Syphilis 

Updated: Jul 11, 2017
Author: Pranatharthi Haran Chandrasekar, MBBS, MD; Chief Editor: Michael Stuart Bronze, MD 

Overview

Background

Syphilis is an infectious venereal disease caused by the spirochete Treponema pallidum. Syphilis is transmissible by sexual contact with infectious lesions, from mother to fetus in utero, via blood product transfusion, and occasionally through breaks in the skin that come into contact with infectious lesions. If untreated, it progresses through 4 stages: primary, secondary, latent, and tertiary. The image below depicts the characteristic chancre observed in primary syphilis.

Syphilis. These photographs depict the characteris Syphilis. These photographs depict the characteristic chancre observed in primary syphilis. Used with permission from Wisdom (Left) A. Color Atlas of Sexually Transmitted Diseases. Year Book Medical Publishers Inc; 1989. (Right) Centers for Disease Control and Prevention

See 20 Signs of Sexually Transmitted Infections, a Critical Images slideshow, to help make an accurate diagnosis.

Also see the Clues in the Oral Cavity: Are You Missing the Diagnosis? slideshow to help identify the causes of abnormalities of the oral cavity.

Syphilis has a myriad of presentations and can mimic many other infections and immune-mediated processes in advanced stages. Hence, it has earned the nickname “the great impostor.” The complex and variable manifestations of the disease prompted Sir William Osler to remark, “The physician who knows syphilis knows medicine.”

Many famous persons throughout history are thought to have suffered from syphilis, including Bram Stoker, Henry VIII, and Vincent Van Gogh. Since the discovery of penicillin in the mid-20th century, the spread of this once very common disease has been largely controlled, but efforts to eradicate the disease entirely have been unsuccessful.

Pathophysiology

Three genera of spirochetes cause human infection:

  • Treponema, which causes syphilis, yaws, and pinta

  • Borrelia, which causes Lyme disease and relapsing fever

  • Leptospira, which causes leptospirosis

The particular spirochete responsible for syphilis is Treponema pallidum.

T pallidum is a fragile spiral bacterium 6-15 micrometers long by 0.25 micrometers in diameter. Its small size makes it invisible on light microscopy; therefore, it must be identified by its distinctive undulating movements on darkfield microscopy. It can survive only briefly outside of the body; thus, transmission almost always requires direct contact with the infectious lesion.

Syphilis is usually classified into 4 stages: primary, secondary, latent, and tertiary. It can be either acquired or congenital. That is, it can be transmitted either by intimate contact with infectious lesions (most common) or via blood transfusion (if blood has been collected during early syphilis), and it can also be transmitted transplacentally from an infected mother to her fetus.

Acquired syphilis

In acquired syphilis, T pallidum rapidly penetrates intact mucous membranes or microscopic dermal abrasions and, within a few hours, enters the lymphatics and blood to produce systemic infection. Incubation time from exposure to development of primary lesions, which occur at the primary site of inoculation, averages 3 weeks but can range from 10-90 days. Studies in rabbits show that spirochetes can be found in the lymphatic system as early as 30 minutes after primary inoculation, suggesting that syphilis is a systemic disease from the outset.

The central nervous system (CNS) is invaded early in the infection; during the secondary stage, examinations demonstrate that more than 30% of patients have abnormal findings in the cerebrospinal fluid (CSF). During the first 5-10 years after the onset of untreated primary infection, the disease principally involves the meninges and blood vessels, resulting in meningovascular neurosyphilis. Later, the parenchyma of the brain and spinal cord are damaged, resulting in parenchymatous neurosyphilis. Go to Neurosyphilis for complete information on this topic.

Regardless of the stage of disease and location of lesions, histopathologic hallmarks of syphilis include endarteritis (which in some instances may be obliterative in nature) and a plasma cell–rich infiltrate. Endarteritis is caused by the binding of spirochetes to endothelial cells, mediated by host fibronectin molecules bound to the surface of the spirochetes. The resultant endarteritis can heal with scarring in some instances.

The syphilitic infiltrate reflects a delayed-type hypersensitivity response to T pallidum, and in certain individuals with tertiary syphilis, this response by sensitized T lymphocytes and macrophages results in gummatous ulcerations and necrosis. Antigens of T pallidum induce host production of treponemal antibodies and nonspecific reagin antibodies. Immunity to syphilis is incomplete.

For example, host humoral and cellular immune responses may prevent the formation of a primary lesion on subsequent infections with T pallidum, but they are insufficient to clear the organism. This may be because the outer sheath of the spirochete is lacking immunogenic molecules, or it may be because of down-regulation of helper T cells of the TH1 class.[1, 2]

Primary syphilis is characterized by the development of a painless chancre at the site of transmission after an incubation period of 3-6 weeks. The lesion has a punched-out base and rolled edges and is highly infectious.

Histologically, the chancre is characterized by mononuclear leukocytic infiltration, macrophages, and lymphocytes. The inflammatory reaction causes an obliterative endarteritis. In this stage, the spirochete can be isolated from the surface of the ulceration or the overlying exudate of the chancre. Whether treated or not, healing occurs within 3-12 weeks, with considerable residual fibrosis.

Secondary syphilis develops about 4-10 weeks after the appearance of the primary lesion. During this stage, the spirochetes multiply and spread throughout the body. Secondary syphilis lesions are quite variable in their manifestations. Systemic manifestations include malaise, fever, myalgias, arthralgias, lymphadenopathy, and rash.

Widespread mucocutaneous lesions are observed over the entire body and may involve the palms, soles, and oral mucosae. Most often, the lesions are macular, discrete, reddish brown, and 5 mm or smaller in diameter; however, they can be pustular, annular, or scaling. Vesicular rash is typically absent. All such lesions contain treponemes. Of these, wet mucous patches are the most contagious. Histologically, the inflammatory reaction is similar to but less intense than that of the primary chancre.

Other skin findings of secondary syphilis are condylomata lata and patchy alopecia. Condylomata lata are painless, highly infectious gray-white lesions that develop in warm, moist sites. The alopecia is characterized by patchy hair loss of the scalp and facial hair, including the eyebrows. Patients with this finding have been referred to as having a “moth-eaten” appearance. During secondary infection, the immune reaction is at its peak and antibody titers are high.

Latent syphilis is a stage at which the features of secondary syphilis have resolved, though patients remain seroreactive. Some patients experience recurrence of the infectious skin lesions of secondary syphilis during this period. About one third of untreated latent syphilis patients go on to develop tertiary syphilis, whereas the rest remain asymptomatic.

Currently, tertiary syphilis disease is rare. When it does occur, it mainly affects the cardiovascular system (80-85%) and the CNS (5-10%), developing over months to years and involving slow inflammatory damage to tissues. The 3 general categories of tertiary syphilis are gummatous syphilis (also called late benign), cardiovascular syphilis, and neurosyphilis.

Gummatous syphilis is characterized by granulomatous lesions, called gummas, which are characterized by a center of necrotic tissue with a rubbery texture. Gummas principally form in the liver, bones, and testes but may affect any organ. Histological examination shows palisaded macrophages and fibroblasts, as well as plasma cells surrounding the margins. Gummas may break down and form ulcers, eventually becoming fibrotic. Treponemes are rarely visualized or recovered from these lesions.

Cardiovascular syphilis occurs at least 10 years after primary infection. The most common manifestation is aneurysm formation in the ascending aorta, caused by chronic inflammatory destruction of the vasa vasorum, the penetrating vessels that nourish the walls of large arteries. Aortic valve insufficiency may result.

Neurosyphilis has several forms. If the spirochete invades the CNS, syphilitic meningitis results. Syphilitic meningitis is an early manifestation, usually occurring within 6 months of the primary infection. CSF shows high protein, low glucose, high lymphocyte count, and positive syphilis serology.

Meningovascular syphilis occurs as a result of damage to the blood vessels of the meninges, brain, and spinal cord, leading to infarctions causing a wide spectrum of neurologic impairments.

Parenchymal neurosyphilis includes tabes dorsalis and general paresis. Tabes dorsalis develops as the posterior columns and dorsal roots of the spinal cord are damaged. Posterior column impairment results in impaired vibration and proprioceptive sensation, leading to a wide-based gait.

Disruption of the dorsal roots leads to loss of pain and temperature sensation and areflexia. Damage to the cortical regions of the brain leads to general paresis, formerly called “general paresis of the insane,” which mimics other forms of dementia. Impairment of memory and speech, personality changes, irritability, and psychotic symptoms develop and may advance to progressive dementia.

