What is Treponema pallidum

Treponema pallidum is a sexually transmitted spirochete bacterium that causes syphilis. Treponema pallidum belongs to the spirochete class and is a corkscrew-shaped, motile microaerophilic bacterium that requires a live rabbit-model system for growth and cannot be viewed by normal light microscopy (Figure 1). This spirochete bacterium is thin (0.1 to 0.18 micrometers in diameter), and 6 to 20 micrometers in length (Figure 1). Treponema pallidum has been erroneously described as gram-negative bacteria, but this organism lacks lipopolysaccharide (LPS), a hallmark of gram-negative organisms.

Syphilis is a complex sexually transmitted disease (STD) or sexually transmitted infection (STI). Syphilis is transmitted from person to person by direct contact with a syphilitic sore, known as a chancre ¹. Chancres can occur on or around the external genitals, in the vagina, around the anus or in the rectum, or in or around the mouth. Transmission of syphilis can occur during vaginal, anal, or oral sex. In addition, pregnant women with syphilis can transmit the infection to their unborn children.

Some people with syphilis have no symptoms, so you may not know you have it unless you get tested. The signs and symptoms of syphilis depend on the stage of disease. There are 4 stages of syphilis infection: primary, secondary, latent and tertiary.

The average time between acquisition of syphilis and the start of the first symptom is 21 days, but can range from 10 to 90 days.

Syphilis usually starts as a painless sore — typically on your genitals, rectum or mouth. Syphilis spreads from person to person via skin or mucous membrane contact with these sores. After the initial infection, the Treponema pallidum bacteria can lie dormant in your body for decades before becoming active again. Early syphilis can be cured, sometimes with a single injection of penicillin. Without treatment, syphilis can severely damage your heart, brain or other organs, and can be life-threatening, or be passed from mother to an unborn child.

Primary syphilis appears as a painless sore (ulcer) where the infection entered your body (usually around the penis, vagina, cervix, anus or mouth) and may go unnoticed. The sore is known as a chancre and this phase is known as primary syphilis. There may also be swollen lymph nodes.

Primary syphilis occurs 3 or 4 weeks after infection (although it can take up to 90 days for the sore to appear).

The sore, or sometimes multiple sores, can go unnoticed because it is usually painless and may be hidden from view in areas such as the back of the throat, vagina or anus.

These sores usually go away by themselves after 3 to 6 weeks, even with no treatment. However, even though the sore heals, if you haven’t been treated, you are still infectious and can pass it on to others.

Secondary syphilis can occur 7 to 10 weeks after the initial infection. Symptoms can last for 6 months or more and may include:

• a red rash on the palms, soles, chest or back
• fever
• enlarged glands in the armpits and groin
• sore throat
• hair loss
• weight loss
• headaches
• pain in the bones, muscles and joints
• tiredness
• ulcers in the mouth, nasal cavity or genitals
• neurological symptoms

After the initial infection, the syphilis bacteria, Treponema pallidum, can remain inactive in your body for decades before becoming active again, this is known as the latent (sleeping) syphilis stage. Generally the person with latent stage syphilis has no symptoms and it is only picked up on blood tests. If syphilis is not treated at this stage, it can remain latent or develop into tertiary syphilis. Latent syphilis is infectious within the first 12 to 24 months.

If the latent stage syphilis is left untreated, tertiary syphilis may develop 5 to 20 years after the primary infection. At the tertiary syphilis stage, the Treponema pallidum bacteria can damage almost any part of your body including your heart, brain, spinal cord, eyes and bones, resulting in heart disease, mental illness, blindness, deafness and neurological problems and can be life-threatening

Early syphilis can be cured, sometimes with a single shot (injection) of penicillin. If you’re allergic to penicillin, your doctor may suggest another antibiotic or recommend penicillin desensitization.

After you’ve been treated for syphilis, your doctor will ask you to:

• Have periodic blood tests and exams to make sure you’re responding to the usual dosage of penicillin. Your specific follow-up will depend on the stage of syphilis you’re diagnosed with.
• Avoid sexual contact with new partners until the treatment is completed and blood tests indicate the infection has been cured.
• Notify your sex partners so that they can be tested and get treatment if necessary.
• Be tested for HIV infection.

