Syphilis is an infectious 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, T pertenue, and T 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 (Go to Endemic Syphilis for more complete information on this topic.)
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.
Children experience 2 forms of syphilis: acquired syphilis, which is almost exclusively transmitted by sexual contact, and congenital syphilis, which results from transplacental transmission of spirochetes (see Etiology).
Syphilis-especially in its later stages-can have numerous and complex manifestations and may resemble a number of other diseases. Syphilitic manifestations are categorized as primary, secondary, and tertiary (see Clinical Presentation).
Serologic testing has the primary role in the diagnosis (see Workup).
Penicillin remains the drug of choice to treat all stages of syphilis (see Treatment and Management, as well as Medications).
Go to Syphilis for more complete information on this topic.
When left 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 the clinical development of the primary lesion. The primary lesion, which contains infectious treponemes, arises within hours after infection and persists throughout the 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 an invasion of the entire body. Thus, tertiary syphilis may involve any organ system.
Secondary infection becomes latent within 1-2 months after 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 syphilis can manifest in various ways. Meningeal syphilis rarely occurs and presents a few years after the original infection. Late neurosyphilis may present as 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. The 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 90% if the mother has untreated primary or secondary syphilis. Fetal infection can develop at any time during gestation. Manifestations are defined as early if they appear in the first 2 years of life and late if they develop after age 2 years. According to a Centers for Disease Control and Prevention report, untreated syphilis, especially early syphilis, during pregnancy can lead to deafness, neurologic impairment, bone deformities, stillbirth, and neonatal death.[1] The clinical presentation of congenital neurosyphilis may be confused with a non-accidental injury.[2]
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.
Syphilis is caused by Treponema pallidum, which belongs to the Spirochaetaceae family. Syphilis transmission usually occurs transplacentally or by sexual contact. Other modes of transmission include contact with contaminated blood or infected tissues.
Children experience 2 forms of syphilis: acquired syphilis, which is almost exclusively transmitted by sexual contact, and congenital syphilis, which results from transplacental transmission of spirochetes. Vertical transmission of early syphilis during pregnancy results in a congenital infection in at least 50-80% of exposed neonates.
From 1985-1990, overall syphilis incidence in the United States 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).[3]
International statistics
Syphilis 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.[4]
Race and socioeconomic factors
Syphilis has no racial predilection. However, its incidence appears to correlate with the socioeconomic factors-often racially imbalanced-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. For example, a report of a syphilis outbreak in North Carolina described an association between crack cocaine and sex for drugs as a causative factor, in a sociosexual network comprised predominantly of blacks.[5]
Sexual disparity in syphilis rates
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 sex distribution of syphilis is in flux.
Age disparities in syphilis rates
Adolescent and young adults are most at risk for syphilis, due to sexual and other risk-taking behaviors (eg, drug use).
With adequate and timely treatment, the prognosis for most patients with syphilis is excellent. However, patients with HIV infection have a high rate of failed serologic response to syphilis treatment. Most patients with HIV infection show no response or inadequate response after being treated for syphilis.
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 patient education information, see the Sexually Transmitted Diseases Center and Pregnancy and Reproduction Center, as well as Sexually Transmitted Diseases, Syphilis, Birth Control Overview, and Birth Control FAQs.
Most recognized syphilitic disease in children is congenital. Medical professionals should assume that children with acquired syphilis have been infected through sexual abuse, unless another mechanism of transmission is identified.
Syphilis-especially in its later stages-can have numerous and complex manifestations and may resemble a number of other diseases. Indeed, William Osler called syphilis "the Great Imitator."
Primary syphilis
The primary lesion, called a chancre, is painless. It usually develops at the site of the inoculation, at 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. If the chancre occurs on the vulva or in the mouth, it is often overlooked by the patient and partner.
Secondary syphilis
Because of the widespread dissemination of spirochetes, frequent constitutional symptoms include the following:
Fever
Malaise
Pharyngitis
Rash
Anorexia
Arthralgias
Generalized painless lymphadenopathy
Renal, hepatic, and ophthalmologic manifestations may be present.