The Argyll-Robertson pupil, a pupil that does not react to light but does constrict during accommodation, may be seen in tabes dorsalis and general paresis. The precise location of the lesion causing this phenomenon is unknown.

Congenital syphilis

Congenital syphilis, discussed briefly here, is a veritable potpourri of antiquated medical terminology. The treponemes readily cross the placental barrier and infect the fetus, causing a high rate of spontaneous abortion and stillbirth. Within the first 2 years of life, symptoms are similar to severe adult secondary syphilis with widespread condylomata lata and rash. “Snuffles” describes the mucopurulent rhinitis caused by involvement of the nasal mucosae.

Later manifestations of congenital syphilis include bone and teeth deformities, such as “saddle nose” (due to destruction of the nasal septum), “saber shins” (due to inflammation and bowing of the tibia), “Clutton’s joints” (due to inflammation of the knee joints), “Hutchinson’s teeth” (in which the upper incisors are widely spaced and notched), and “mulberry molars” (in which the molars have too many cusps).

Tabes dorsalis and general paresis may develop as in adults, with 8th cranial nerve deafness and optic nerve atrophy as well as a variety of other ophthalmologic involvement leading to blindness being additional features.

From 2012-2014, the number of congenital syphilis cases in the United States increased from 334 to 458. This appears to be associated with an increase in the rate of primary and secondary syphilis among women.[3]

Go to Pediatric Syphilis for complete information on this topic.

Etiology

The cause of syphilis is infection with the spirochete T pallidum.T pallidum is solely a human pathogen and does not naturally occur in other species. T pallidum has, however, been cloned in Escherichia coli and has been used experimentally in rabbits.

Transmission of T pallidum occurs via penetration of the spirochetes through mucosal membranes and abrasions on epithelial surfaces. It is primarily spread through sexual contact but can be spread by exposure to blood products and transferred in utero. T pallidum is a labile organism that cannot survive drying or exposure to disinfectants; thus, fomite transmission (eg, from toilet seats) is virtually impossible.

Unprotected sex is the major risk factor for the acquisition of syphilis, especially among men who have sex with men (MSM), who accounted for 83.7% of all syphilis cases in the United States.[4]

Epidemiology

United States statistics

Since reporting began in 1941, the incidence of primary and secondary syphilis in the United States has varied. The incidence dropped from 66.4 cases per 100,000 in 1947 to 3.9 cases per 100,000 in 1956 following the introduction of penicillin.

During the mid-1980s, however, this trend reversed. Increases in the use of intravenous (IV) drugs and crack cocaine, the exchange of sex for drugs, indiscriminate or anonymous sex, and the number of people with multiple sexual partners contributed to the turnaround. From 1986-1990, the rate of syphilis nearly doubled, reaching a peak of 53.8 cases per 100,000 population in 1990.

After 1990, the incidence decreased again; there were 53,000 reported cases (11,387 primary and secondary cases) in 1996, compared with 113,000 cases (33,962 primary and secondary cases) reported in 1992. In 2000, the number of syphilis cases reported was at an all-time low, with rates falling to 2.1 cases per 100,000 population. Increased awareness, aggressive screening, and emphasis on primary prevention contributed to the decrease.

Since 2000, however, the number of syphilis cases in the United States has been on the rise. From 2005-2013, the number of primary and secondary syphilis cases reported each year in the United States nearly doubled, from 8,724 to 16,663; the annual rate increased from 2.9 to 5.3 cases per 100,000 population.[5] Most of this increase has been noted in men, particularly among MSM, who accounted for 87.3% of all primary and secondary syphilis cases in 2013. Rates have increased in all racial groups in the past decade, but black and Hispanic men have an overall higher rate than other racial groups. The overall highest rate was in the western United States, not in the South, for the first time in at least 50 years.[6]  

International statistics

Internationally, the prevalence of syphilis varies by region. Syphilis remains prevalent in many developing countries and in some areas of North America, Asia, and Europe, especially Eastern Europe. The highest rates are in South and Southeast Asia, followed closely by sub-Saharan Africa. The third highest rates are in the regions of Latin America and the Caribbean.[7] In some regions of Siberia, as of 1999, prevalence was 1300 cases per 100,000 population.[8]

Age distribution of syphilis

Syphilis is most common during the years of peak sexual activity. Most new cases occur in men and women aged 20-29 years. In 2013, the rate of primary and secondary syphilis was highest in people aged 25-29 years (27 per 100,000).[4]

The incidence of congenital syphilis has increased to 11.6 cases per 100,000 live births in 2014, the highest congenital syphilis rate reported since 2001. The number of congenital syphilis cases declined in the United States during 2008-2012, from 446 to 334 cases (10.5 to 8.4 cases per 100,000 live births) but is increasing; from 2012-2014, the number of reported congenital syphilis cases in the United States increased from 334 to 458.[3]  

Sex distribution of syphilis

Men are affected more frequently with primary or secondary syphilis than women. This difference has varied over time. Male-to-female ratios of primary and secondary syphilis increased from 1.6:1 in 1965 to nearly 3:1 in 1985. After, the ratio decreased, reaching a nadir in 1994-95. The past decade has seen a sharp rise in syphilis cases among men, driven mostly by the MSM community. Males with primary and secondary syphilis outnumber females 10 to 1. Among women, the reported primary and secondary syphilis rate increased from 0.9 to 1.5 per 100,000 population per year during 2005-2008 and decreased to 0.9 in 2013.[4]

Prevalence of syphilis by race or ethnicity

In the United States, syphilis is more prevalent among persons of minority race and ethnicity. Non-Hispanic blacks are at higher risk for syphilis than all other racial groups. In 2013, the primary and secondary syphilis rate among black men was 5.2 times that among white men (27.9 vs 5.4 cases per 100,000 population); the rate among black women was 13.3 times that among white women (4 vs 0.3). The rate among Hispanic men was 2.1 times that among white men (11.6 vs 5.4), and the rate among Hispanic women was 2.7 times that among white women (0.8 vs 0.3). These disparities were similar to disparities observed in 2005 and represent an increase in syphilis rates in all racial groups.[4]

HIV and syphilis co-infection

Syphilis acquisition increases the risk of HIV acquisition by 2- to 5-fold and makes transmission of HIV more efficient via various methods. First, primary syphilis infection causes a genital ulcer, which disrupts the mucous membrane, making it more vulnerable to penetration by the HIV virus. Second, genital ulcers bleed easily during sex, increasing the risk of viral transmission. Third, genital ulcers attract CD4 cells to the ulcer surface, increasing targets for the HIV virus to infect. Fourth, the risk behaviors associated with acquiring syphilis also increase the likelihood of acquiring HIV.[9]

The rate of HIV and syphilis co-infection is high. More than 50% of MSM with syphilis are also infected with HIV, and this number increases with each recurrence.[10, 11]

Prognosis

The morbidity of syphilis ranges from the relatively minor symptoms of the primary stages of infection to the more significant constitutional systemic symptoms of secondary syphilis and the significant neurological and cardiovascular consequences of tertiary disease. Since latent syphilis can persist for years or decades, the manifestations of tertiary syphilis often occur much later in life, causing significant morbidity and even death if not identified and treated.

These figures have continued to increase since the emergence of the AIDS epidemic, since genital ulcer diseases (including syphilis) are cofactors for the sexual transmission of HIV. Additionally, untreated patients who are HIV seropositive have an increased risk for rapid progression to neurosyphilis. In addition, patients with HIV are at greater risk for development or relapse of early symptomatic neurosyphilis for up to 2 years after treatment with intramuscular or intravenous penicillin.

The morbidity and mortality of untreated syphilis must be estimated from the limited data available regarding its natural course. These data are largely from one retrospective study of autopsies and two prospective studies, most notably the famous Tuskegee Study of Untreated Syphilis in the Negro Male, which fell under serious ethical scrutiny in later years for exploiting a vulnerable patient population and not offering treatment for the disease when it became available after the study was underway.

These data indicate that approximately one third of patients left untreated will develop late complications, with 10% of the total developing cardiovascular syphilis; 6%, neurosyphilis; and 16%, gummatous syphilis. Mortality rates in general are greater among those affected, and late complications appear to occur more commonly in men than in women.[12, 13]

For patients diagnosed with either primary or secondary syphilis (without auditory/neurologic/ocular involvement), the prognosis is good following appropriate treatment. T pallidum remains highly responsive to the penicillins, and cure is likely. Among patients diagnosed with tertiary syphilis, the prognosis is less sanguine. Twenty percent of untreated patients with tertiary syphilis die of the disease, making syphilis one of the few sexually transmitted diseases (SDTs) capable of killing its host. However, with adequate treatment, 90% of patients with neurosyphilis have a clinical response.