Figure 1. Treponema pallidum bacteria

[Source ² ]

Treponema pallidum transmission

The major routes of transmission for Treponema pallidum are sexual and vertical (in utero via hematogenous spread to a fetus). The most common route of transmission is through contact with an infected person’s sore during sexual activity. Treponema pallidum enters the body via skin and mucous membranes through macroscopic and microscopic abrasions during sexual contact. An infected individual is contagious to sex partners during the primary and secondary stages of infection when lesions or rash are present and sometimes in the early latent period. Although predominantly transmitted at genital sites, primary lesions have been described at diverse sites, including mouth, anorectal areas, and chest or neck from human bites. Less commonly, Treponema pallidum may spread through direct unprotected close contact with an active lesion (such as during kissing) or through an infected mother to her baby during pregnancy or childbirth (congenital syphilis). Transfusion-associated syphilis was well-recognized prior to the 1940s, but has been eliminated in the United States blood supply; this mode of transmission now occurs only in resource-limited countries ³.

Treponema pallidum syphilis can’t be spread by using the same toilet, bathtub, clothing or eating utensils, or from doorknobs, swimming pools or hot tubs.

Once cured, syphilis doesn’t recur on its own. However, you can become reinfected if you have contact with someone’s syphilis sore.

Risk factors for Treponema pallidum infection

You face an increased risk of acquiring syphilis if you:

• Engage in unprotected sex
• Have sex with multiple partners
• Are a man who has sex with men
• Are infected with HIV, the virus that causes AIDS

Treponema pallidum symptoms

Syphilis has often been called “the great imitator” because so many of the signs and symptoms may be difficult to differentiate from those of other diseases ⁴. Before clinical signs or symptoms appear, Treponema pallidum accesses the circulatory system, including the lymphatic system and regional lymph nodes. Syphilis develops in stages, and symptoms vary with each stage. But the stages may overlap, and symptoms don’t always occur in the same order. You may be infected with syphilis and not notice any symptoms for years. Invasion of the central nervous system can occur during any stage of syphilis. Early clinical manifestations (primary and secondary stages) predominantly involve the skin and mucosal surfaces, although secondary syphilis may be accompanied by systemic manifestations. Latent disease has no clinical signs or symptoms, but late manifestations (seen after years of infection) may affect virtually any organ system. Neurosyphilis and ocular syphilis can occur at any stage of infection. Obtaining a detailed history is critical for determining the duration of infection and assessing for the possibility of reinfection.

Primary Syphilis

Following the inoculation of Treponema pallidum at the entry site, organisms proliferate, sensitize lymphocytes, and activate macrophages, causing the formation of a primary lesion or “chancre” at the site of inoculation ⁵. The initial manifestation of the chancre typically occurs about 3 weeks (range 10 to 90 days) after the acquisition of the infection ⁶. Chancres progress from a papule to an ulcer, which is typically painless, indurated, well circumscribed, round to oval in shape, with a clean base. The most common sites where chancres develop include the penis (Figure 2), labia, perianal region, or mouth (Figure 3). Regional firm, non-tender, lymphadenopathy often develops in proximity to primary syphilitic lesions (inguinal adenopathy with genital lesions and cervical adenopathy with oral lesions); in most patients, the lymphadenopathy is bilateral ⁷. Syphilitic chancres are highly infectious and heal spontaneously within 1 to 6 weeks; untreated patients may go on to develop other manifestations of syphilis. Less typical lesions often develop, with one study reporting only 42.7% had a “classic” single lesion. Atypical features may include painful lesions or multiple lesions; in some instances chancres can mimic herpes simplex infection or chancroid ⁸. Evaluation of patients with genital ulcers should include serologic testing for syphilis and a diagnostic evaluation for genital herpes. In addition, if available, suspected primary syphilis should be evaluated with darkfield microscopy or a polymerase chain reaction (PCR) test for Treponema pallidum. In geographic regions where chancroid is endemic (Asia, Africa, and the Caribbean), testing for Haemophilus ducreyi should also be performed.

