AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Syphilis is a communicable disease caused by Treponema pallidum, which belongs to the Spirochaetaceae family. The genus name, Treponema, is derived from the Greek term for "turning thread." Pathogenic members of this genus include T pallidum, Treponema pertenue, and Treponema carateum.

Between 1905 and 1910, Schaudinn and Hoffman identified T pallidum as the cause of syphilis, and Wasserman described a diagnostic test for the long-recognized infection. Pathogenic treponemes are associated with the following 4 diseases:

• Venereal syphilis, caused by T pallidum pallidum
• Yaws, caused by T pallidum pertenue
• Endemic syphilis (bejel), caused by T pallidum endemicum
• Pinta, caused by T carateum

The treponemes responsible for these diseases cannot be distinguished serologically, morphologically, or by genome analysis, and they have not been successfully cultivated on artificial media.

Pathophysiology

When untreated, syphilis is a lifelong infection that progresses in 3 clear characteristic stages. After initial invasion through mucous membranes or skin, the organism rapidly multiplies and widely disseminates. The organism spreads through the perivascular lymphatics and then the systemic circulation before clinical development of the primary lesion. The primary lesion, which contains infectious treponemes, arises within hours after infection and persists throughout primary and secondary disease.

Secondary lesions develop when spirochetal invasion of tissues of ectodermal origin (eg, skin, mucous membranes, CNS) precipitates an inflammatory response. These lesions develop 6-12 weeks after infection. This stage of rapid spirochete multiplication and dissemination may bring invasion of the entire body. Thus, tertiary syphilis may involve any organ system.

Secondary infection becomes latent within 1-2 months after the rash onset. Relapses with secondary manifestations can be seen during the first year of latency, a period referred to as the early latent period. Early latent syphilis (ie, duration <1 y) is when the recurrent lesions of secondary syphilis are most likely to occur. No relapses occur after the first year; what follows is late syphilis, which may be either asymptomatic (ie, late latent) or symptomatic (ie, tertiary). Late latent syphilis is associated with resistance to both reinfection and relapse.

Tertiary neurosyphilis can manifest in various ways. Meningeal syphilis rarely occurs and presents a few years following the original infection. Late neurosyphilis may present with focal ischemia of the CNS or stroke as a result of endarteritis of small blood vessels of the brain. Meningovascular syphilis can affect any part of the CNS. Actual destruction of the nerve cells in the cerebral cortex leads to a combination of psychiatric manifestations and neurologic findings.

Congenital syphilis is caused by transplacental transmission of spirochetes; the transmission rate approaches 100%. Perinatal death may result from congenital infection in more than 40% of affected, untreated pregnancies. Among survivors, manifestations have traditionally been divided into early and late stages. Manifestations are defined as early if they appear in the first 2 years of life and late if they develop after age 2 years.

Because inflammatory changes do not occur in the fetus until after the first trimester of pregnancy, organogenesis is unaffected. Nevertheless, all organ systems may be involved. With early onset disease, manifestations result from transplacental spirochetemia and are analogous to the secondary stage of acquired syphilis. Congenital syphilis does not have a primary stage. Late-onset disease is seen in patients older than 2 years and is not considered contagious.

Frequency

United States

From 1985-1990, overall syphilis incidence increased 75%. This resurgence was primarily due to increased illegal drug use (particularly crack cocaine) that was associated with an exchange of sex for drugs. Concomitant infection with human immunodeficiency virus (HIV) is also common because HIV and syphilis affect similar patient groups.

An overall increase in syphilis incidence has been observed in the United States, and most infected individuals are men who have sex with other men; this may also lead to an increase in HIV infection and other sexually transmitted diseases (STDs).¹

International

The disease occurs worldwide, predominantly in large cities. With the exception of the United States, syphilis is less common in developed nations.

Certain European countries have seen an increase in congenital syphilis cases, and syphilis remains a major public health problem in sub-Saharan Africa and in the developing world. The main focus in controlling syphilis is antenatal screening and treatment of mothers who are infection.
 
A high prevalence of syphilis and other STDs was noted in Venezuela in a recent study.²

Mortality/Morbidity

Syphilis causes untold morbidity and remains a significant cause of mortality if left untreated.

Race

Syphilis has no racial predilection, although its incidence appears to correlate with the socioeconomic factors that contribute to disease prevalence among individuals with low incomes, who live in urban and overcrowded areas, in whom drug use and the exchange of sex for drugs may be more common.

Sex

Historically, men were more commonly infected than women; however, a study involving high-risk adolescents has reported 69% of cases involved young women, indicating that the gender distribution of syphilis is in flux.

Age

Adolescent and young adults are most at risk due to sexual and other risk-taking behaviors (eg, drug use).

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Most recognized syphilitic disease in children is congenital. A pregnant woman with syphilis who has not received therapy or who has received inadequate therapy may transmit the infection to the fetus at any clinical stage of the disease. Assume children with acquired syphilis have been infected through sexual abuse, unless another method of transmission is identified. Syphilis, previously known as the great imitator, can have numerous and complex manifestations.