Overall prognosis for tertiary syphilis depends on the extent of scarring and tissue damage, as treatment arrests further damage and inflammation but cannot reverse previous tissue damage. For example, the prognosis or advanced symptomatic disease in cardiovascular syphilis is poor. In contrast, syphilitic gummas typically resolve promptly with high-dose penicillin.

Congenital syphilis is the most serious outcome of syphilis in women. It has been shown that a higher proportion of infants are affected if the mother has untreated secondary syphilis, compared to untreated early latent syphilis. Since T pallidum does not invade the placental tissue or the fetus until the fifth month of gestation, syphilis causes late abortion, stillbirth, or death soon after delivery in more than 40% of untreated maternal infections.[14, 15] Neonatal mortality usually results from pulmonary hemorrhage, bacterial superinfection, or fulminant hepatitis.

For patients who are pregnant and have early syphilis, it is likely that the mother will deliver a child not infected by syphilis (assuming the mother was treated appropriately).

Patient Education

Patients who abuse IV drugs should be advised to avoid sharing needles and to use clean needles. Needle exchange programs are in place in some areas; however, the establishment and existence of these programs remain controversial in many communities.

It is also important to stress to patients the importance of compliance with their entire antibiotic course and follow-up visits.

As with all STDs, patient education must stress the importance of safer sexual practices and the need for prompt medical evaluation of chancres and other symptoms of STDs. All patients diagnosed with an STD should be screened for HIV infection. All MSM who test positive for syphilis should be considered at risk for HIV if not already infected and should be targeted for intensive HIV prevention interventions with pre-exposure prophylaxis (PrEP).

Patients with syphilis should be counseled to notify their partners of infection and to inform them of the need to be treated. Information regarding management of sex partners infected with syphilis can be found at the CDC Web site.

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.

 

Presentation

History

Physicians must keep a high index of suspicion for the diagnosis of syphilis, as the manifestations of syphilis (particularly advanced syphilis) are nonspecific and may masquerade as many other diseases. Rigorous attention to the time course of symptoms is required for proper staging. Obtain a thorough sexual and social history, including the number of sexual partners, condom use, history of STDs in the patient and their partners, intravenous (IV) drug use, and exposure to blood products.

In children and infants, seek a maternal history, history of exposure to individuals with syphilis or blood products, and a history of sexual abuse.

Primary syphilis

Primary syphilis occurs 10-90 days after contact with an infected individual. It manifests mainly on the glans penis in males and on the vulva or cervix in females. Ten percent of syphilitic lesions are found on the anus, fingers, oropharynx, tongue, nipples, or other extragenital sites. Regional nontender lymphadenopathy follows invasion.

Lesions (chancres) usually begin as solitary, raised, firm, red papules that can be several centimeters in diameter. The chancre erodes to create an ulcerative crater within the papule, with slightly elevated edges around the central ulcer (see the images below). It usually heals within 4-8 weeks, with or without therapy.

Syphilis. These photographs depict the characteris Syphilis. These photographs depict the characteristic chancre observed in primary syphilis. Used with permission from Wisdom (Left) A. Color Atlas of Sexually Transmitted Diseases. Year Book Medical Publishers Inc; 1989. (Right) Centers for Disease Control and Prevention
Syphilitic chancre Syphilitic chancre

Although genital chancres are frequently solitary, they may be multiple in some patients. Sometimes they appear as “kissing” lesions on opposing skin surfaces—for example, the labia (see the image below).

Syphilis. This photograph depicts primary syphilis Syphilis. This photograph depicts primary syphilis "kissing" lesions. Used with permission from Wisdom A. Color Atlas of Sexually Transmitted Diseases. Year Book Medical Publishers Inc; 1989.

Secondary syphilis

Secondary syphilis manifests in various ways. It usually presents with a cutaneous eruption within 2-10 weeks after the primary chancre and is most florid 3-4 months after infection. The eruption may be subtle; 25% of patients may be unaware of skin changes. A localized or diffuse mucocutaneous rash (generally nonpruritic and bilaterally symmetrical) with generalized nontender lymphadenopathy is typical (see the image below). Patchy alopecia and condylomata lata may also be observed.

Syphilis. These photographs show the disseminated Syphilis. These photographs show the disseminated rash observed in secondary syphilis. Used with permission from Wisdom A. Color Atlas of Sexually Transmitted Diseases. Year Book Medical Publishers Inc; 1989.

Mild constitutional symptoms of malaise, headache, anorexia, nausea, aching pains in the bones, and fatigue often are present, as well as fever and neck stiffness. A small number of patients develop acute syphilitic meningitis and present with headache, neck stiffness, facial numbness or weakness, and deafness.

Other less-common manifestations include GI involvement, hepatitis, nephropathy, proctitis, arthritis, and optic neuritis.

Latent syphilis

Latency may last from a few years to as many as 25 years before the destructive lesions of tertiary syphilis manifest. Affected patients may recall symptoms of primary and secondary syphilis. They are asymptomatic during the latent phase, and the disease is detected only by serologic tests.

Latent syphilis is divided into early latent and late latent. The distinction is important because treatment for each is different. The early latent period is the first year after the resolution of primary or secondary syphilis. Asymptomatic patients who have a newly active serologic test after having a serologically negative test result within 1 year are also considered to be in the early latent period. Late latency syphilis is not infectious; however, women in this stage can spread the disease in utero.

Tertiary syphilis

Tertiary (late) syphilis is slowly progressive and may affect any organ. The disease is generally not thought to be infectious at this stage. Manifestations may include the following:

  • Impaired balance, paresthesias, incontinence, and impotence
  • Focal neurologic findings, including sensorineural hearing and vision loss
  • Dementia
  • Chest pain, back pain, stridor, or other symptoms related to aortic aneurysms

The lesions of gummatous tertiary syphilis usually develop within 3-10 years of infection. The patient complaints are usually secondary to bone pain, which is described as a deep boring pain characteristically worse at night. Trauma may predispose a specific site to gumma involvement.

CNS involvement may occur, with presenting symptoms representative of the area affected (ie, brain involvement [headache, dizziness, mood disturbance, neck stiffness, blurred vision] and spinal cord involvement [bulbar symptoms, weakness and wasting of shoulder girdle and arm muscles, incontinence, impotence]).

Some patients may present up to 20 years after infection with behavioral changes and other signs of dementia, which is indicative of paresis.

Congenital syphilis

Early congenital syphilis occurs within the first 2 years of life. Late congenital syphilis emerges in children older than 2 years. A small percentage of infants infected in utero may have a latent form of infection that becomes apparent during childhood and, in some cases, during adult life. The earliest symptom that occurs prior to age 2 years is rhinitis (snuffles), soon followed by cutaneous lesions. After age 2 years, parents may note problems with the child’s hearing and language development and with vision. Facial and dental abnormalities may be noted.

Physical Examination

Conduct the physical examination with the manifestations of primary, secondary, and tertiary syphilis in mind. The lesions and exanthem of primary and secondary syphilis are infectious; thus, gloves and other relevant personal protective equipment must be worn.

Primary syphilis

The patient is typically afebrile, with a chancre at the site of inoculation, often accompanied by inguinal adenopathy.

The chancre of primary syphilis usually begins as a single, painless papule that rapidly becomes eroded and indurated, with a surrounding red areola. The edge and base of the ulcer have a cartilaginous (buttonlike) consistency on palpation. Although classic chancres are not painful, they can become so if suprainfected with bacteria or if located in the anal canal. Atypical primary lesions are common and may manifest as a papular lesion without subsequent ulceration or induration.

The primary lesion usually is associated with regional lymphadenopathy that may be unilateral or bilateral. Inguinal adenitis is usually discrete, firm, mobile, and painless, without overlying skin changes.

Chancres usually are located on the penis in heterosexual men, but in homosexual men, they may be found in the anal canal, mouth, or external genitalia. Common primary sites in women include the cervix and labia. Extragenital chancres occur most commonly above the neck, typically affecting the lips or oral cavity.

The lesion is highly infectious; when abraded, it exudes a clear serum containing numerous T pallidum organisms.

Secondary syphilis

Secondary syphilis may present in many different ways but usually includes a localized or diffuse mucocutaneous rash and generalized nontender lymphadenopathy. The exanthem may be macular, papular, pustular, or mixed (see the images below).