Figure 2. Primary syphilis chancre

Figure 3. Primary syphilis chancre

Secondary Syphilis

Secondary lesions reflect hematogenous dissemination of Treponema pallidum and generally appear 4 to 8 weeks after the onset of the primary chancre; patients with secondary syphilis may develop a wide array of cutaneous lesions ⁹. Signs and symptoms of secondary syphilis often are the first observed clinical manifestation of syphilis in those practicing receptive vaginal, oral, or anal intercourse because primary lesions may occur in the vagina, mouth, or anus and may not be recognized by the patient. In some patients, primary and secondary stages may overlap. Relapses of secondary symptoms may occur in up to 25% of untreated patients, usually within the first year of infection.

• Rash: A rash occurs in 75% to 100% of patients with secondary syphilis. The rash can be macular, papular, squamous, pustular (rarely), or a combination ¹⁰. Rash with secondary syphilis is usually nonpruritic, and characteristically involves the chest, back, palms and soles. Any new onset of macular, papular, or squamous rash should be evaluated to rule out secondary syphilis.
• Lymphadenopathy: In 50% to 86% of cases, patients will develop lymphadenopathy. Epitrochlear lymphadenopathy should prompt consideration of secondary syphilis.
• Systemic Symptoms: Patients often present with malaise, fever, and other nonspecific constitutional symptoms.
• Mucous Patches: The development of mucous patches occurs in 6% to 30% of patients and manifest as flat patches located in the oral cavity (Figure 19), pharynx, larynx, or genital region.
• Condylomata Lata: Approximately 10% to 20% of patients will have condylomata lata lesions, which appear as moist, heaped-up, wart-like papules in warm intertriginous areas (most commonly gluteal folds, perineum, and perianal) (Figure 4); these lesions are highly contagious.
• Alopecia: About 5% of patients develop patchy alopecia, most often in the occipital or bitemporal scalp region, but some patients will have loss of the lateral region of the eyebrows.
• Visceral Organ Involvement: In some cases, syphilis may involve one or more visceral organs, including liver, kidney, lungs, gastrointestinal tract, and spleen.
• Neurologic Symptoms: Patients with secondary syphilis can develop neurosyphilis, characterized by either asymptomatic infection of the central nervous system, or acute syphilitic meningitis, a basilar meningitis that typically causes headache and stiff neck and may involve cranial nerves, which may result in hearing loss, facial weakness, or visual disturbances. Strokes may also occur. Patients may also develop ocular or otic syphilis without basilar meningitis.

Figure 4. Condylomata lata

Latent syphilis

Latent syphilis is a stage of syphilis characterized by the persistence of Treponema pallidum organisms in the body without causing signs or symptoms. Periods of clinical latency may occur between the primary and secondary stages, between secondary relapses, and after the secondary stage. The diagnosis of latent syphilis is made when an individual has: (1) seroreactivity indicating infection with Treponema pallidum, (2) no past diagnosis of syphilis, and (3) no evidence of active primary, secondary, or tertiary syphilis ¹¹. Latent syphilis is classified into three subcategories based on duration of the infection: early latent, late latent, and latent of unknown duration ¹². It is often difficult to determine the duration of infection in a patient with latent syphilis. Individuals with latent syphilis should have HIV testing at the time of syphilis diagnosis (and at a 3-month follow-up if high risk for HIV acquisition), unless they are already known to have HIV infection. When evaluating an individual with latent syphilis, the health care provider should ask the patient whether they recall having symptoms of primary or secondary syphilis, and whether they had sex with someone with primary or secondary syphilis within the past year. A careful physical examination, with an emphasis on mucosal surfaces, and review of prior serology results are also useful tools for clarification of the duration of infection.

Early latent syphilis (infection of less than 1 year in duration)

Persons with latent syphilis are classified in the subcategory of early latent syphilis if they have no past diagnosis of syphilis, no clinical signs or symptoms of syphilis, and at least one of the following ¹³:

• A documented seroconversion or a sustained (longer than 2 weeks) fourfold or greater increase in titer of a nontreponemal test during the prior 12 months
• Uneqivacal symptoms of primary or secondary syphilis during the prior 12 months
• A history of sexual exposure to a partner within the prior 12 months who had documented primary, secondary, or early latent syphilis
• Sexual debut occurred in the prior 12 months and only possible sexual contact occurred in the prior 12 months

If an individual has a reactive nontreponemal and treponemal tests and the only possible exposure occurred during the previous 12 months, early latent syphilis can be assumed.