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 symptoms and signs:
P ersonality
A ffect
R eflexes (eg, hyperactive)
E ye (eg, Argyll Robertson pupils)
S ensorium (eg, illusions, delusions, hallucinations)
I ntellect (eg, decreased recent memory, orientation, judgment, insight)
S peech 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.
Go to Interstitial Keratitis for more complete information on this topic.
Syphilis in HIV-exposed infants
Several studies have demonstrated atypical features of congenial syphilis in infants simultaneously infected with HIV and treponema. These features include fever, cough, blister or nonblister rash, and sores around the corners of the mouth. One should have a high index of suspicion with any such findings in a newborn that cannot be explained by any one entity.
Primary syphilis is characterized by a nontender 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 spontaneously heal within 3-6 weeks.
Secondary syphilis
Mucocutaneous lesions are the most frequent signs of secondary syphilis 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. (See the photographs below.)
Abnormal cerebrospinal fluid (CSF) examination results occur in 30% of patients with secondary syphilis, but the patient may be asymptomatic.
View Image
These photographs illustrate examples of condylomata lata. The lesions resemble genital warts (condylomata acuminata). Fluids exuding from these lesio....
Mucous patches are superficial, silver-gray erosions that occur on mucous membranes.
No pathognomonic signs are noted for ocular syphilis. Ocular involvement is usually evident beyond the primary stage of syphilis. Acute iridocyclitis in as many as 4% of patients with secondary syphilis.[6]
Tertiary syphilis
Tertiary syphilis manifestations are divided into the following subgroups: benign, cardiovascular, and late.
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. (See the photographs below.)
View Image
These photographs show close-up images of gummas observed in tertiary syphilis. Used with permission from Wisdom A. Color Atlas of Sexually Transmitte....
Cardiovascular tertiary syphilis can cause aortitis, aortic aneurysm, coronary stenosis, aortic insufficiency, and myocarditis.
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.[7] Any woman who delivers a stillborn infant after 20 weeks' gestation should be tested for syphilis. Infected infants may experience significant morbidity during infancy, childhood, and adolescence.
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 in the United States.
Screen women at high risk for syphilis more frequently because they may have repeat infections during pregnancy or may become reinfected late in pregnancy. A study in Nigeria has demonstrated the usefulness of syphilis screening during pregnancy. These researchers recommended that syphilis screening should be continued as part of routine antenatal testing.[8]
Early-onset congenital syphilis (diagnosed before or at age 2 y)
Early manifestations of congenital infection vary and involve multiple organ systems. About 60% of infants born with congenital syphilis are asymptomatic at birth. Symptoms develop within the first 2 months of life. In symptomatic infants, the most common physical finding, reported in almost 100% of cases, is hepatomegaly; biochemical evidence of liver dysfunction is usually observed.
The other common findings are skeletal abnormalities, rash, and generalized lymphadenopathy. Radiographic abnormalities, periostitis or osteitis, involve multiple bones and are seen in the vast majority of symptomatic infants, but they also can be found in on fifth of infants with no symptoms or relevant findings on physical examination. Sometimes, the lesion is painful and an infant will favor an extremity (pseudopalsy). The rash is maculopapular and may involve palms and soles. In contrast to acquired syphilis, a vesicular rash and bullae may develop. These lesions are also highly contagious.
Mucosal involvement may present as rhinitis ("snuffles"). Nasal secretions are highly contagious.
Hematological abnormalities include anemia and thrombocytopenia. Some have leukocytosis. Abnormal CSF examination is seen in a half of symptomatic infants but also can be found in 10% of those who are asymptomatic.
Late-onset congenital syphilis (diagnosed >2 y)
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, as follows:
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.[9] 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.[10, 11]
CDC policy states that no newborn should leave a hospital without documentation of the mother's serologic status at least once during the 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. Serologic testing should also be performed at delivery in communities and populations at risk of acquiring congenital syphilis.
Test for syphilis any woman who delivers a stillborn infant after 20 weeks' gestation. 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.