Secondary syphilis - Exanthem Secondary syphilis - Exanthem
Secondary syphilis - Exanthem Secondary syphilis - Exanthem

Initial lesions are bilaterally symmetric, pale red to pink (in light-skinned persons) or pigmented (in dark-skinned persons), discrete, round, nonpruritic macules that measure 5-10 mm in diameter and are distributed on the trunk and proximal extremities. After several days or weeks, red papular lesions 3-10 mm in diameter appear. These lesions often become necrotic and are distributed widely with frequent involvement of the palms and soles (see the image below).

Syphilis. Palmar lesions observed in secondary syp Syphilis. Palmar lesions observed in secondary syphilis. Used with permission from Wisdom (Left) A. Color Atlas of Sexually Transmitted Diseases. Year Book Medical Publishers Inc; 1989. (Right) Centers for Disease Control and Prevention

Tiny papular follicular syphilids involving hair follicles may result in patchy alopecia. In addition to the classic moth-eaten alopecia, a diffuse alopecia also has been reported.

Reddish-brown papular lesions on the penis or anogenital area can coalesce into large elevated plaques up to 2-3 cm in diameter, known as condylomata lata (see the image below). Lesions usually progress from red, painful, and vesicular to “gun metal grey” as the rash resolves. Condylomata lata are highly infectious. They are sometimes confused with condylomata acuminata or venereal warts.

These photographs illustrate examples of condyloma 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.

From 10-15% of patients with secondary syphilis develop superficial mucosal erosions, usually painless, on the palate, pharynx, larynx, glans penis, vulva, or in the anal canal and rectum. These mucous patches are circular silver-gray erosions with a red areola. The erosions harbor treponemes and can transmit disease.

Ocular abnormalities, such as iritis, are a rare clinical finding, although anterior uveitis has been reported in 5-10% of patients with secondary syphilis. Less common findings include periostitis, arthralgias, meningitis, nephritis, hepatitis, proctitis, and ulcerative colitis. Go to Interstitial Keratitis for complete information on this topic.

Thirty percent of patients experience recurring symptoms after the primary or secondary stage of syphilis. Lesions are less numerous but are still infectious.

Tertiary syphilis

Symptomatic tertiary syphilis is the result of a chronic, progressive inflammatory process that eventually produces clinical symptoms years to decades after the initial infection. The liver and skeleton are possible sites of infection; such infections are characterized by fever, jaundice, anemia, and/or nighttime skeletal pain.

Gummatous syphilis is characterized by coalescent granulomatous lesions, called gummas, that usually affect skin, bone, and mucous membranes but may involve any organ system, often causing local destruction of the affected organ system (see the image below). Cutaneous gummas are indurated, nodular, papulosquamous or ulcerative lesions that form characteristic circles or arcs with peripheral hyperpigmentation. They may mimic other granulomatous ulcerative lesions and may be histologically indistinguishable from them.

Syphilis. These photographs show close-up images o Syphilis. 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.

Although gummas may be identified on the skin, in the mouth, and in the upper respiratory tract, they appear most commonly on the leg just below the knee. Gummas may be multiple or diffuse but usually are solitary lesions that range from less than 1 cm to several centimeters in diameter. They are generally asymmetric and grouped together.

Cardiovascular syphilis usually involves the aorta, though other large arteries may be affected as well. Invading treponemes cause scarring of the tunica media. Over many years, the inflammatory scarring weakens the aortic wall, leading to aneurysm formation, which causes incompetence of the aortic valve and narrowing of the coronary ostia.

The most common clinical finding on cardiovascular examination is a diastolic murmur with a tambour quality, secondary to aortic dilation with valvular insufficiency.

Neurosyphilis may be either asymptomatic or symptomatic.

In asymptomatic neurosyphilis, no signs or symptoms are present, but CSF abnormalities are demonstrable, including possible pleocytosis, elevated protein, decreased glucose, or a reactive CSF Venereal Disease Research Laboratory (VDRL) test.

Symptomatic neurosyphilis may manifest in the following three forms:

  • Syphilitic meningitis, cranial neuritis, or meningovascular disease

  • Meningovascular neurosyphilis

  • Parenchymatous neurosyphilis

Syphilitic meningitis, cranial neuritis, and meningovascular disease usually develop within 6 months to several years of initial infection. Patients with syphilitic meningitis present with typical symptoms of meningitis, including headache, nausea and vomiting, and photophobia, but are typically afebrile. Patients may exhibit cranial nerve abnormalities.

Meningovascular syphilis typically manifests 5-10 years after infection and is the result of endarteritis, inflammation of small blood vessels of the meninges, brain, and spinal cord. Patients may present with CNS vascular insufficiency or outright stroke. The most common presentation of meningovascular syphilis (diffuse inflammation of the pia and arachnoid along with widespread arterial involvement) is an indolent stroke syndrome involving the middle cerebral artery.

Cranial nerve palsies and pupillary abnormalities occur with basilar meningitis.

Parenchymatous neurosyphilis results from direct parenchymal CNS invasion by T pallidum and is usually a late development (15-20 years after primary infection). It includes general paresis and tabes dorsalis. Paretic syphilis is the result of widespread parenchymal invasion that causes individual cell death and brain atrophy. Tabes dorsalis is the result of damage to the sensory nerves in dorsal roots, producing ataxia and loss of pain sensation, proprioception, and deep tendon reflexes in joints.

Patients with parenchymatous neurosyphilis present with ataxia; incontinence; paresthesias; and loss of position, vibratory, pain, and temperature sensations. Paresis and dementia, with changes in personality and intellect, may develop.

Tabes dorsalis presents with signs of demyelination of the posterior columns, dorsal roots, and dorsal root ganglia (eg, ataxic wide-based gait and foot slap, areflexia and loss of position, deep pain and temperature sensations). Deep ulcers of the feet can result from loss of pain sensation.

Argyll Robertson pupil, which occurs almost exclusively in neurosyphilis, is a small irregular pupil that reacts normally to accommodation but not to light.

Rare findings include iritis, with possible adhesion of the iris to the anterior lens, producing a fixed pupil (not to be confused with Argyll Robertson pupil).

Go to Neurosyphilis for complete information on this topic.

Congenital syphilis

The manifestations of untreated congenital syphilis can be divided into those that are expressed prior to age 2 years (early) or after age 2 years (late).

Clinical evidence of early congenital syphilis is similar to that of secondary syphilis in adults.[16] Early signs and symptoms include development of a diffuse rash, characterized by extensive sloughing of the epithelium, particularly on the palms, soles, and skin around the mouth and anus. The rash has a higher probability of being atypical and can be vesicular or bullous instead of the characteristic reddish brown macular rash.

A compilation of early clinical presentations of congenital syphilis in 9 studies involving a total of 212 infants included abnormal bone radiographs (61%); hepatomegaly (51%); splenomegaly (49%); petechiae (41%); other skin rashes (35%); anemia (34%); lymphadenopathy (32%); jaundice (30%); pseudoparalysis, often due to pain secondary to osteochondritis (28%); and snuffles (23%).

A classic mucocutaneous sign is depressed linear scars radiating from the orifice of the mouth (perioral fissures), termed rhagades (Parrot lines).

Additional symptoms of early congenital syphilis include the following:

  • Hemorrhagic rhinitis

  • Periostitis

  • Mucous patches

  • Hydrops

  • Glomerulonephritis

  • Thrombocytopenia

  • Neurologic involvement

  • Ocular involvement (see the image below.)

    Syphilis. This photograph illustrates chorioretini Syphilis. This photograph illustrates chorioretinitis of congenital syphilis. Used with permission from Wisdom A. Color Atlas of Sexually Transmitted Diseases. Year Book Medical Publishers Inc; 1989.

The clinical manifestations of untreated congenital neurosyphilis present in 25% of patients older than age 6 years and correspond to those of adult neurosyphilis. Cardiovascular abnormalities are rare. Findings include the following[17] :

  • Bony abnormalities, including prominent frontal bones, depression of nasal bridge, abnormal maxilla development, anterior tibial bowing, frontal bossing of Parrot, and Higoumenakia sign (unilateral irregular enlargement of the sternoclavicular portion of the clavicle secondary to periostitis)

  • Clutton joints (arthritis of both knees)

  • Interstitial keratitis

  • Hutchinson incisors (centrally notched and widely spaced, peg-shaped, upper central incisors; see the image below)

  • Mulberry molars (sixth-year molars with multiple poorly developed cusps)

  • Cranial nerve VIII involvement - Deafness

  • Paroxysmal cold hemoglobinuria

  • Gummatous involvement - Gummatous periostitis occurs in patients aged 5-20 years and tends to cause destructive lesions of the palate and nasal septum (saddle nose).