Late latent syphilis (infection greater than 1 year in duration)

Persons with latent syphilis are classified in the subcategory of late latent syphilis when there is no evidence that Treponema pallidum was acquired in the prior 12 months, they do not have clinical signs or symptoms consistent with syphilis, and they meet criteria for at least one of the following:

• Reactive nontreponemal and treponemal tests and no past diagnosis of syphilis and no prior
• A past history of syphilis therapy and a current nontreponemal test titer demonstrating fourfold or greater increase from the last nontreponemal test titer

Latent syphilis of unknown duration

In the situation when it is not possible to determine likely the duration of infection in a person with latent syphilis, they are categorized as having latent syphilis of unknown duration. From a practical standpoint, individuals with latent syphilis of unknown duration are effectively managed the same as persons with late latent syphilis.

Tertiary syphilis (other than neurosyphilis)

Tertiary syphilis, also referred to as late syphilis, is rare because of widespread availability and use of antibiotics. Without treatment, however, approximately 30% of patients eventually progress to the tertiary stage of syphilis within 1 to 20 years of the original infection. Gummatous lesions can occur in skeletal, spinal, and mucosal areas, eyes, and viscera (lung, stomach, liver, genitals, breast, brain, and heart). The destructive lesions can clinically mimic carcinoma. The average onset is 10 to 15 years after infection. Cardiovascular syphilis is indicated by pathologic lesions of the aortic vasa vasorum. It clinically presents as ascending aortic aneurysm, aortic insufficiency, or coronary ostial stenosis. The average appearance is about 20 to 30 years after infection.

Neurosyphilis

Syphilis can invade the nervous system at any stage of infection, and causes a wide range of symptoms, including headache, altered behavior, difficulty coordinating muscle movements, paralysis, sensory deficits, and dementia ¹⁴, ¹⁵. This invasion of the nervous system is called “neurosyphilis”.

• Early neurosyphilis: Cerebrospinal fluid (CSF) abnormalities can occur in 50 to 60% of persons with early syphilis and are of unknown significance in the absence of neurologic signs or symptoms ¹⁶, ¹⁷. The most common manifestation of early neurosyphilis is meningeal syphilis, which usually occurs weeks to months (and almost always within a year) after initial infection ¹⁴. Symptomatic syphilitic meningitis often resembles aseptic meningitis, and symptoms may include fever, headache, and stiff neck; with basilar involvement, cranial nerve abnormalities can develop, particularly cranial nerves 2, 6, and 8 ¹⁴. Meningovascular syphilis typically develops 5 to 12 years after initial infection, but it can occur earlier. Meningovascular syphilis, which results from Treponema pallidum infection and inflammation of small and medium central nervous system blood vessels, most often manifests as a stroke-like syndrome with seizures ¹⁸.
• Late neurosyphilis: Late forms of neurosyphilis usually occur multiple years or even decades (typically at least 15 years) after infection ¹⁴, ¹⁹. In the modern era, this type of neurosyphilis is rarely seen. Clinical manifestations include general paresis and tabes dorsalis but can present with a wide variety of neurologic symptoms, including dementia ¹⁴, ¹⁵.

Ocular syphilis

Since Treponema pallidum can potentially infect any part of the eye, the range of manifestations associated with ocular syphilis is broad and patients may present with an array of symptoms ²⁰. Ocular syphilis can develop at any stage of syphilis and patients can present with acute or chronic symptoms ²¹. Ocular complications of syphilis have been reported in clusters in recent years ²². Several recent studies have analyzed molecular strain type and found no clear evidence of a predominant strain trophic for the eye ²³. Ocular syphilis can be seen in isolation with other neurologic symptoms—it can present with anterior, posterior, or pan-uveitis and can occur at any stage of syphilis ²⁰. Other described manifestations include lid involvement, episcleritis, vitritis, retinitis, papillitis, interstitial keratitis, acute retinal necrosis, and retinal detachment. Primary optic atrophy is unique to late syphilis (classically described with tabes dorsalis). The clinical presentations can have significant overlap with eye disease caused by tuberculosis, toxoplasmosis, histoplasmosis, and ocular Toxocara canis infections. Non-infectious causes such as rheumatoid arthritis and sarcoidosis must also be considered. Patients with syphilis and ocular complaints should undergo prompt ophthalmologic evaluation and have a lumbar puncture performed for cerebrospinal fluid evaluation ¹¹. Significant improvement of symptoms (including vision) may occur after treatment for syphilis, but this depends on the type of pathology and timing of initiating antimicrobial therapy; if scarring is present, it is unlikely to significantly change following treatment.