• Primary syphilis: The primary lesion, called a chancre, is painless but slightly tender. It usually develops at the site of the infection an average of 3 weeks after exposure to T pallidum. Patients may ignore a visible lesion because it is painless unless it becomes secondarily infected.
• Secondary syphilis
• • Because of the widespread dissemination of spirochetes, frequent constitutional symptoms include fever, malaise, pharyngitis, rash, anorexia, arthralgias, and generalized painless lymphadenopathy.
  • Renal, hepatic, and ophthalmologic manifestations may be present.
  • Meningitis occurs in 30% of patients with secondary syphilis but may be asymptomatic. Symptomatic aseptic meningitis occurs in 1-2% of patients and is characterized by headache, stiff neck, nausea, and vomiting.
• Tertiary syphilis
• • Tertiary neurosyphilis presents with symptoms of meningitis or with focal deficits consistent with stroke. The mnemonic device "PARESIS" is an aid to recall the following types of symptoms:
  • • Personality
    • Affect
    • Reflexes (eg, hyperactive)
    • Eye (eg, Argyll Robertson pupils)
    • Sensorium (eg, illusions, delusions, hallucinations)
    • Intellect (eg, decreased recent memory, orientation, judgment, insight)
    • Speech abnormalities
  • Syphilis at any stage can affect ears and eyes. Such involvement may be the only presentation, and, therefore, any patient with unexplained hearing loss, vestibular abnormalities, or ocular inflammation should be tested for treponemal antibodies. Syphilis should be considered in the differential diagnosis of inflammatory ocular hypertension syndrome. Patients may present with uveitis and serologic evidence of syphilis.
• Early onset congenital syphilis
• • Most affected infants are asymptomatic at birth and are identified only by routine prenatal screening. If untreated, symptoms develop within weeks or months. The typical stillborn or highly symptomatic newborn is born prematurely with an enlarged liver and spleen, skeletal involvement, and often pneumonia and bullous skin lesions.
  • The earliest signs of congenital syphilis may be poor feeding and snuffles (ie, syphilitic rhinitis).

Physical

• Primary syphilis
• • Primary syphilis is characterized by a painless papule at the site of inoculation that quickly erodes, leaving an ulcer (the chancre). The base of the ulcer is smooth, without exudate, and the borders are raised and firm.
  • Painless nonsuppurative enlargement of local lymph nodes accompanies the chancre and can persist for months.
  • Primary chancres heal within 3-6 weeks.
• Secondary syphilis
• • Mucocutaneous lesions are the most frequent signs of disease and strongly suggest the diagnosis. Discrete, macular, pink-to-red lesions are 3-10 mm in diameter and may spread to involve the entire body, including the palms, soles, and other locations.
  • Unlike the primary lesions, secondary lesions do not ulcerate. These lesions often evolve from macules into red papules and, in a few patients, finally progress to pustules. 
  • Vesicular lesions are conspicuously absent. 
  • Painless generalized lymphadenopathy is found in 85% of patients. 
  • Broad grayish plaques called condyloma lata may be found in warm, moist, intertriginous areas. 
  • Mucous patches are superficial, silver-gray erosions that occur on mucous membranes.
• Tertiary syphilis manifestations are divided into the following subgroups:
• • In benign tertiary syphilis, gummatous lesions are found in skin and bones but rarely in other organs. Gummas are considered benign because they rarely involve vital body structures.
  • Cardiovascular tertiary syphilis can cause aortitis, aortic aneurysm, coronary stenosis, aortic insufficiency, and myocarditis. Prevention of late syphilis can be adequately achieved by treating early syphilis. The treatments of choice are penicillin administration and surgical intervention in severe cases.
  • Meningitic tertiary neurosyphilis manifests with signs of meningitis and is differentiated from other causes of aseptic meningitis by a reactive result on a Venereal Disease Research Laboratory (VDRL) test of cerebrospinal fluid (CSF); this test is termed a CSF VDRL.
  • Late neurosyphilis may present with focal neurological findings suggestive of a stroke.
• Syphilis in pregnancy
• • Syphilis in pregnancy can lead to spontaneous abortion, stillbirth, premature delivery, or perinatal death. It can also cause significant morbidity during infancy, childhood, and adolescence. A very strict follow-up of pregnant women before delivery and an active approach to identify and treat exposed neonates born to infected mothers are strongly recommended.
  • A study in Nigeria has demonstrated the usefulness of syphilis screening during pregnancy and recommended that syphilis screening should be continued as part of routine antenatal testing.³
• Early onset congenital syphilis
• • Early manifestations of congenital infection vary and involve multiple organ systems. The most striking lesions affect the mucocutaneous tissues and bones. Mucous patches, rhinitis, and condylomatous lesions are highly characteristic features of mucous membrane involvement in congenital syphilis.
  • Nasal fluid is highly infectious. Snuffles are followed quickly by a diffuse maculopapular desquamative rash that involves extensive sloughing of the epithelium, particularly on the palms and soles and around the mouth and anus. In contrast to acquired syphilis, a vesicular rash and bullae may develop. These lesions are highly infectious.
  • Hepatomegaly is reported in almost 100% of cases, and biochemical evidence of liver dysfunction is usually observed.
• Late-onset congenital syphilis
• • Scarring from the early systemic disease causes late manifestations of congenital syphilis.
  • Manifestations include neurosyphilis and involvement of the teeth, bones, eyes, and the eighth cranial nerve.

Causes

Syphilis transmission usually occurs transplacentally or by sexual contact. Vertical transmission of early syphilis during pregnancy results in a congenital infection in at least 50-80% of exposed neonates. Other modes of transmission include contact with contaminated blood or infected tissues. Children encounter 2 forms of syphilis: acquired syphilis, which is almost exclusively transmitted by sexual contact, and congenital syphilis, which results from transplacental transmission of spirochetes. A report of a syphilis outbreak in North Carolina described an association between crack cocaine and sex for drugs as a causative factor. ⁴

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Anthrax
Bejel
Granuloma inguinale
Lymphogranuloma venereum
Pinta
Rat-bite fever
Relapsing fever
Sepsis
Venereal warts
Yaws