  • Corneal opacities

    Syphilis. This photograph shows an example of Hutc Syphilis. This photograph shows an example of Hutchinson teeth in congenital syphilis. Note notching. Used with permission from Wisdom A. Color Atlas of Sexually Transmitted Diseases. Year Book Medical Publishers Inc; 1989.

Go to Pediatric Syphilis for complete information on this topic.

Complications

Complications of syphilis may include the following:

  • Cardiovascular disease - Aortic aneurysm
  • CNS disease - Dementia, stroke
  • Membranous glomerulonephritis
  • Paroxysmal cold hemoglobinemia
  • Irreversible end-organ damage
  • Disfigurement by gummas
 

DDx

Diagnostic Considerations

Syphilis, a reportable disease, is tracked by the Centers for Disease Control and Prevention (CDC). Syphilis has an extensive differential diagnosis. In particular, the extremely variable manifestations of tertiary syphilis produce an extremely broad differential diagnosis, and care must be taken to consider syphilis in cardiac, dermatologic, and neurologic disorders as is relevant. Patients diagnosed with syphilis should also be tested for other sexually transmitted diseases (STDs), including chlamydia, gonorrhea, trichomoniasis, bacterial vaginosis, and HIV infection.

When making a primary diagnosis of a generalized rash or an STD, always include syphilis in the differential diagnoses because of its varying manifestations. 

Other problems to consider

Other problems to consider include the following:

  • Brain tumors

  • Carcinoma

  • Congestive heart failure

  • Fungal infection (superficial and deep)

  • Lymphoma

  • Mycotic infection

  • Other CNS infections

  • Sarcoid

  • Seizures

  • Stroke

  • Trauma

  • Traumatic superinfected lesions

  • Venereal chlamydial infections

Differential Diagnoses

 

Workup

Approach Considerations

T pallidum cannot be cultivated in vitro and is too small to be seen under the light microscope. Serologic testing is considered the standard method of detection for all stages of syphilis. (Note, however, that serologic tests cannot be used to differentiate the different species of the treponeme family—for example, yaws.)

In suspected acquired syphilis, the traditional approach has been to first perform nontreponemal serology screening using the Venereal Disease Research Laboratory (VDRL), rapid plasma reagin (RPR), or the recently developed ICE Syphilis recombinant antigen test.

Sensitivity of the VDRL and RPR tests are estimated to be 78-86% for detecting primary syphilis, 100% for detecting secondary syphilis, and 95-98% for detecting tertiary syphilis. Specificity ranges from 85-99% and may be reduced in individuals who have coexisting conditions (ie, collagen vascular disease, pregnancy, intravenous drug use, advanced malignancy, tuberculosis, malaria, viral and rickettsial diseases).[18]

VDRL test results turn positive 1-2 weeks after chancre formation. Nontreponemal tests usually become nonreactive with time after treatment. Serology values in patients with HIV infection may take longer to fall than in patients without HIV infection. In some patients, nontreponemal antibodies can persist, sometimes for life, a conditioned referred to as ”serofast.”[19]

Because of the possibility of false-positive results, confirmation for any positive or equivocal nontreponemal test result should follow with a treponemal test, such as the fluorescent treponemal antibody-absorption (FTA-ABS), microhemagglutination assay T pallidum (MHA-TP), T pallidum hemagglutination (TPHA), and T pallidum particle agglutination (TPPA) tests.[20, 21] Treponemal enzyme immunoassay (EIA) for immunoglobulin G (IgG) and immunoglobulin M (IgM) may be performed.

FTA-ABS is commonly used as a confirmatory test following positive VDRL or RPR test findings. FTA-ABS has a sensitivity of 84% for detecting primary syphilis infection and almost 100% sensitivity for detecting syphilis infection in other stages. Its specificity is 96%.[18]

Some labs have adopted reverse sequence screening in order to reduce time, labor, and costs. Reverse screening test sera first by automatable treponemal enzyme and chemiluminescence immunoassays (EIA/CIA), followed by testing of reactive sera with a nontreponemal test. Results of the first direct comparison of traditional and reverse screening suggest reverse screening may not be as inferior to traditional testing as previously thought. Six out of 1000 patients tested were falsely reactive by reverse screening, compared to none by traditional testing. However, reverse screening identified 2 patients with possible latent syphilis that were not detected by RPR.[22] The CDC recommends traditional testing, but if reverse screening is used all sera that produce reactive EIA/CIA results should be reflexively tested with a quantitative nontreponemal test. Sera with discordant results should be reflexively tested with a confirmatory TPPA test. If the result is positive, the patient should be offered treatment if no treatment history can be elucidated.

Darkfield microscopy is a possible mode of evaluating moist cutaneous lesions, such as the chancre of primary syphilis or the condyloma lata of secondary syphilis. If darkfield microscopy is not available, direct immunofluorescence staining of fixed smears (direct fluorescent antibody T pallidum [DFA-TP]) is an option. Both procedures detect the causative organism at a rate of approximately 85-92%.

Slit-lamp examination and ophthalmic assessment can be used to differentiate between acquired and congenital syphilis (presence of interstitial keratitis) in patients with latent infection of uncertain duration.

Diagnosis of neurosyphilis can be challenging. The VDRL test for CSF (VDRL-CSF) is highly specific but has low sensitivity. Therefore, the diagnosis of neurosyphilis usually depends on a combination of CSF cell count, CSF protein, and clinical manifestations with or without a reactive VDRL-CSF. Some specialists recommend performing an FTA-ABS test on CSF. The CSF FTA-ABS is less specific for neurosyphilis than the VDRL-CSF, but it is highly sensitive. A negative CSF FTA-ABS test result effectively rules out neurosyphilis.[23]

Patients with confirmed syphilis infections should be tested for other STDs, including HIV infection. If the HIV test is negative, the patient should be retested for HIV in 3 months except in areas with low HIV prevalence.[19]  

Diagnosis of syphilis in pregnant women

The United States Preventive Services Task Force (USPSTF) has reaffirmed its recommendation for screening all pregnant women for syphilis infection at the first prenatal visit. High-risk women (eg, uninsured women, women living in poverty, sex workers, illicit drug users, those with other STDs, those living in communities with high syphilis morbidity) should also be tested in the third trimester and at delivery.

If the test results are positive for syphilis, the treatment of choice is parenteral benzathine penicillin G. Dosage and the length of treatment depend on the stage and clinical manifestations of the disease.[24]

According to the 2015 CDC STD treatment guidelines, pregnant women who are seropositive should be considered infected unless there is evidence of adequate treatment in the medical records and sequential serologic antibody titers have decreased by 4-fold.[19] ​ Serologic titers should be checked monthly if the patient is at risk for reinfection or lives in an area with high syphilis prevalence.

Per CDC guidelines, any woman who delivers a stillborn infant after 20 weeks’ gestation should also be tested for syphilis. No infant should leave the hospital without the maternal serologic status having been determined at least once during pregnancy.

For further information, see the 2015 CDC guidelines for syphilis and pregnancy.

Diagnosis of congenital syphilis

Consider congenital syphilis and sexual abuse in all children who present with syphilis.

Most infants with congenital syphilis are born to mothers with syphilis who were either not treated in pregnancy or treated too late during pregnancy. Treponemal tests (ie, TPPA, FTA-ABS, EIA, CIA) using neonatal serum are not recommended owing to passive transfer of IgG antibodies, which react with the reagents in these tests. All infants born to mothers with syphilis should be evaluated with a quantitative nontreponemal serologic test (RPR or VDRL) performed using the neonate’s serum.

The treatment algorithm below is provided in the 2015 CDC congenital syphilis guidelines for determining the need for further diagnostic workup and/or treatment

Proven or highly probable congenital syphilis

Proven or highly probably congenital syphilis is defined as any one of the following:

  • Abnormal physical examination findings that are consistent with congenital syphilis
  • A serum quantitative nontreponemal serologic titer that is fourfold higher than the mother’s titer
  • A positive darkfield test result or positive PCR result using lesions or body fluid(s)

The recommended evaluation in proven or highly probable congenital syphilis includes the following:

  • CSF analysis for VDRL, cell count, and protein
  • Complete blood cell (CBC) count with differential and platelet count
  • Other tests as clinically indicated (eg, radiography of long bones, chest radiography, liver function tests, neuroimaging, ophthalmologic examination, and auditory brain stem response)

Possible congenital syphilis

Congenital syphilis should be considered possible in any neonate who has normal physical examination findings and a serum quantitative nontreponemal serologic titer equal to or less than fourfold the maternal titer in addition to one of the following:

  • Mother was not treated, inadequately treated, or has no documentation of having received treatment
  • Mother was treated with erythromycin or a regimen other than those recommended in these guidelines (ie, a non–penicillin G regimen)
  • Mother received recommended treatment less than 4 weeks before delivery

The recommended evaluation in possible congenital syphilis is as follows:

  • CSF analysis for VDRL, cell count, and protein
  • CBC count, differential, and platelet count
  • Long-bone radiography

Less-likely congenital syphilis

Congenital syphilis is considered less likely in any neonate who has normal physical examination findings and a serum quantitative nontreponemal serologic titer equal to or less than fourfold the maternal titer and both of the following:

  • Mother was treated during pregnancy, treatment was appropriate for the stage of infection, and treatment was administered more than 4 weeks before delivery
  • Mother has no evidence of reinfection or relapse

No evaluation is recommended in these cases.

