure to T. Pallidum. Chancre heals spontaneously in 3-6 weeks, even without treatment.
  • Secondary syphilis – results from blood borne spread of T. pallidum and can have numerous manifestations. Common features include rash, fever, lymphadenopathy, condyloma latum. Secondary syphilis, despite its name, is still considered an early stage of the disease.
  • Latent syphilis – normal physical exam with positive serology.
  • Tertiary syphilis – develops years after the initial infection and can involve any organ system: gummas, cardiovascular or CNS.

B. History Part 2: Prevalence:

Syphilis had been considered a historic disease with peak incidence in the 1940s. After the penicillin era, it had all but vanished until the late 1980s, early 1990s when there was a peak in incidence that correlated with recognition of HIV as a risk factor. Increased incidence since 2001 has primarily been attributed to increased cases among men with ratio of male to female of more than 11:1. Men who have sex with men (MSM) account for over 60% of all cases of primary and secondary syphilis in the United States.

C. History Part 3: Competing diagnoses that can mimic syphilis.

The differential diagnosis of primary syphilis is that of genital ulcers and includes herpes simplex virus (HSV), chancroid, traumatic injury, drug eruptions, and granuloma inguinale.

Secondary syphilis involves diffuse mucocutaneous lesions, systemic symptoms, and generalized nontender lymphadenopathy. Presentations include hepatitis, nephropathy, uveitis, and other gastrointestinal (GI) disturbance. Often syphilis is considered when typical treatments are non-responsive.

D. Physical Examination Findings.

Primary syphilis
  • Painless, indurated, and nonpurulent chancre with regional lymphadenopathy
Secondary syphilis
  • Macular, papular, papulosquamous, or pustular (never vesicular) rash involving the trunk, limbs and often the palms and soles
  • In intertriginous areas, the papules can enlarge to form pink or gray-white infectious lesions known as condyloma lata
  • Mucous patches can also involve the oral or genital mucosa
  • Lymphadenopathy, alopecia, meningitis, ocular abnormalities such as uveitis
Latent syphilis
  • No physical exam findings of syphilis
Tertiary syphilis
  • Argyll Robertson pupil
  • Paresthesia, ataxia, pain, changes in sensation
  • Gummas
  • Aortic regurgitation

E. What diagnostic tests should be performed?

Other STD screening including HIV testing is recommended.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

T. pallidum cannot be cultured; detection or serologic methods are used for diagnosis. Dark field microscopy and direct fluorescent antibody testing are used for the microscopic examination of specimen from the lesion looking for spirochete. Serologic testing can be divided into non-treponemal and treponemal tests.

Non-treponemal tests, rapid plasma reagin (RPR) and Venereal Disease Research Laboratory (VDRL), check for antibodies to cardiolipin-lecithin-cholesterol antigen. These tests are often used for screening because they are easy to perform; however, there is a higher risk of false positive because they can be falsely positive in the setting of other infections, immunization, or autoimmune disease. A reactive non-treponemal test must be confirmed with a treponemal test. RPR and VDRL are particularly useful as titers can be followed to determine responsiveness to treatment.

Treponemal tests, fluorescent treponemal antibody absorption (FTA-ABS), microhemagglutination assay for treponema pallidum (MHA-TP), treponema pallidum particle agglutination assay (TPPA), and treponema pallidum enzyme immunoassay (TP-EIA), are typically reserved for confirmation because they are more difficult to perform. These are antibodies directed against treponemal antigens, are qualitative only, and can often remain positive even after years of successful treatment.

In 2008, the Center for Disease Control (CDC) looked at labs that reversed the order of testing (i.e. did treponemal tests first and performed non-treponemal tests for confirmation). For high volume laboratories, the reversal of the tests can be an economic advantage. Because there is not a lot of data on how to interpret these reversed results, CDC concluded that individuals positive to both tests should be interpreted as they have an untreated infection and treatment should be offered. If a person is positive to a treponemal test but then negative to a non-treponemal test, a second treponemal test should be considered. If negative, then treatment could be deferred.