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Serologic testing is commonly used to confirm a diagnosis of syphilis. Direct examination for spirochetes is definitive, when positive, and histopathology may also be useful. Ancillary testing is generally required, depending on the clinical circumstance.
• Because the organism cannot be cultured on artificial media, simple laboratory stains fail to demonstrate the spirochetes. Clinical manifestations of infection are protean. Serology has the primary role in confirming the diagnosis. The 2 types of serologic tests for syphilis are nontreponemal reaginic tests and treponema-specific tests.
• • Nontreponemal reaginic serologic tests
  • • A positive nontreponemal reaginic test must be confirmed by a treponema-specific test. Depending on the clinical circumstance, treatment can begin before confirmation is received.
    • Nontreponemal reaginic tests include the rapid plasma reagin (RPR), the VDRL, and the automated reagin test (ART), all of which are useful in routine screening and are equally sensitive, inexpensive, simple to perform, and rapid. These tests are also useful for ongoing measurement of disease activity (eg, measuring response to treatment or testing for reinfection).
    • These tests measure antibody directed against a lipoidal antigen that results from the interaction of host tissues with T pallidum or to the spirochete itself. Nonspecific antibodies develop 4-8 weeks following infection.
    • Seroreactivity occurs in 70% of patients within 2 weeks of developing a chancre and in 100% of patients with secondary and latent disease. The tests may have false-negative findings in early primary syphilis, latent acquired syphilis of long duration, and late congenital syphilis.
    • Quantitative results of these tests tend to correlate with disease activity; thus, they are very helpful for screening. A 4-fold or greater rise in titer may be seen during the evolution of early syphilis. In secondary syphilis, test results are always positive and often at a high titer (ie, at least 1:32).
    • A prozone phenomenon occurs in approximately 2% of patients, especially in those with secondary syphilis and those who are pregnant. High levels of antibody in undiluted serum cause an obscured positive test result. When clinical findings strongly suggest syphilis (eg, an infant with the appearance of congenital syphilis, despite negative maternal serology), perform appropriate dilutions to exclude this phenomenon.
    • The quantitative RPR, VDRL, or ART tests should become nonreactive one year after successful therapy in primary syphilis, 2 years after successful treatment in secondary or congenital syphilis, and 5 years after successful therapy in late syphilis. Meanwhile, a sustained 4-fold decrease in titer demonstrates adequate therapy.
    • Similarly, a 4-fold increase in titer following therapy suggests reinfection or relapse and necessitates reevaluation.
    • False-positive test results occur when the antigen recognized in the nontreponemal tests is found in other tissues. When findings become negative within 6 months, the case is termed acute, whereas cases that persist longer are termed chronic. False-positive test findings in acute illness may result from an acute immunologic stimulus (eg, acute bacterial or viral infection, vaccination, early HIV infection). False-positive test results in chronic syphilis may be due to parenteral drug use, autoimmune or connective tissue diseases (especially systemic lupus erythematosus), aging, and hypergammaglobulinemic states. A false-positive nontreponemal test finding can usually be identified by using treponema-specific tests.
  • Treponema-specific tests
  • • These tests, which measure antibodies specific for T pallidum, include T pallidum immobilization (TPI), fluorescent treponemal antibody absorption (FTA-ABS), and microhemagglutination assay for antibodies to T pallidum (MHA-TP).
    • Use these tests in all cases to confirm a positive nontreponemal reaginic test.
    • Treponema-specific tests are not completely specific for syphilis because false-positive reactions can occur with other spirochetal diseases (eg, yaws, pinta, leptospirosis, rat-bite fever, relapsing fever, Lyme disease [which causes a negative VDRL test result]).
    • These test findings become positive soon after infection and typically remain positive for life, despite adequate treatment. Test results do not correlate with disease activity and tests are not quantified.
    • The immunoglobulin M (IgM) FTA-ABS measures antibody specific to the infant born to an infected mother. However, this test is less specific than once thought and is available only at the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia so its general usefulness is questionable.
• Direct examination for spirochetes is as follows:
• • An uncommon method to achieve definitive diagnosis is to identify spirochetes by microscopic darkfield examination or by direct fluorescent antibody tests on exudate or tissue. Examination of a serous transudate from moist lesions (eg, the primary chancre, condyloma latum, mucous patch, placenta) is most productive because these lesions have the largest numbers of treponemes.
  • Darkfield microscopy is particularly helpful early in the disease, prior to development of seroreactivity.
  • Consider a suspicious lesion to be nonsyphilitic only after 3 competent examinations with negative findings have been performed.
  • Specimens from the oral cavity cannot be used because nonpathogenic treponemes are part of the normal oropharyngeal flora.
• The organism's presence can be demonstrated by histopathology (see Histologic Findings) and by the following ancillary tests:
• • Cerebrospinal fluid (CSF) analysis
  • • The CNS becomes involved in as many as 40% of patients because of seeding during the inevitable spirochetemia. Asymptomatic involvement can be detected only by CSF analysis for pleocytosis, increased protein concentration, and a VDRL test. A CSF WBC count greater than 10/μL (10 × 10⁶/L) or a CSF protein level greater than 50 mg/dL (0.50 g/L) indicates possible neurosyphilis.
    • CSF examination is essential in evaluating any seropositive patient with neurologic signs or symptoms and is recommended for all untreated patients who have had syphilis more than one year or when duration is unknown.
    • Although the only specific diagnostic test for CNS disease in congenital syphilis is a reactive CSF VDRL test result, newborns may have a negative CSF VDRL test result and still develop signs of neurosyphilis. Therefore, all those with presumptive congenital syphilis should be treated for neurosyphilis.
    • A nonquantitative VDRL test is the only serologic test that should be performed on CSF. Because this test is highly specific, but relatively insensitive, a negative result does not exclude neurosyphilis.
  • CBC count
  • • Congenital syphilis is characterized by anemia, thrombocytopenia, and either leukopenia or leukocytosis.
    • Monocytosis is common.
    • Evidence of Coombs-negative hemolytic anemia or a leukemoid reaction may be present.
  • LFT
  • • Syphilitic hepatitis is characterized by a disproportionately high alkaline phosphatase level and a normal or moderately elevated serum bilirubin level but no cholestasis.
    • Aspartate aminotransferase and alanine aminotransferase levels are often elevated.
    • Prothrombin time may be increased.
  • HIV testing: Fifteen percent of adolescents and adults with syphilis are co-infected with HIV. All patients who present with syphilis should be offered HIV testing, and all patients with HIV infection should be regularly screened for syphilis.
  • Testing for other STDs: Any patient diagnosed with either syphilis or HIV should also be tested for Chlamydia species, gonorrhea, hepatitis B, and hepatitis C infection.