Unlikely congenital syphilis

Congenital syphilis is considered unlikely in any neonate who has normal physical examination findings and a serum quantitative nontreponemal serologic titer equal to or less than fourfold the maternal titer and both of the following:

  • Mother’s treatment was adequate before pregnancy
  • Mother’s nontreponemal serologic titer remained low and stable (ie, serofast) before and during pregnancy and at delivery (VDRL <1:2; RPR <1:4)

No evaluation is recommended in these cases.

​For more information, see the 2015 CDC guidelines for congenital syphilis treatment.

Imaging Studies

Imaging studies should be performed depending on the organ system involved. For example, granulomatous disease of the liver can be seen on computed tomography (CT) of the abdomen.

Obtain chest radiography in patients with tertiary syphilis to screen for aortic dilatation. Linear calcification of the ascending aorta on chest films suggests asymptomatic syphilitic aortitis. Radiologic abnormal findings commonly seen with advanced gummas of bone include periostitis, destructive osteitis, or sclerosing osteitis.

Angiography may be useful to distinguish between abdominal aneurysms of syphilitic versus arteriosclerotic origin. About 10% of syphilitic aneurysms occur superior to the renal arteries, while arteriosclerotic abdominal aneurysms usually are found inferior to the renal arteries.

Lumbar Puncture

Invasion of the central nervous system (CNS) by treponemes occurs in 30-40% of patients with primary or secondary syphilis; however, no studies show this to be a predictor of poor neurologic outcome. According to the 2015 CDC STD treatment guidelines, CSF laboratory abnormalities are common in persons with early syphilis, even when clinical neurological findings are absent. If clinical evidence of neurological involvement is found, a CSF examination should be performed.[19]

Current guidelines state that physicians should evaluate CSF in individuals with late latent syphilis if treatment fails or if neurologic or ocular symptoms are present. It is also indicated if there are other changes indicative of tertiary syphilis (eg, gumma, aortitis).

LP should be performed in patients suspected of having neurosyphilis with no contraindication. There is no single test available for the definitive diagnosis of neurosyphilis; rather, the clinical symptoms, serology, and CSF values (CSF cell count or protein and a reactive CSF-VDRL) must be used in combination to determine the diagnosis. CSF examination is the only means by which the occurrence of asymptomatic neurosyphilis in latent syphilis can be excluded; however, it is not recommended unless the patient is asymptomatic or fails to respond serologically to treatment.

Examination of the CSF should include the VDRL test, cell count, and protein level. Abnormalities of any of these measurements combined with a suggestive history and examination strongly indicate the presence of neurosyphilis. A positive VDRL test result is highly sensitive for active syphilis. Among persons with HIV infection and active syphilis, the CSF leukocyte count is usually elevated (>5 WBCs/µL), so more than 20 cells/µL should be considered positive.[19]

Histologic Findings

The primary lesion of syphilis is a chancre. Histologically, skin and mucosal lesions show a perivascular and perijunctional infiltrate of lymphocytes, plasma cells, and macrophages. At times, capillary endothelial proliferation and subsequent obliteration of small blood vessels may be appreciable. Focal erosion or ulceration is common.

The inflammatory reaction of secondary syphilis is histologically similar to that of the primary chancre but is less intense. Skin lesions are typified by a “lichenoid-psoriasiform” configuration with a perijunctional infiltrate of lymphocytes, histiocytes, and plasmacytes (see the image below). Often the histiocytic component of the infiltrate is prominent, and thus the biopsy may assume a “lichenoid-granulomatous” configuration.

Lues hematoxylin and eosin stain. Histopathologica Lues hematoxylin and eosin stain. Histopathological examination shows a lichenoid infiltrate that is stereotypical of the secondary stage of syphilis. Note that vacuolar alteration of the superjacent epithelium can be seen much like a noninfectious form of lichenoid dermatitis. The subjunctional infiltrate is rich in histiocytes and plasmacytes. At times, an overtly granulomatous lichenoid infiltrate can be seen.

Small numbers of neutrophils may be included in the perijunctional infiltrate, and neutrophils may also be present in an expanded overlying stratum corneum. Organisms are readily demonstrable using T pallidum immunoperoxidase staining during the secondary stage (see the image below).

Lues TP stain. Immunoperoxidase staining for T pal Lues TP stain. Immunoperoxidase staining for T pallidum highlights many slender coiled organisms residing in the perijunctional zone. Occasionally, organisms can also be found in the upper dermis or around adnexal structures.

In tertiary syphilis, histological examination shows gummas consisting of granulomatous inflammation with central necrosis flanked by plump or palisaded macrophages and fibrocytes surrounded by large numbers of mononuclear leukocytes, including many plasma cells. Treponemes are rare in these lesions and typically cannot be cultured or visualized.

Aortitis reveals inflammatory scarring of the tunica media, secondary to obliterative endarteritis of the vasa vasorum. Uneven loss of the medial elastic fibers and muscle cells may be evident.

 

Treatment

Approach Considerations

Key principles for the treatment of syphilis include the following:[25]

  • Penicillin is the drug of choice to treat syphilis.
  • Doxycycline is the best alternative for treating early and late latent syphilis. Syphilis associated with HIV infection does not require any enhanced antimicrobial therapy.
  • In the treatment of late syphilis by weekly injections, missing a dose of penicillin for a period of 10-14 days does not require restarting the entire course of injections.
  • The exception to this is in the case of pregnant women in whom there is no latitude for missing a dose of penicillin.
  • There is evidence that an interval of 7-9 days between doses may produce better results.
  • CSF testing to detect neurosyphilis is strongly recommended in patients with tertiary syphilis or with neurological signs or symptoms consistent with neurosyphilis and in patients without symptoms whose serologic titers do not decline appropriately after being treated with recommended therapy.
  • Reinfection rates among MSM are high, so frequent serological testing in this group is recommended.
  • CDC recommends the use of the RPR-based screening algorithm. When there is a low epidemiologic risk or clinical probability of syphilis, the positive predictive value of an isolated unconfirmed reactive treponemal chemoluminescence test or enzyme immunoassay is low.

Antibiotic Therapy

Penicillin

Penicillin was established as an effective treatment for syphilis before the widespread use of randomized clinical trials.[26] The treatment guidelines published by the CDC (see current CDC recommendations) are based largely on uncontrolled trials and expert opinion. Guidelines are based on staging, with later stages requiring longer courses of treatment due to the slower rate of bacterial replication.[27]

Penicillin remains the mainstay of treatment and the standard by which other modes of therapy are judged.[28] The 2015 CDC STD treatment guidelines support the use of penicillin as the preferred drug for treating all stages of syphilis.[19] Penicillin is the only recommended therapy for neurosyphilis, congenital syphilis, or syphilis during pregnancy. Rarely, T pallidum has been found to persist following adequate penicillin therapy; however, there is no indication that the organism has acquired resistance to penicillin.

The following regimens are recommended for penicillin treatment:

  • Primary or secondary syphilis - Benzathine penicillin G 2.4 million units intramuscularly (IM) in a single dose
  • Early latent syphilis - Benzathine penicillin G 2.4 million units IM in a single dose
  • Late latent syphilis or latent syphilis of unknown duration - Benzathine penicillin G 7.2 million units total, administered as 3 doses of 2.4 million units IM each at 1-week intervals
  • Pregnancy - Treatment appropriate to the stage of syphilis is recommended.

Clinicians should be aware that only benzathine penicillin product (Bicillin L-A) should be used, not benzathine-procaine penicillin (Bicillin C-R). In addition, oral penicillin is never appropriate for the treatment of syphilis.