In neurosyphilis, a lumbar puncture should be performed; typical findings are pleocytosis, elevated protein, and VDRL positivity.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Other than direct microscopy, there is no imaging for syphilis.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Beginning the work-up with non-treponemal tests seems to be more cost-effective than a treponemal-test first algorithm.

III. Default Management.

  • The recommended regimen for adults is Benzathine penicillin G 2.4 million units IM in a single dose for primary, secondary, and early latent syphilis.
  • In non-pregnant adults with penicillin allergy, regimens of doxycycline 100 mg PO BID for 14 days, tetracycline 500 mg PO q6H for 14 days, or azithromycin 2 grams PO x1 may be effective. Local resistance pattern of syphilis to macrolide should be considered prior to prescribing azithromycin.
  • For late latent syphilis, latent syphilis of unknown duration, or non-central nervous system (CNS) tertiary syphilis, the recommendation is Benzathine penicillin G 7.2 million units administered as three dose of 2.4 million units IM each at 1 week intervals. In non-pregnant individuals with an allergy to penicillin, doxycycline 100 mg PO BID or tetracycline 500 mg PO q6H for 28 days may be considered in conjunction with close serologic and clinical follow-up. Cardiovascular syphilis can be treated with ceftriaxone 1 gram IV or IM daily for 10-14 days in patients with mild penicillin allergy.
  • In patients who have neurosyphilis or syphilitic eye disease, the recommended regimen is aqueous crystalline penicillin G 18-24 million units per day administered as 3-4 million units IV every 4 hours for 10-14 days. An alternative regimen is procaine penicillin 2.4 million units IM once daily with probenicid 500 mg PO q6H for 10-14 days. For those with mild penicillin allergy, ceftriaxone 2 grams IV or IM for 10-14 days is an option.
  • Penicillin is the only recommended treatment for pregnant patients with all stages of syphilis and those who are allergic should undergo desensitization.
  • Treatment of HIV infected persons will be discussed below.

A. Immediate management.

There are no treatments that need to be initiated within hours; it is acceptable to wait for confirmatory testing.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

  • Patients should be re-examined clinically and serologically 6 months and 12 months after treatment.
  • Failure of nontreponemal test titers to decline four-fold within 6 months after therapy for primary or secondary syphilis may indicate treatment failure and patients should be re-evaluated for HIV and cerebral spinal fluid should be tested to rule out neurosyphilis.
  • In patients with neurosyphilis, CSF parameters should be monitored every 6 months. If the pleocytosis does not improve by 6 months, or the CSF profile has not normalized within 2 years, a second course of therapy for neurosyphilis should be administered.

D. Long-term management.

In general, syphilis is treated with a one time dose of penicillin. Tertiary syphilis or neurosyphilis should be followed by infectious disease providers and possibly neurology or ophthalmology depending on symptoms.

E. Common Pitfalls and Side-Effects of Management

Patients should be informed of Jarisch-Herxheimer reaction, an acute febrile reaction frequently accompanied by headache, myalgia and other symptoms that usually occur within the first 24 hours after therapy for early syphilis.

IV. Management with Co-Morbidities


A. Renal Insufficiency.

No change in management

B. Liver Insufficiency.

Doxycycline and tetracycline should be avoided in patients with liver insufficiency.

C. Systolic and Diastolic Heart Failure

No change in management.

D. Coronary Artery Disease or Peripheral Vascular Disease

No change in management.

E. Diabetes or other Endocrine issues

No change in management.

F. Malignancy

No change in management.

G. Immunosuppression (HIV, chronic steroids, etc).

Compared with HIV-negative patients, HIV-positive patients with early syphilis may be at increased risk for developing neurosyphilis and some studies have suggested evaluation with lumbar puncture in that population in the presence of serum RPR ≥ 1:32 or a CD4 count <350 cells/mm3. No treatment regimen for syphilis has been demonstrated as being more effective. HIV-infected persons should be evaluated clinically and serologically for treatment failure at 3, 6, 9, 12, and 24 months after therapy and lumbar puncture should be performed in case of treatment failure.