Imaging Studies

• Chest radiography: Syphilitic pneumonia is common in congenital syphilis and appears as a fluffy diffuse infiltrate termed pneumonia alba.
• Long bone radiography
• • Bone involvement is common in congenital syphilis. Radiologic abnormalities are exceedingly common in early syphilis and are found in 95% of symptomatic infants and as many as 20% of infants with asymptomatic disease.
  • Bone involvement includes multiple sites of osteochondritis at the wrists, elbows, ankles, and knees and periostitis of long bones and, rarely, the skull.
  • Lesions are symmetric and involve multiple bones. The lower extremities almost always are affected.
  • Metaphyseal lesions (ie, osteochondritis) vary from punctate lucencies to more destructive changes.
• Neuroradiography: Neuroradiological findings in patients with neurosyphilis are nonspecific and may mimic herpes simplex virus and limbic encephalitides infection. MRI may reveal cerebral hypertrophy and hyperintensity in the temporal lobes.

Other Tests

• LIAISON Treponema Assay (DiaSorin; Saluggia, Italy), a one-step sandwich chemiluminescent immunoassay (CLIA), was compared with conventional tests.⁵The test demonstrated higher sensitivity and specificity as a screening and confirmatory tool compared with conventional methods.
• If discrepancies are noted between enzyme-linked immunoassay (ELISA) immunoglobulin G (IgG) test findings and T pallidum hemagglutination (TPHA) test findings, the Captia SelectSyph-G test (Trinity Biotech; Jamestown, NY) is a highly sensitive and specific test that can be used as a confirmatory test.⁶
• Real-time polymerase chain reaction (PCR) is an effective and sensitive assay used to detect T pallidum in the vitreous in patients with syphilitic chorioretinitis.
  
  

Procedures

• Lumbar puncture: In addition to serology (VDRL test), direct examination of CSF by darkfield microscopy may be diagnostic.

Histologic Findings

The presence of obliterative endarteritis, which consists of concentric endothelial and fibroblastic proliferative thickening, strongly suggests syphilis. These pathologic changes are found in all stages of syphilis. In the primary chancre, polymorphonuclear leukocytes and macrophages can often be revealed to be ingesting treponemes. In biopsy specimens, the spirochete may be visualized with specific immunofluorescence or immunoperoxidase staining.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Penicillin remains the DOC to treat all stages of syphilis; no evidence suggests an increasing penicillin resistance. Primary, secondary, and early latent diseases are treated with a single intramuscular (IM) dose of benzathine penicillin G (50,000 U/kg; not to exceed 2.4 million U). Although other regimens can be considered in patients with a penicillin allergy, desensitization followed by penicillin is the most preferred method.

Patients who are allergic to penicillin and do not have neurosyphilis and are not pregnant may be treated with either doxycycline (100 mg PO bid for 2 wk) or tetracycline (500 mg PO qid for 2 wk). Shorter-acting forms of penicillin must be used to treat neurosyphilis to produce reliably therapeutic levels in the CSF.

Indications for CSF examination prior to initiating treatment of syphilis include the following:

• Evidence of neurosyphilis
• Evidence of tertiary syphilis (eg, aortitis, gumma, iritis)
• Treatment failure
• Patients with HIV infection with late latent syphilis or syphilis of unknown duration
• Rapid plasma reagin (RPR) test result exceeding 1:32 (unless syphilis duration <1 y)

CSF interpretation is difficult in newborns because the normal values for CSF cell count and protein concentration widely vary. In addition, a negative CSF VDRL test result cannot exclude neurosyphilis. Conversely, the CSF VDRL test result can be positive in an uninfected newborn with a transplacentally acquired high serum VDRL finding. Thus, all infants suspected of having congenital syphilis should be treated for neurosyphilis.