According the 2009 Red Book, "Darkfield examinations and direct fluorescent antibody (DFA) tests of lesion exudate or tissue are the definitive methods for diagnosing early syphilis. Serologic tests for syphilis allow for a presumptive diagnosis of syphilis and for following response to therapy. A nontreponemal serologic test must be confirmed by a treponemal serologic test."[12]
Laboratory evaluation of sexually abused children should include serologic testing for syphilis if the assailant is known to have a sexually transmitted infection (STI) or is at high risk of having an STI (eg, previous STI, multiple partners) or has an unknown history. The suspicion of child sexual abuse mandates filing a report with child protective services or law enforcement agencies.
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.
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.
Because clinical manifestations of syphilis are protean, serologic testing has the primary role in confirming the diagnosis. Because the causative microorganism cannot be cultured on artificial media and because simple laboratory stains fail to demonstrate the spirochetes, a presumptive diagnosis of syphilis, as well as evaluation of response to therapy, are based on serologic test results.
The 2 types of serologic tests for syphilis are nontreponemal reaginic tests and treponema-specific 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 serologic tests
Nontreponemal reaginic tests include the rapid plasma reagin (RPR) and the Venereal Disease Research Laboratory (VDRL), both 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 Treponema 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. False -negative results may occur 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 and VDRL 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 T pallidum particle agglutination (TPPA). 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 are not quantified.
The immunoglobulin M (IgM) measures antibodies specific to T pallidum, and polymerase chain reaction tests are not yet widely available.
Direct examination for spirochetes provides a definitive diagnosis, when positive, and histopathology may also be useful. Examination by dark field microscopy or by direct fluorescent antibody testing visualizes spirochetes in an exudate or a 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 following ancillary tests may be indicated in patients with suspected syphilis:
Cerebrospinal fluid (CSF) analysis
Complete blood count (CBC)
Liver function tests (LFTs)
HIV testing
Testing for other sexually transmitted diseases (STDs)
Cerebrospinal fluid 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/uL (10 X 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.
Go to Neurosyphilis for more complete information on this topic.
Complete blood 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.
Liver function tests
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 sexually transmitted diseases
Any patient diagnosed with either syphilis or HIV should also be tested for the following STDs:
Syphilitic pneumonia is common in congenital syphilis and appears as a fluffy diffuse infiltrate and is called pneumonia alba (white-out). Radiographs of long bones may disclose bone involvement, which 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.
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.
LIAISON Treponema Assay (DiaSorin; Saluggia, Italy), a one-step sandwich chemiluminescent immunoassay (CLIA), has demonstrated higher sensitivity and specificity as a screening and confirmatory tool compared with conventional methods.[13]
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.[14]
Real-time polymerase chain reaction (PCR) is an effective and sensitive assay. PCR has been used to detect T pallidum in the vitreous in patients with syphilitic chorioretinitis and to detect T pallidum in a diagnostically challenging case of syphilitic osteomyelitis.[15]
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.
Penicillin remains the drug of choice 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).
In patients with primary syphilis, doxycycline and tetracycline have shown a high serological treatment success rate, comparable to penicillin.[16] Azithromycin has also demonstrated a high cure rate in a long-term follow-up.[17]
Patients who are allergic to penicillin and do not have neurosyphilis and are not pregnant may be treated with either doxycycline (100 mg oral [PO] bid for 2 wk) or tetracycline (500 mg PO qid for 2 wk).
Although other regimens can be considered in patients with a penicillin allergy, desensitization to penicillin is the most advisable approach.
Serologic testing after treatment is important for all patients with syphilis, particularly those co-infected with HIV.
Go to Syphilis for more complete information on this topic.
Shorter-acting forms of penicillin must be used to treat neurosyphilis to produce reliably therapeutic levels in the cerebrospinal fluid (CSF). The recommended treatment is aqueous crystalline penicillin G (200,000-300,000 U/kg/d IM [50,000 U/kg every 4-6 h]) for 10-14 days (adult dose, 12-24 million U/d [2-4 million U every 4 h]), followed by a single dose of benzathine penicillin (50,000 U/kg/dose, not to exceed 2.4 million U) in 3 weekly doses.
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 Venereal Disease Research Laboratory (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.