H. Primary Lung Disease (COPD, Asthma, ILD)

No change in management.

I. Gastrointestinal or Nutrition Issues

No change in management.

J. Hematologic or Coagulation Issues

No change in management.

K. Dementia or Psychiatric Illness/Treatment

No change in management.

V. Transitions of Care

A. Sign-out considerations While Hospitalized.

Not applicable.

B. Anticipated Length of Stay.

Once diagnosed, therapy and follow-up can be achieved as an outpatient.

D. Arranging for Clinic Follow-up


1. When should clinic follow up be arranged and with whom.

  • It is best to have this condition followed by an infectious disease specialist. Follow-up should be arranged at completion of antibiotics.
  • If there are ophthalmologic symptoms or neurologic symptoms then follow-up with these specialities is recommended.
  • If the patient is to be on long-term penicillin then follow-up with either a general medicine doctor or infectious disease specialist is recommended for lab monitoring.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

Baseline complete blood count (CBC) with differential and renal function if the patient will be discharged on penicillin.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

For long-term administration of penicillin, CBC and renal function should be followed.

E. Placement Considerations.

Patients can typically go home with outpatient administration of subsequent doses.

F. Prognosis and Patient Counseling.

Patients should be counseled on safe sex practices as well as signs and symptoms of partially treated/latent infection.

VI. Patient Safety and Quality Measures

A. Core Indicator Standards and Documentation.

Syphilis is a reportable disease.

What’s the evidence?

“Centers for Disease Control and Prevention: Syphilis Fact Sheet”.

Singh, AE, Romanowski, B. “Syphilis: review with emphasis on clinical, epidemiologic, and some biologic features”. Clin Microbiol Rev. vol. 12. 1999. pp. 187-209.

“Centers for Disease Control and Prevention: Syphilis Figures”.

“Centers for Disease Control and Prevention: Primary and secondary syphilis–United States, 2005-2013”. MMWR Morb Mortality Wkly Rep. vol. 63. 2014. pp. 402-406.

“Centers for Disease Control and Prevention: Syphilis”.

Larsen, SA, Steiner, BM, Rudolph, AH. “Laboratory diagnosis and interpretation of tests for syphilis”. Clin Microbiol Rev. vol. 8. 1995. pp. 1-21.

“Centers for Disease Control and Prevention: Syphilis testing algorithms using treponemal tests for initial screening–four laboratories, New York City, 2005-2006”. MMWR Morb Mortality Wkly Rep. vol. 57. 2008. pp. 872-875.

Owusu-Edusei, K, Koski, KA, Ballard, RC. “The tale of two serologic tests to screen for syphilis–treponemal and nontreponemal: does the order matter”. Sex Transm Dis. vol. 38. 2011. pp. 448-456.

“Center for Disease Control and Prevention. STD Surveillance case definitions”.

“Center for Disease Control and Prevention: Syphilis – 2015 STD Treatment Guidelines”.

Larsen, SA. “Syphilis”. . vol. 9. 1989. pp. 545

Workowski, KA, Bolan, GA. “Sexually transmitted diseases treatment guidelines, 2015”. . vol. 64. 2015. pp. 1

Brown, ST, Saidi, A, Larsen, SA, Reynolds, GH. “Serological response to syphilis treatment. A new analysis of old data”. . vol. 253. 1985. pp. 1296

Marra, CM, Maxwell, CL, Smith, SL. “Cerebrospinal fluid abnormalities in patients with syphilis: association with clinical and laboratory features”. . vol. 189. 2004. pp. 369

Ghanem, KG, Moore, RD, Rompalo, AM. “Lumbar puncture in HIV-infected patients with syphilis and no neurologic symptoms”. . vol. 48. 2009. pp. 816

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