• Congenital syphilis in newborns: Treat the congenital infection, either proven or presumed, with 10-14 days of aqueous penicillin G or procaine penicillin G. Aqueous crystalline penicillin G is recommended if congenital syphilis is proved or is highly suspected. Base dosage on chronologic, not gestational, age. The recommended dosage is 100,000-150,000 U/kg/d IV q8-12h to complete a 10- to 14-day course. Procaine penicillin G (50,000 U/kg IM) has been recommended as an alternative to treat congenital syphilis, but adequate CSF concentration may not be consistently achieved. Infection is suspected with the following:
• • Physical or radiographic evidence of active disease
  • Serum quantitative nontreponemal titer at least 4 times greater than the maternal titer
  • Reactive CSF VDRL test result or abnormal CSF cell count and/or protein levels
  • Positive IgM FTA-ABS test findings
  • Positive darkfield microscopy findings or positive findings when staining for treponemes in placenta or umbilical cord
• Congenital syphilis in older infants and children: Treat diagnosed infants older than 4 weeks with aqueous crystalline penicillin (200,000-300,000 U/kg/d IV divided q6h for 10-14 d). 
• Syphilis in pregnancy
• • Treat all pregnant patients with syphilis with penicillin, regardless of the stage of pregnancy.
  • Administer 3 doses of benzathine penicillin (2.4 million U IM at 1-wk intervals).
  • No proven alternative therapy is available for patients who are allergic to penicillin.
  • Erythromycin treatment for the pregnant patients who are allergic to penicillin is not a reliable treatment for the fetus.
• Early-acquired syphilis (ie, primary, secondary, latent syphilis of <1 y duration): A single dose of IM benzathine penicillin G in a total dose of 50,000 U/kg (not to exceed 2.4 million U) is the recommended treatment. Exclude neurosyphilis by CSF examination in all pediatric patients.
• Syphilis (>1 y duration): The recommended treatment is benzathine penicillin G, 50,000 U/kg IM (not to exceed 2.4 million U) weekly for 3 successive weeks.
• Neurosyphilis: The recommended treatment is aqueous crystalline penicillin G (200,000-300,000 U/kg/d IM [50,000 U/kg q4-6h]) for 10-14 days (adult dose, 12-24 million U/d [2-4 million U q4h]), followed by a single dose of benzathine penicillin (50,000 U/kg/dose, not to exceed 2.4 million U) in 3 weekly doses.

Consultations

• Infectious disease specialist: Consultation with an infectious disease specialist is useful in most cases.
• Neurologist: Consultation with a neurologist is prudent if neurosyphilis is present or suspected.
• Ophthalmologist: Keratitis and optic atrophy are common; slit lamp examination and follow-up are important.
• Orthopedist: Skeletal gummas most often involve the legs. Bony involvement in congenital syphilis frequently resolves in the first 6 months, but lesions may be painful until healed.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

T pallidum is extremely sensitive to penicillin. Primary, secondary, and early latent syphilis are treated with a single IM dose of penicillin G benzathine (50,000 U/kg; not to exceed 2.4 million U). Nonpregnant patients who are allergic to penicillin and have no evidence of neurosyphilis can be treated with either doxycycline or tetracycline. Incubating syphilis can also be managed with penicillin. Spectinomycin is ineffective for incubating syphilis. Current recommendations for management of congenital syphilis include administration of IV penicillin G aqueous and IM penicillin G procaine for 10-14 days. Either penicillin regimen is considered adequate to manage congenital syphilis.

The Jarisch-Herxheimer reaction is the major complication of therapy and occurs in 50% of patients with primary syphilis, in 90% of those with secondary syphilis, and in 25% of those with early latent syphilis. First described in patients with syphilis by Jarisch in 1895 and then Herxheimer in 1902, the reaction occurs during the first 24 hours of treatment and consists of the abrupt onset of fever, chills, myalgias, headache, tachycardia, hyperventilation, vasodilation with flushing, and mild hypotension.

Onset begins within 2 hours of treatment initiation; the temperature peaks at about 7 hours, and defervescence takes place within 12-24 hours. The reaction, which is self-limited, is associated with an increase in circulating levels of tumor necrosis factor, interleukin (IL)-6, and IL-8.

Drug Category: Antibiotics

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the clinical setting. Antibiotic selection should be guided by blood-culture sensitivity whenever feasible.

Drug Name	Penicillin G procaine (Crysticillin A.S., Wycillin)
Description	An injection (300,000 U/mL, 500,000 U/mL, and 600,000 U/mL) that contains 120 mg procaine per 300,000 U; seldom recommended for congenital syphilis because adequate levels in the CSF may not be achieved.
Pediatric Dose	Congenital syphilis: Neonates: 50,000 U/kg/d IM qd for 10-14 d
Contraindications	Documented hypersensitivity
Interactions	Increases risk of bleeding when concurrently administered with warfarin; ethacrynic acid, aspirin, indomethacin, and furosemide may compete with penicillin G for renal tubular secretion, increasing penicillin serum concentrations; probenecid increases serum levels
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	IM administration only, do not administer IV; cardiac arrest and death may occur with high doses

Drug Name	Penicillin G (Pfizerpen)
Description	Aqueous penicillin injection (K): 1, 5, 10, and 20 million U (contains 1.7 mEq K and 0.3 mEq Na/1 million U penicillin G) Injection (Na): 5 million U (contains 2 mEq Na/1 million U penicillin G) Interferes with synthesis of cell wall mucopeptide during active multiplication, resulting in bactericidal activity against susceptible microorganisms.
Adult Dose	Neurosyphilis: 2.4 million U IV q4h for 10-14 d
Pediatric Dose	Congenital syphilis: Neonates: 50,000 U/kg IV q12h for first 7 d, then 50,000 U/kg IV q8h for a total of 10-14 d Infants and children 4 wk and older: 200,000-300,000 U/kg/d IV divided q6h for 10-14 d
Contraindications	Documented hypersensitivity
Interactions	Probenecid can increase effects of penicillin; coadministration of tetracyclines can decrease effects of penicillin
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Caution in impaired renal function

Drug Name	Tetracycline (Sumycin)
Description	May be an alternative to penicillin in nonpregnant patients who are allergic to penicillin; inhibits bacterial protein synthesis by binding with 30S and, possibly, 50S ribosomal subunits.
Adult Dose	500 mg PO qid for 2 wk
Pediatric Dose	Not recommended
Contraindications	Documented hypersensitivity; severe hepatic dysfunction
Interactions	Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; can decrease effects of PO contraceptives, causing breakthrough bleeding and increased risk of pregnancy; tetracyclines can increase hypoprothrombinemic effects of anticoagulants
Pregnancy	D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions	Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (final half of pregnancy through age 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines

Drug Name	Doxycycline (Vibramycin)
Description	Another alternative to penicillin for nonpregnant patients who are allergic to penicillin; inhibits protein synthesis and, thus, bacterial growth by binding to 30S and, possibly, 50S ribosomal subunits.
Adult Dose	100 mg PO bid for 2 wk
Pediatric Dose	Not recommended
Contraindications	Documented hypersensitivity; severe hepatic dysfunction
Interactions	Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; tetracyclines can increase hypoprothrombinemic effects of anticoagulants; tetracyclines can decrease effects of PO contraceptives, causing breakthrough bleeding and increased risk of pregnancy
Pregnancy	D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions	Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (final half of pregnancy through age 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines

Drug Name	Erythromycin (E.E.S., E-Mycin, Ery-Tab)
Description	An alternative to penicillin for patients who are allergic to penicillin; inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes causing RNA-dependent protein synthesis to arrest.
Adult Dose	500 mg PO qid for 2 wk
Pediatric Dose	Not recommended
Contraindications	Documented hypersensitivity; hepatic impairment
Interactions	Coadministration may increase toxicity of theophylline, digoxin, carbamazepine, and cyclosporine; may potentiate anticoagulant effects of warfarin; coadministration with lovastatin and simvastatin, increases risk of rhabdomyolysis
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Does not effectively treat fetal infection; caution in liver disease; GI adverse effects are common (administer give doses pc); discontinue use if nausea, vomiting, malaise, abdominal colic, or fever occur

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Standard precautions are recommended for all patients with primary and secondary syphilis because these lesions are moist and potentially infectious.

Further Outpatient Care

• Follow up congenital syphilis with evaluation at ages 1, 2, 4, 6, and 12 months. Obtain nontreponemal titers at ages 3, 6, and 12 months after conclusion of treatment. Nontreponemal antibody titers should decline by age 3 months and should be nonreactive by age 6 months. Consider retreatment for patients with persistently stable titers, including low titers.
• Infants who are treated for congenital neurosyphilis should undergo repeat clinical evaluation and CSF examination at 6-month intervals until their CSF examination result is normal. A positive CSF VDRL result at age 6 months is an indication for retreatment.
• Follow up early acquired syphilis with a quantitative nontreponemal test at 3-, 6-, and 12-month intervals after conclusion of treatment. Patients with syphilis for more than one year also should undergo serologic testing 24 months after treatment. Pregnant patients who have received treatment should have quantitative serologic testing monthly for the remainder of their pregnancy.

Transfer

• Transfer to another facility is appropriate if the required specialists or treatments are unavailable locally.

Deterrence/Prevention

• Although rates of early syphilis are declining, maintaining a high index of suspicion about at-risk patients is important. Indications for syphilis screening include the following:
• • Exposure to a known case of infectious syphilis
  • All women at first prenatal visit and high-risk women again at 28 weeks' gestation (Forty six of the 50 states [90%] and the District of Columbia have laws regarding antenatal syphilis screening during pregnancy and at delivery.)
  • All women that deliver a stillborn infant
  • All newborns older than 22 weeks' gestation whose mothers were not screened
  • Anyone diagnosed with a STD or anyone presenting for STD evaluation
  • Any person who tests positive for HIV
  • Anyone engaging in high-risk behaviors (eg, drug use, prostitution, unprotected sex)
• Drainage and secretion precautions are necessary for all patients who have suspected or proven syphilis until therapy has been administered for at least 24 hours.
• Trace and contact all sexual partners of infected patients
• All persons (including health care providers) who have had close, unprotected contact with early congenital syphilis before identification of the disease or during the first 24 hours of therapy should be examined clinically for the presence of lesions 2-3 weeks after contact. Serologic testing should be performed and repeated 3 months after contact or earlier if symptoms occur. Consider immediate treatment if the degree of exposure may have been significant.
• Many people who are sexually assaulted do not comply with recommended follow-up, so consider empiric therapy for these patients.

Complications

• Virtually any organ in the body can be involved.
• Fatal osteomyelitis of sternal bone caused by syphilis infection has been reported in a homosexual man.⁷ T pallidum DNA PCR was used for the first time to diagnose this condition with very promising results.

Prognosis

• With adequate and timely treatment, prognosis is excellent.
• Patients with HIV infection have a high rate of failed serologic response to syphilis treatment. Most of them show no response or inadequate response after being treated for syphilis.

Patient Education

• Until a practical and effective vaccine is developed, syphilis prevention depends on abstinence, the use of condoms, and detection and identification of infectious cases. Education about STDs, treatment of sexual contacts, and the reporting of each case to local public health authorities are essential.
• For excellent patient education resources, visit eMedicine's Sexually Transmitted Diseases Center and Pregnancy and Reproduction Center. Also, see eMedicine's patient education articles Sexually Transmitted Diseases, Syphilis, Birth Control Overview, and Birth Control FAQs.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Routine prenatal screening for syphilis remains the most important factor in identifying infants at risk of developing congenital syphilis. Screening is legally required at the beginning of prenatal care in all states.
• No newborn should leave the hospital without determination of maternal serologic status at least once during pregnancy.
• Testing of mother's serum is preferred to testing cord blood or the infant's serum because the titers frequently are lower in the infant and may be nonreactive if the mother was infected late in pregnancy. 
• Test for syphilis any woman who delivers a stillborn infant after 20 weeks' gestation.
• Screen women at high risk for syphilis more frequently because they may have repeat infections during pregnancy or become reinfected late in pregnancy.
• Laboratory evaluation of sexually abused children should include serologic testing for syphilis if the assailant has a history of syphilis or other STD. A suspicion of child sexual abuse mandates filing a report with child protective services or law enforcement agencies.
• Syphilitic stillbirth is considered fetal death after 20 weeks' gestation or when a fetus weighs more than 500 g and the mother had untreated or inadequately treated syphilis at delivery. Report these cases as congenital syphilis.
• Diseases that cause genital ulcers, including syphilis, may provide vascular portals of entry for HIV. Evaluate any patient with known or suspected syphilis for the possibility of neurosyphilis, which is known to have an increased incidence among individuals with HIV infection.
• Consider STD prophylaxis for rape victims.