When distribution shortages of aqueous penicillin G occur, substitution of ampicillin or ceftriaxone may be necessary (see the CDC Web page "Alternatives to intravenous penicillin G for specific infections" for the most up-to-date recommendations).
Go to Neurosyphilis for more complete information on this topic.
Treat 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 every 8-12 hours to complete a 10-day 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 immunoglobulin M (IgM) fluorescent treponemal antibody absorption (FTA-ABS) test findings
Positive darkfield microscopy findings or positive findings when staining for treponemes in placenta or umbilical cord
Treat all pregnant patients with syphilis with penicillin, regardless of the stage of pregnancy.[18, 19] Administer 3 doses of benzathine penicillin (2.4 million U IM at 1-wk intervals). A meta-analysis regarding penicillin use in pregnancy has shown that the dose of 2.4 million IU results in reduction of clinical congenital syphilis by 97%, whereas same dose is associated with a reduction of 82% of stillbirths, 64% of preterm deliveries, and 80% of neonatal death.
No proven alternative therapy is available for patients who are allergic to penicillin. Erythromycin treatment for pregnant patients who are allergic to penicillin is not a reliable treatment for the fetus.
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 guidelines issued by the Centers for Disease Control and Prevention.
For primary, secondary, or latent syphilis that is less than a year's 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.
Late Syphilis
For syphilis of longer than 1 year in 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.
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 cerebrospinal fluid (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.
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 syphilis or has a history of syphilis (current or untreated) should be considered for CSF examination and should be treated for neurosyphilis.
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. It was first described in patients with syphilis by Jarisch in 1895 and then Herxheimer in 1902. The reaction, which is self-limited, is associated with an increase in circulating levels of tumor necrosis factor, interleukin (IL)-6, and IL-8.
Onset begins within 2 hours of treatment initiation and consists of the abrupt onset of fever, chills, myalgias, headache, tachycardia, hyperventilation, vasodilation with flushing, and mild hypotension. The temperature peaks at about 7 hours, and defervescence takes place within 12-24 hours.
Warn pregnant patients about the risk of a Jarisch-Herxheimer reaction. This reaction may be associated with mild premature contractions but rarely results in premature delivery.
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:[20]
Exposure to a known case of infectious syphilis
All women at first prenatal visit and high-risk women again at 28 weeks' gestation (46 states and the District of Columbia have laws regarding antenatal syphilis screening during pregnancy and at delivery) - A recent study showed a 50% reduction in stillbirth rates with early screening and treatment in pregnancy
All women that deliver a stillborn infant
All newborns older than 22 weeks' gestation whose mothers were not screened
Anyone diagnosed with a sexually transmitted disease (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)
For health care personnel, standard precautions are recommended for all patients with primary and secondary syphilis because these lesions are moist and potentially infectious. 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.
Consider STD prophylaxis for rape victims. Many people who are sexually assaulted do not comply with recommended follow-up, so consider empiric therapy for these patients.
Given the protean manifestations of syphilis, consultation with a range of specialists may be valuable, such as the following
Consultation with an infectious disease specialist is useful in most cases.
Consultation with a neurologist is prudent if neurosyphilis is present or suspected
Consultation with an ophthalmologist is helpful because keratitis and optic atrophy are common; slit lamp examination and follow-up are important.
An orthopedist can provide support for skeletal gummas, which most often involve the legs; bony involvement in congenital syphilis frequently resolves in the first 6 months, but lesions may be painful until healed.
Otolaryngology consultation may be required because congenital syphilis is a known cause of progressive sensorineural hearing loss; therefore, hearing screening is recommended for all pediatric patients with congenital syphilis.[21]
Congenital syphilis requires follow-up at age 1 month, 2 months, 4 months, 6 months, and 12 months. Obtain nontreponemal titers at age 3 months, 6 months, 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 re-treatment 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 Venereal Disease Research Laboratory (VDRL) result at age 6 months is an indication for retreatment.
Early acquired syphilis requires follow-up with a quantitative nontreponemal test at 3-month, 6-month, 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.[10]
Treponema 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.