Congenital syphilis

Congenital syphilis occurs when Treponema pallidum is transmitted from a pregnant woman with syphilis to her fetus ²⁴, ²⁵. Less often, perinatal transmission of Treponema pallidum can occur at the time of the delivery if the newborn has contact with maternal genital lesions ²⁴, ²⁵. Transmission to the fetus in pregnancy can occur during any stage of syphilis, but the risk is much higher with primary or secondary syphilis, especially if the mother acquires Treponema pallidum in the third trimester of pregnancy ²⁶. Fetal infection can occur during any trimester of pregnancy. For pregnant women only penicillin therapy can be used to treat syphilis and prevent passing the disease to her baby; treatment with penicillin is extremely effective (success rate of 98%) in preventing mother-to-child transmission ²⁷. Pregnant women who are allergic to penicillin should be referred to a specialist for desensitization to penicillin.

All pregnant women should be tested for syphilis at the first prenatal visit. For women who are at high risk for syphilis, live in areas of high syphilis morbidity, are previously untested, or had a positive screening test in the first trimester, the syphilis screening test should be repeated during the third trimester (28 to 32 weeks gestation) and again at delivery ²⁸. Any woman who delivers a stillborn infant after 20 week’s gestation should also be tested for syphilis.

Depending on how long a pregnant woman has been infected, she may have a high risk of having a stillbirth or of giving birth to a baby who dies shortly after birth. Untreated syphilis in pregnant women results in infant death in up to 40 percent of cases.

An infected baby born alive may not have any signs or symptoms of disease ²⁶, ²⁹, ³⁰. However, if not treated immediately, the baby may develop serious problems within a few weeks. Untreated babies may become developmentally delayed, have seizures, or die. All babies born to mothers who test positive for syphilis during pregnancy should be screened for syphilis and examined thoroughly for evidence of congenital syphilis ²⁸.

Congenital syphilis is traditionally classified as either early or late disease ³¹. Early manifestations occur within the first two years of life, and late manifestations occur after two years of age. Although infants with congenital syphilis most often display some early manifestations, some do not have clinical manifestations of active disease at the time of birth or early in life. Accordingly, regardless of symptoms, all neonates with a reactive serologic test for syphilis or who are at risk for congenital should undergo a thorough examination for signs or symptoms of congenital syphilis, as well as testing for HIV ³².

Early congenital syphilis

Early congenital syphilis is usually defined as manifestations of syphilis in infants and children younger than 2 years of age, with abnormalities that include the following:

• Hepatosplenomegaly is very common but is a non-specific finding.
• Bone involvement is the most common specific manifestation and is seen in 60% to 80% of infected infants ³³.
• Skin (bullous or exudative lesions) or mucous membranes lesions may be seen.
• Alopecia, generalized lymphadenopathy, meningitis, osteitis or osteochondritis can also occur.
• Hematologic abnormalities such as thrombocytopenia and anemia manifest in some cases.

Late congenital syphilis

Late congenital syphilis is generally defined as manifestations of syphilis in children older than 2 years of age, with disorders that include the following:

• Clinical manifestations typically result from scarring and chronic inflammatory changes from persistent infection and inflammation.
• Bone lesions including frontal bossing, shortened maxilla, high palatal arch are most common ³⁴.
• Interstitial keratitis is seen in about 40% of cases.
• Perforation of the hard palate may be observed.
• Hutchinson’s triad is the classic association of eighth cranial nerve deafness, interstitial keratitis, and Hutchinson teeth and is described in 75% of patients ³⁴.