Special Concerns

• Syphilis in pregnancy
• • Treponemes appear able to cross the placenta at any time during pregnancy, thereby infecting the fetus. Syphilis can cause preterm delivery, stillbirth, congenital infection, or neonatal death, depending on the stage of maternal infection and the duration of fetal infection prior to delivery. The American College of Obstetricians and Gynecologists and the American Academy of Pediatrics in their joint publication, Guidelines for Perinatal Care, recommend screening for syphilis at the first prenatal visit for all women and at 32-36 weeks’ gestation for women who are at risk.⁸ In the  2003 Red Book: Report of the Committee on Infectious Diseases, the American Academy of Pediatrics recommends screening early in pregnancy and preferably again at delivery.⁹
  • All pregnant women should have a nontreponemal serologic test for syphilis at the first prenatal visit. Perform a second test during the third trimester, especially in those at increased risk of contracting disease. Seropositivity with a nontreponemal test requires complete evaluation, including quantitative nontreponemal serology and confirmatory treponemal serology.
  • CDC policy states that no newborn should leave a hospital without documentation of the mother's serologic status at least once during the pregnancy. Serologic testing should also be performed at delivery in communities and populations at risk of acquiring congenital syphilis.
  • Penicillin is the only recommended therapy for syphilis in pregnancy. If the patient has a penicillin allergy that is confirmed by the demonstration of an immediate wheal-and-flare response to skin testing with penicilloyl-polylysine or penicillin G minor determinant mixture, desensitization and penicillin treatment should be performed in a hospital, following the 1993 STD guidelines issued by CDC.
  • Warn patients about the risk of a Jarisch-Herxheimer reaction; this reaction may be associated with mild premature contractions but rarely results in premature delivery.
• Syphilis in persons with HIV
• • Concomitant HIV and syphilis is common.
  • Serologic tests for syphilis may be modified by the presence of HIV, usually resulting in extremely high titers and failure to decrease in response to adequate treatment.
  • A serologic response may fail to develop.
  • Treatment of co-infected individuals may require high-dose or prolonged therapy.
  • Some authorities, persuaded by reports of the persistence of T pallidum in the CSF of persons infected by HIV after standard penicillin benzathine therapy for early syphilis, now recommend CSF examination of all co-infected patients for neurosyphilis, regardless of the clinical stage of syphilis. These authorities treat for neurosyphilis when no CSF examination is performed or when examination reveals CSF abnormalities.
  • Serologic testing after treatment is important for all patients with syphilis, particularly those co-infected with HIV.
• Persistent infection
• • The question of persistent infection despite adequate therapy has been controversial. Sequestration of spirochetes has been reported in such sites as the anterior chamber of the eye, the CNS, and the labyrinth of the inner ear. CSF parameters are expected to normalize within 2 years. Failure to normalize may warrant retreatment.
  • Anyone with neurologic, optic, or otic abnormalities who has or has a history of syphilis (current or untreated) should be considered for CSF examination and should be treated for neurosyphilis.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Heffelfinger JD, Swint EB, Berman SM, Weinstock HS. Trends in primary and secondary syphilis among men who have sex with men in the United States. Am J Public Health. Jun 2007;97(6):1076-83. [Medline].
2. Vasquez-Manzanilla O, Dickson-Gonzalez SM, Salas JG, Rodriguez-Morales AJ, Arria M. Congenital syphilis in valera, Venezuela. J Trop Pediatr. Aug 2007;53(4):274-7. [Medline].
3. Taiwo SS, Adesiji YO, Adekanle DA. Screening for syphilis during pregnancy in Nigeria: a practice that must continue. Sex Transm Infect. Aug 2007;83(5):357-8. [Medline].
4. Sena AC, Muth SQ, Heffelfinger JD, et al. Factors and the sociosexual network associated with a syphilis outbreak in rural North Carolina. Sex Transm Dis. May 2007;34(5):280-7. [Medline].
5. Knight CS, Crum MA, Hardy RW. Evaluation of the LIAISON Treponema Assay, a Chemiluminescent Immunoassay for the Diagnosis of Syphilis. Clin Vaccine Immunol. Apr 25 2007;[Medline].
6. Woznicova V, Valisova Z. Performance of CAPTIA SelectSyph-G enzyme-linked immunosorbent assay in syphilis testing of a high-risk population: analysis of discordant results. J Clin Microbiol. Jun 2007;45(6):1794-7. [Medline].
7. Kandelaki G, Kapila R, Fernandes H. Destructive osteomyelitis associated with early secondary syphilis in an HIV-positive patient diagnosed by Treponema pallidum DNA polymerase chain reaction. AIDS Patient Care STDS. Apr 2007;21(4):229-33. [Medline].