Clinical Context:
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). It interferes with the synthesis of cell wall mucopeptides during active multiplication, which results in bactericidal activity. It is a spirocheticide with in vivo activity against T pallidum. It also interferes with cell wall mucopeptide synthesis during replication.
Clinical Context:
Treat congenital infection, either proven or presumed, with 10-14 days of aqueous penicillin G or procaine penicillin G. Procaine penicillin G (50,000 U/kg IM) has been recommended as an alternative to treat congenital syphilis, but adequate cerebrospinal fluid (CSF) concentration may not be consistently achieved.
Clinical Context:
Penicillin interferes with the synthesis of cell wall mucopeptide during active multiplication, resulting in bactericidal activity against susceptible microorganisms. Aqueous crystalline penicillin G is recommended if congenital syphilis is proved or is highly suspected. The dosage should be based on chronologic, not gestational, age.
Clinical Context:
Doxycycline is a broad-spectrum, synthetically derived bacteriostatic antibiotic in the tetracycline class. It is almost completely absorbed, concentrates in bile, and is excreted in urine and feces as a biologically active metabolite in high concentrations. It inhibits protein synthesis and, thus, bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria. It may block dissociation of peptidyl t-RNA from ribosomes, causing RNA-dependent protein synthesis to arrest.
Clinical Context:
Tetracycline is an alternative therapy for syphilis infection. It inhibits bacterial growth by binding to the 30S ribosomal unit, preventing protein synthesis.
Clinical Context:
Probenecid inhibits tubular secretion of penicillin, and it usually increases penicillin plasma levels by any route the antibiotic is administered. A 2- to 4-fold elevation has been demonstrated for various penicillins. It is used as an adjunct to penicillin in late latent and neurosyphilis.
Penicillins are the drug of choice to treat all stages of syphilis. In patients with primary syphilis, doxycycline and tetracycline have shown a high serological treatment success rate, comparable to penicillin.[16]
Muhammad Waseem, MBBS, MS, FAAP, FACEP, FAHA, Professor of Emergency Medicine in Clinical Pediatrics, Weill Cornell Medical College; Attending Physician, Departments of Emergency Medicine and Pediatrics, Lincoln Medical and Mental Health Center; Adjunct Professor of Emergency Medicine, Adjunct Professor of Pediatrics, St George's University School of Medicine, Grenada
Disclosure: Nothing to disclose.
Coauthor(s)
Muhammad Aslam, MD, Professor of Pediatrics, University of California, Irvine, School of Medicine; Neonatologist, Division of Newborn Medicine, Department of Pediatrics, UC Irvine Medical Center
Disclosure: Nothing to disclose.
Specialty Editors
Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Nothing to disclose.
Chief Editor
Russell W Steele, MD, Clinical Professor, Tulane University School of Medicine; Staff Physician, Ochsner Clinic Foundation
Disclosure: Nothing to disclose.
Acknowledgements
Leslie L Barton, MD Professor Emerita of Pediatrics, University of Arizona College of Medicine
Leslie L Barton, MD is a member of the following medical societies: American Academy of Pediatrics, Association of Pediatric Program Directors, Infectious Diseases Society of America, and Pediatric Infectious Diseases Society
These photographs illustrate examples of condylomata lata. The lesions resemble genital warts (condylomata acuminata). Fluids exuding from these lesions are highly infectious. Used with permission from Wisdom A. Color Atlas of Sexually Transmitted Diseases. Year Book Medical Publishers Inc; 1989.
These photographs show close-up images of gummas observed in tertiary syphilis. Used with permission from Wisdom A. Color Atlas of Sexually Transmitted Diseases. Year Book Medical Publishers Inc; 1989.
These photographs show close-up images of gummas observed in tertiary syphilis. Used with permission from Wisdom A. Color Atlas of Sexually Transmitted Diseases. Year Book Medical Publishers Inc; 1989.
These photographs illustrate examples of condylomata lata. The lesions resemble genital warts (condylomata acuminata). Fluids exuding from these lesions are highly infectious. Used with permission from Wisdom A. Color Atlas of Sexually Transmitted Diseases. Year Book Medical Publishers Inc; 1989.
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