Treponema pallidum test

The laboratory diagnosis of syphilis is challenging and requires using a combination of clinical and laboratory criteria to differentiate active infection, prior infection, and absence of infection ³⁵. Treponema pallidum cannot be cultivated on artificial medium, but the organism can be grown using special techniques that involve inoculation in rabbits. In clinical samples, spirochetes can occasionally be visualized in specimens taken from cutaneous lesions using dark-field microscopy techniques. In addition, silver staining and immunohistochemical staining of tissue samples can demonstrate characteristic spirochetes on clinical biopsy specimens. Use of dark-field microscopy or immunohistochemical staining on oral specimens is not recommended due to the extremely poor specificity caused by abundant non-syphilitic oral Treponema species. Serologic testing remains the primary tool for diagnosis in most patients with syphilis and these tests include “nontreponemal” and “treponemal” tests. Although PCR testing is sometimes used for research purposes, there is no FDA-approved PCR test for syphilis at present. Research use of PCR detection of Treponema pallidum DNA has expanded the clinical sites from which Treponema pallidum can be detected.

The most common syphilis tests detect antibodies in the blood that are produced in response to a Treponema pallidum infection. Some methods that are used less commonly directly detect the bacterium or its genetic material (DNA).

Direct detection of Treponema pallidum

Dark-Field Microscopy

Dark-field microscopy of lesion exudate or tissue is the definitive method for diagnosing early syphilis ¹¹. Treponema pallidum cannot be viewed by normal light microscopy. Dark-field microscopy can identify Treponema pallidum with its spiral shape, 10 to 14 coils, corkscrew motion, and a total length of 6 to 20 micrometers. Dark-field microscopy is rarely used in clinical practice because most facilities do not have dark-field microscopy and most clinicians do not know how to appropriately obtain specimens. Dark-field microscopy has the potential advantage of making a definitive and rapid diagnosis of primary or secondary syphilis. Several disadvantages exist with dark-field microscopy, including (1) requirement for specialized, expensive equipment, (2) need for clinician training on how to appropriately collect and prepare a specimen for dark-field microscopy, (3) need for experienced microscopist who can correctly identify Treponema pallidum with dark-field microscopy, (4) potential false-positive results in oral specimens (from nonpathogenic spirochetes in the oral cavity), (5) potential false-negative results if topical agents have been applied by the patient or the specimen is not collected appropriately, and (6) need to immediately view any collected specimen. Clinicians need to take special precautions to protect themselves from inoculation when collecting specimens for dark-field microscopy, since the lesions contain abundant viable organisms.

Direct Fluorescent Antibody Test

The direct fluorescent antibody test can detect Treponema pallidum antigens in tissue samples. The test uses antibodies specific to pathogenic treponemes and can generally identify Treponema pallidum in samples—such as oral or rectal lesions—that may have background non-pathogenic spirochetes ³⁶.

Treponema pallidum antibody test

In the absence of dark-field microscopy, a probable diagnosis of syphilis is possible with the use of two types of serologic tests: nontreponemal and treponemal. Use of only one type of serologic test is insufficient for diagnosis since each test used alone has major limitations, including false-positive results in persons without syphilis and the inability for treponemal tests to distinguish between recent and distant infection. Both types of tests have several advantages and disadvantages as well as differing test characteristics.

Nontreponemal serologic tests

The nontreponemal tests include Venereal Disease Research Laboratory (VDRL), Rapid Plasma Reagin (RPR), Toluidine Red Unheated Serum Test (TRUST), and Unheated Serum Reagin (USR) ³⁵. These tests measure IgM and IgG antibody and are not specific for Treponema pallidum. Nontreponemal test results are reported with a qualitative result and a quantitative titer, which usually correlates with disease activity ¹¹. A fourfold change in titer, equivalent to a change of two dilutions (e.g., from 1:16 to 1:4 or from 1:8 to 1:32) is considered necessary to demonstrate a clinically significant difference ³⁷. Sequential serologic tests in individual patients should be performed using the same testing method, preferably by the same laboratory. The Venereal Disease Research Laboratory (VDRL) and RPR tests are equally valid assays, but quantitative results from the two tests cannot be compared directly because RPR titers are often slightly higher than Venereal Disease Research Laboratory (VDRL) titers. TRUST is similar to RPR test whereas Unheated Serum Reagin (USR) is similar to VDRL, though in the United States TRUST and Unheated Serum Reagin (USR) are not often used. The nontreponemal tests have several drawbacks, including (1) they are labor intensive to perform, (2) results are typically not available for at least 7 days, (3) the tests have low sensitivity in certain stages, particularly early primary, late latent, and tertiary, and (4) false-positive reactions can occur. Nontreponemal tests usually become nonreactive with time after treatment. In some patients, however, nontreponemal antibodies can persist at a low titer (the definition “low” titer is dependent on laboratory and clinical context, but less than 1:8 is generally consider “low”) for a long period of time, sometimes for the life of the patient. This response is referred to as the “serofast reaction.” In addition, in some patients, nontreponemal tests may, with time, become nonreactive in the absence of therapy.