If the patient arrives late for subsequent doses, clinical experience suggests that an interval of 10-14 days between doses of benzathine penicillin for latent syphilis might be acceptable before restarting the sequence of injections; however, according to pharmacokinetics/pharmacodynamics, an interval of 7-9 days between doses is more optimal.[29, 30, 31] In pregnancy, missed doses are not acceptable. Pregnant patients must repeat the full course of therapy.[32]

In patients with a history of penicillin allergy, desensitization may be necessary in cases of pregnancy, neurosyphilis, congenital syphilis, or tertiary syphilis.

According to the 2015 CDC STD guidelines, no treatment regimens for syphilis have been shown to be more effective in preventing neurosyphilis in patients who are HIV positive than the syphilis regimens recommended for patients who are HIV negative. Careful monitoring after therapy is required, as patients with HIV infection are at higher risk for reinfection and have a slower serologic response than patients without HIV infection.[19]

Alternatives to penicillin

As stated in the 2015 CDC guidelines, several therapies exist that might be effective in nonpregnant, penicillin-allergic patients with primary or secondary syphilis.[19]

Tetracycline, erythromycin, and ceftriaxone[33] have shown antitreponemal activity in clinical trials; however, they currently are recommended only as alternative treatment regimens in patients allergic to penicillin. A 10- to 14-day trial of ceftriaxone is effective for treating early syphilis, although the optimal dose and duration have not been established. Doxycycline and tetracycline for 28 days have been used for many years and are the only acceptable alternatives to penicillin for the treatment of latent syphilis. Doxycycline is the preferred alternative to penicillin owing to its tolerability.[26]

Azithromycin has also been studied. A meta-analysis of randomized clinical trials comparing azithromycin to benzathine penicillin G for early syphilis was published in 2008 showing favorable results for azithromycin.[34] A 2010 study by Hook et al showed a single dose of azithromycin (2 g PO) to be equivalent to the treatment of choice, benzathine penicillin G (2.4 million units IM) in patients with early syphilis without HIV. Serological cure after 6 months of follow-up was not significant between the 2 treatments, although azithromycin recipients had a higher incidence of adverse effects (mostly self-limited gastrointestinal symptoms).[35] Although azithromycin is effective, resistance is increasing in the United States, with some areas reporting up to 84% resistance; therefore, azithromycin should be used only in areas of low resistance or in early syphilis with close clinical follow-up.[19, 36]

Jarisch-Herxheimer reaction

Following the initiation of treatment, the dying treponemes release inflammatory molecules that trigger a cytokine cascade possibly leading to a response known as the Jarisch-Herxheimer reaction. Symptoms include myalgias, fever, headache, and tachycardia, sometimes with exacerbation of whatever current syphilitic lesions are manifested (eg, rash or chancre).

The reaction is common, develops within several hours after beginning antibiotic treatment, and usually clears within 24 hours after onset. Its exact etiology is unclear, although it may be due to an immunological reaction to the rupture of spirochetes.

Management of this reaction often involves symptomatic treatment (eg, with antipyretics and analgesics) and observation. In pregnant women, treatment may induce early labor or cause fetal distress. Patients should be informed of the possibility of this reaction before undergoing antibiotic therapy. As stated in the CDC 2015 STD treatment guidelines, although the Jarisch-Herxheimer reaction might induce obstetric complications such as early labor or fetal distress, this risk should not preclude or delay therapy for syphilis. Women are advised to seek obstetric care after treatment if they notice any fever, uterine contractions, or a decrease in fetal movement.[19]

Procaine toxicity

Some patients experience severe anxiety and other psychological disturbances after the administration of procaine penicillin. Fever, hallucinations, hyperventilation, and convulsions characterize the reaction. Circulatory collapse is occasionally reported.

Resuscitation and supportive care are necessary in severe cases; however, most reactions are mild, requiring only reassurance or symptomatic relief. Symptoms usually dissipate within 30 minutes.

Surgical Care

Surgical care is reserved for treating the complications of tertiary syphilis (eg, aortic valve replacement).

Prevention of Syphilis

The primary goal of prevention is to limit the spread of syphilis. This entails counseling patients to use safe sex practices and advising patients who abuse intravenous (IV) drugs to never share needles and to use clean needles. Notification and treatment of sexual partners and exposed drug partners are paramount. Prevention also entails educating health care workers to use universal precautions when treating all patients.

Empiric treatment with one dose of benzathine penicillin G 2.4 million units intramuscularly (IM) is recommended in all patients who have had sexual contact with a partner who has tested positive for primary, secondary, or early latent syphilis within the preceding 90 days.[19]

Studies of primary screening for syphilis in clinics and emergency departments are favorable for screening of high-risk, urban populations. Routine screening is advocated for all at-risk mothers.

Two reports from 2009 indicate that circumcision does not help prevent the transmission of syphilis, although circumcision may help reduce the transmission of other STDs such as HIV infection.[37, 38]

Consultations

Consultation with an infectious diseases specialist may be required for difficult or complex cases of syphilis. Consult with a dermatologist, vascular surgeon, ophthalmologist, or neurologist should also be obtained as necessary to assist with the variable presentations of syphilis.

Additionally, the CDC, the World Health Organization (WHO), and Morbidity and Mortality Weekly Report (MMWR) are excellent updated references. Syphilis may be reportable to public health authorities in some jurisdictions.

Long-Term Monitoring

Monitor patients with syphilis to ensure adequacy of treatment. Patients with early syphilis should be monitored with repeat RPR or VDRL at 6- and 12-month intervals. Patients with HIV infection and patients treated with a nonpenicillin regimen should be seen at 3, 6, 9, and 12 months. Patients with latent syphilis should be monitored with RPR or VDRL at 6-, 12-, and 24-month intervals.

Generally speaking, therapy is considered a failure if the signs and symptoms of syphilis return or fail to improve. This occurs when the titer of the nontreponemal test increases 4-fold or a 4-fold decrease from the initial VDRL titer does not occur within 1 year.

However, clearly defined criteria regarding treatment failure are lacking. In their literature review, Augenbraun and Rolfs found that 15-25% of patients treated for syphilis do not have a 4-fold decrease in titers over a 3-month period, and some do not have a decrease for 6 months or longer.[39] Information is lacking on whether these patients are at higher risk for progression. Currently accepted guidelines are as follows:

  • Any reappearance of symptoms is defined as a relapse.
  • More than a double-dilution increase (ie, a 4-fold titer increase) in serologic tests is a relapse.
  • Patients with latent syphilis who have initially high titers (≥1:32) and fail to have a double-dilution decrease (4-fold titer decline) 12-24 months after therapy should be reevaluated for neurosyphilis and possible retreatment.
  • Some treponemal test results may remain positive for life despite effective treatment. Individuals in this circumstance require proper documentation to avoid unnecessary retreatment.
  • Supervise retreatment to ensure compliance.

Recommendations for specific patient subsets are as follows.

Patients with treated primary or secondary syphilis

Patients treated for primary and secondary syphilis should have follow-up VDRL testing at 6, and 12 months after treatment. Patients with HIV infection should be monitored at 3, 6, 9, and 12 months, as they are known to have more rapid progression of disease. Most patients with primary syphilis who are treated adequately have a nonreactive VDRL within 1 year, and almost all patients treated for secondary syphilis have a negative VDRL result within 2 years. A small minority of patients remain seropositive in spite of successful treatment. If all clinical and serologic examinations remain satisfactory for 2 years following treatment, the patient can be reassured that cure is complete, and no further follow-up care is needed.

Patients with latent syphilis

Perform quantitative RPR/VDRL testing for up to 2 years. Schedule annual follow-up visits for an indefinite period of time for patients with persistently positive serologic tests.

The 2010 CDC STD treatment guidelines state that HIV-infected individuals with latent syphilis should receive the same stage-specific treatment as recommended for HIV-negative individuals.[26]

Patients with benign tertiary or cardiovascular syphilis

Patients should be observed by the physician for the rest of their lives to monitor for complications.

Patients with neurosyphilis

Patients with neurosyphilis should have follow-up at 6-month intervals for at least 3 years with physical examinations, CSF evaluation (eg, cell count, protein, VDRL), and serologic testing.

Go to Neurosyphilis for complete information on this topic.

Pregnant patients with syphilis

Pregnant women treated for syphilis should have monthly VDRL testing for the duration of their pregnancy.