8. American Academy of Pediatrics, American College of Obstetricians. Guidelines for Perinatal Care. 5^th ed. American Academy of Pediatrics; 2002.
9. American Academy of Pediatrics. Syphillis. In: Red Book: Report of the Committee on Infectious Diseases. 26^th ed. 2003:595-607.
10. Aktas G, Young H, Moyes A, Badur S. Evaluation of the fluorescent treponemal antibody absorption test for detection of antibodies (immunoglobulins G and M) to Treponema pallidum in serologic diagnosis of syphilis. Int J STD AIDS. Apr 2007;18(4):255-60. [Medline].
11. Behrman RE, Kliegman RM, Jenson HB. Syphilis. In: Textbook of Pediatrics. 2004:978-982.
12. Brion LP, Manuli M, Rai B. Long-bone radiographic abnormalities as a sign of active congenital syphilis in asymptomatic newborns. Pediatrics. Nov 1991;88(5):1037-40. [Medline].
13. Brown DL, Frank JE. Diagnosis and management of syphilis. Am Fam Physician. Jul 15 2003;68(2):283-90. [Medline].
14. Carrada-Bravo T. [Cardiovascular syphilis: diagnosis, treatment]. Arch Cardiol Mex. Oct-Dec 2006;76 Suppl 4:S189-96. [Medline].
15. Chakraborty R, Luck S. Managing congenital syphilis again? The more things change ... Curr Opin Infect Dis. Jun 2007;20(3):247-52. [Medline].
16. Feigin RD, Cherry JD. Syphilis. In: Textbook of Pediatric Infectious Diseases. 1998:1543-56.
17. Fiumara NJ. The diagnosis and treatment of infectious syphilis. Compr Ther. Nov 1995;21(11):639-44. [Medline].
18. Ghanem KG, Erbelding EJ, Wiener ZS, Rompalo AM. Serological response to syphilis treatment in HIV-positive and HIV-negative patients attending sexually transmitted diseases clinics. Sex Transm Infect. Apr 2007;83(2):97-101. [Medline].
19. Gomella TL, Cunningham MD, Eyal FG. Syphilis. Neonatology. 1999;430-2.
20. Gorbach SL, Bartlett JG, Blacklow NR. Syphilis. Infect Dis. 1998;980-6.
21. Gunn RA, Lee M, Oh C, Brodine S. Syphilis Serologic Prevalence Monitoring Among STD Clinic Clients: Correlation With Reported Syphilis Incidence, San Diego, CA, 1985-2004. Sex Transm Dis. Oct 2007;34(10):749-753. [Medline].
22. Gurses C, Bilgic B, Topcular B, et al. Clinical and magnetic resonance imaging findings of HIV-negative patients with neurosyphilis. J Neurol. Mar 2007;254(3):368-74. [Medline].
23. Hirshfeld AB, Getachew A, Sessions J. Drug doses. In: The Harriet Lane Handbook: A Manual for Pediatric House Officers. 2000:599-892.
24. Hollier LM, Cox SM. Syphilis. Semin Perinatol. Aug 1998;22(4):323-31. [Medline].
25. Hollier LM, Harstad TW, Sanchez PJ, et al. Fetal syphilis: clinical and laboratory characteristics. Obstet Gynecol. Jun 2001;97(6):947-53. [Medline].
26. Hollier LM, Hill J, Sheffield JS, Wendel GD Jr. State laws regarding prenatal syphilis screening in the United States. Am J Obstet Gynecol. Oct 2003;189(4):1178-83. [Medline].
27. Long SS, Pickering LK, Prober CG. Treponema pallidum (syphilis). In: Principles and Practice of Pediatric Infectious Diseases. 1997:1049-56.
28. Lukehart SA, Holmes KK. Syphilis. In: Harrison's Principles of Medicine. 1992:726-37.
29. Lynn WA, Lightman S. Syphilis and HIV: a dangerous combination. Lancet Infect Dis. Jul 2004;4(7):456-66. [Medline].
30. Mandell GL, Bennett JE, Dolin R. Treponema pallidum (syphilis). In: Principles and Practice of Infectious Diseases. 2000:2474-90.
31. Muller M, Ewert I, Hansmann F, et al. Detection of Treponema pallidum in the vitreous by PCR. Br J Ophthalmol. May 2007;91(5):592-5. [Medline].
32. Noordhoek GT, Cockayne A, Schouls LM. A new attempt to distinguish serologically the subspecies of Treponema pallidum causing syphilis and yaws [published erratum appears in J Clin Microbiol 1990 Dec;28(12):2853]. J Clin Microbiol. Jul 1990;28(7):1600-7. [Medline].
33. Pandhi D, Kumar S, Reddy BS. Sexually transmitted diseases in children. J Dermatol. Apr 2003;30(4):314-20. [Medline].
34. Reddy S, Cubillan LD, Hovakimyan A, Cunningham ET. Inflammatory ocular hypertension syndrome (IOHS) in Patients with Syphilitic Uveitis. Br J Ophthalmol. May 23 2007;[Medline].
35. Rome ES. Sexually transmitted diseases: testing and treating. Adolesc Med. Jun 1999;10(2):231-41, vi. [Medline].
36. Sanchez PJ, Wendel GD. Syphilis in pregnancy. Clin Perinatol. Mar 1997;24(1):71-90. [Medline].
37. Stamos JK, Rowley AH. Timely diagnosis of congenital infections. Pediatr Clin North Am. Oct 1994;41(5):1017-33. [Medline].
38. Steele RW. Prevention and management of sexually transmitted diseases in adolescents. Adolesc Med. Jun 2000;11(2):315-26. [Medline].
39. Tintinalli JE, Kelen KD, Stapczynski JS. Sexually transmitted diseases. Emerg Med. 2004;909-13.
40. Walker GJ, Walker DG. Congenital syphilis: A continuing but neglected problem. Semin Fetal Neonatal Med. Jun 2007;12(3):198-206. [Medline].
41. Wilson EK, Gavin NI, Adams EK, Tao G, Chireau M. Patterns in Prenatal Syphilis Screening Among Florida Medicaid Enrollees. Sex Transm Dis. Jun 2007;34(6):378-383. [Medline].

Article Last Updated: Oct 2, 2007