 

Guidelines

WHO Guidelines on the Treatment of Syphilis by the World Health Organization

Guidelines on the treatment of Treponema pallidum infection (syphilis) by the World Health Organization (WHO) are summarized below.[40]

Early Syphilis in Adults and Adolescents

WHO recommendations on the treatment of early syphilis in adults and adolescents are as follows:

  • Benzathine penicillin G 2.4 million units once intramuscularly is recommended over no treatment.
  • Benzathine penicillin G 2.4 million units once intramuscularly is recommended over procaine penicillin G 1.2 million units 10-14 days intramuscularly.
  • When benzathine or procaine penicillin cannot be used (eg, owing to penicillin allergy) or is not available (eg, owing to stock-outs), the guidelines suggest using doxycycline 100 mg twice daily orally for 14 days or ceftriaxone 1 g intramuscularly once daily for 10-14 days or, in special circumstances, azithromycin 2 g once orally.
  • Doxycycline is preferred over ceftriaxone owing to its lower cost and oral administration.
  • Doxycycline should not be used in pregnant women.
  • Azithromycin is an option in special circumstances only when local susceptibility to azithromycin is likely. If the stage of syphilis is unknown, recommendations for people with late syphilis (see below) should be followed.

Early Syphilis in Pregnant Women

WHO recommendations on the treatment of early syphilis in pregnancy are as follows:

  • Benzathine penicillin G 2.4 million units once intramuscularly is preferred over no treatment.
  • Benzathine penicillin G 2.4 million units once intramuscularly is preferred over procaine penicillin G 1.2 million units intramuscularly once daily for 10 days.
  • When benzathine or procaine penicillin cannot be used (eg, owing to penicillin allergy when penicillin desensitization is not possible) or is not available (eg, owing to stock-outs), the guidelines suggest using, with caution, erythromycin 500 mg orally 4 times daily for 14 days or ceftriaxone 1 g intramuscularly once daily for 10-14 days or azithromycin 2 g once orally.
  • Erythromycin and azithromycin do not cross the placental barrier completely, so the fetus does not receive treatment. It is therefore necessary to treat the newborn soon after delivery.
  • Doxycycline should not be used in pregnant women.

Late Syphilis in Adults and Adolescents

WHO recommendations on the treatment of late syphilis in adults and adolescents are as follows:

  • Benzathine penicillin G 2.4 million units intramuscularly once weekly for 3 consecutive weeks is preferred over no treatment.
  • The interval between consecutive doses of benzathine penicillin should not exceed 14 days.
  • Benzathine penicillin G 2.4 million units intramuscularly once weekly for 3 consecutive weeks is preferred over procaine penicillin 1.2 million units once daily for 20 days.
  • When benzathine or procaine penicillin cannot be used (eg, owing to penicillin allergy where penicillin desensitization is not possible) or is not available (eg, owing to stock-outs), the guidelines suggest using doxycycline 100 mg twice daily orally for 30 days.

Late Syphilis in Pregnant Women

WHO recommendations on the treatment of late syphilis in pregnancy are as follows:

  • Benzathine penicillin G 2.4 million units intramuscularly once weekly for 3 consecutive weeks is recommended over no treatment.
  • Benzathine penicillin G 2.4 million units intramuscularly once weekly for 3 consecutive weeks is recommended over procaine penicillin 1.2 million units intramuscularly once daily for 20 days.
  • When benzathine or procaine penicillin cannot be used (eg, owing to penicillin allergy where penicillin desensitization is not possible) or is not available (eg, owing to stock-outs), the guidelines suggest using, with caution, erythromycin 500 mg orally 4 times daily for 30 days.
  • Although erythromycin treats the pregnant woman, it does not cross the placental barrier completely, so the fetus does not receive treatment. It is therefore necessary to treat the newborn soon after delivery.
  • Doxycycline should not be used in pregnant women.

Syphilis in Infants

WHO recommendations on the treatment of syphilis in infants are as follows:

  • Aqueous benzyl penicillin or procaine penicillin is recommended in infants with confirmed congenital syphilis or infants who are clinically healthy but whose mothers had untreated syphilis, inadequately treated syphilis (including treatment within 30 days of delivery), or syphilis treated with non-penicillin regimens.
  • Aqueous benzyl penicillin 100,000-150,000 U/kg/day is administered intravenously for 10-15 days.
  • Procaine penicillin 50,000 U/kg/day as a single dose is administered intramuscularly for 10-15 days.
  • If an experienced venipuncturist is available, aqueous benzyl penicillin may be preferred over intramuscular injections of procaine penicillin.
  • In infants who are clinically healthy and whose mothers had syphilis that was adequately treated with no signs of reinfection, the guidelines suggest close monitoring of the infants.
  • The risk of syphilis transmission to the fetus depends on numerous factors, including maternal titers from non-treponemal tests (eg, RPR), timing of maternal treatment, and stage of maternal infection. If treatment is provided, benzathine penicillin G 50,000 U/kg/day as a single dose intramuscularly is an option.
 

Medication

Medication Summary

The goal of pharmacotherapy is to eradicate the causative organism of syphilis, T pallidum. Penicillin is the mainstay of treatment, the standard by which other modes of therapy are judged, and the only therapy recommended for neurosyphilis, congenital syphilis, or syphilis during pregnancy.

Penicillin

The drug of choice is parenteral penicillin G for all stages of syphilis. According to the 2010 CDC STD treatment guidelines, penicillin G is the only therapy that is clinically documented to be effective against syphilis during pregnancy.[26] Since the dividing time of T pallidum is slow (days), penicillin G benzathine is the only penicillin effective for single-dose therapy because it is in depo form and levels remain therapeutic in the blood for up to 30 days. Avoiding Bicillin C-R (combination procaine and benzathine), which remains in blood for only 7 days, is essential.

On rare occasions, T pallidum has been found to persist after adequate penicillin therapy; however, no indication exists that T pallidum has acquired resistance to the drug.

According to the Centers for Disease Control and Prevention (CDC; see current CDC recommendations), patients with known penicillin allergies should undergo penicillin allergy skin testing and penicillin desensitization, if necessary.[41]

Alternatives to penicillin

Since T pallidum resistance to penicillin has not emerged, the primary need for alternative drugs in treating syphilis is reserved for penicillin-allergic patients.

Researchers are studying the efficacy of ceftriaxone and azithromycin in treating syphilis. Central nervous system (CNS) penetration and its similarity to penicillin support the use of ceftriaxone in the treatment of syphilis. Studies are presently inconclusive, and CDC guidelines neither support nor refute its use. Given the limited data available to support its efficacy, prudence dictates a 5- to 7-day course of treatment for early syphilis.

The long half-life of azithromycin and its clinical efficacy in vitro against syphilis support its use in treating early syphilis. At present, however, clinical data remain insufficient to recommend its use, and widespread resistance limits the use in many areas (especially in the Pacific Northwest).

Doxycycline may be an option for patients who refuse parenteral therapy or who have penicillin allergy.

Antibiotics

Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Penicillin G benzathine (Bicillin L-A)

Benzathine penicillin G is the first-line agent for primary and secondary syphilis infection. It is a spirocheticide with in vivo activity against T pallidum. It interferes with cell wall mucopeptide synthesis during replication.

Penicillin G procaine

Penicillin G procaine is the first-line agent for treating late latent syphilis.

Doxycycline (Doryx, Vibramycin)

Doxycycline is used as alternative therapy for syphilis infection. It inhibits bacterial growth by binding to the 30S ribosomal unit, preventing protein synthesis.

Tetracycline (Sumycin)

Tetracycline is used as alternative therapy for syphilis infection. It inhibits bacterial growth by binding to the 30S ribosomal unit, preventing protein synthesis.

Erythromycin (E.E.S., E-Mycin)

Erythromycin inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. In children, age, weight, and severity of infection determine proper dosage. When twice-daily dosing is desired, half of the total daily dose may be taken q12h. For more severe infections, double the dose.

Ceftriaxone (Rocephin)

Ceftriaxone is an alternative agent for penicillin-allergic patients, with limited data to support its use. It is a third-generation cephalosporin. It arrests bacterial growth by binding to one or more penicillin binding proteins.

Azithromycin (Zithromax)

Azithromycin acts by binding to the 50S ribosomal subunit of susceptible microorganisms and blocks dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Nucleic acid synthesis is not affected.

Azithromycin concentrates in phagocytes and fibroblasts as demonstrated by in vitro incubation techniques. In vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues. This drug is used to treat mild-to-moderate microbial infections.

Uricosuric agents

Class Summary

Uricosuric agents are used to increase serum concentration of certain antibiotics and other drugs.

Probenecid

Probenecid inhibits tubular secretion of penicillin and usually increases penicillin plasma levels by any route the antibiotic is administered. A 2- to 4-fold elevation has been demonstrated for various penicillins. Probenecid is used as an adjunct to penicillin in late latent and neurosyphilis.