Treponemal serologic tests

The treponemal serologic tests include Treponema pallidum particle agglutination (TP-PA), fluorescent treponemal antibody absorption (FTA-ABS), and various enzyme immunoassays (EIAs) and chemiluminescence immunoassays ³⁵. These tests measure antibody directed against Treponema pallidum antigens by particle agglutination, immunofluorescence, or enzyme immunoassay; some detect IgG only whereas others detect both IgM and IgG. These qualitative tests most often remain reactive for life, even after adequate treatment, but 15% to 25% of patients treated during the primary stage revert to being serologically nonreactive after two to three years ³⁸. Treponemal antibody titers correlate poorly with disease activity, and they should not be used to assess treatment response.

Patterns of serologic reactivity and sensitivity of tests

The common patterns for serologic reactivity with syphilis tests depend on the specific test used, the stage of syphilis, and whether the patient has received treatment ³⁹. The sensitivity of serologic testing also varies based on the test used and stage of syphilis (Table 1). Serologic testing for syphilis has the highest yield during secondary syphilis. Serologic tests for syphilis may be negative during very early primary syphilis. Thus, when serologic tests do not correspond with clinical findings suggestive of primary syphilis, presumptive treatment is recommended if the patient has known risk factors for syphilis; in this setting, use of other tests, such as dark-field microscopy, biopsy, or PCR, should be considered.

Table 1. Sensitivity and Specificity of common serological tests in Untreated Syphilis

	Sensitivity During Stage of Infection, % (range)				Specificity, % range
Test	Primary	Secondary	Latent	Late
VDRL	78 (74-87)	100	95 (88-100)	71 (37-94)	98 (96-99)
RPR	86 (77-99)	100	98 (95-100)	73	98 (93-99)
FTA-ABS	84 (70-100)	100	100	96	97 (94-100)
TP-PA	88 (86-100)	100	100	NA	96 (95-100)
ELISA (IgG)	100	100	100	NA	100

Footnotes: *FTA-ABS and TP-PA are generally considered equally sensitive in the primary stage of disease.

Abbreviations:

• VDRL = Venereal Disease Research Laboratory
• RPR = Rapid Plasma Reagin
• FTA-ABS = Fluorescent Treponemal Antibody Absorbed
• TP-PA =Treponema pallidum-Particle agglutination
• ELISA= Enzyme Linked Immunoassay

[Source ⁴⁰ ]

Prior Serologic Testing for Syphilis

The healthcare professional should determine the date and results of the patient’s most recent serologic test for syphilis, even if the patient reports no history of the disease. Prior results, if available, are particularly helpful when evaluating a patient that has a low titer serologic test for syphilis, no signs or symptoms that suggest a clinical diagnosis of syphilis, and no known contact with an early case of syphilis. Local health departments can often provide information on whether the patient has been reported as having had syphilis in the past, including reported serologic test results and treatment history.

Serologic testing algorithms

Given that treponemal and nontreponemal tests each have significant advantages and disadvantages, these lab tests are used together as part of a screening algorithm in order to maximize sensitivity and specificity for the detection of syphilis infection. Clinicians should be aware of their institution’s chosen method in order to most efficiently use serologic tests to screen for, diagnose, and monitor syphilis disease.

Standard (Traditional) Syphilis Screening Algorithm

Traditionally, the syphilis screening algorithm has consisted of initial screening with a nontreponemal test (VDRL or RPR), with further testing on a positive initial test with a treponemal test (TP-PA or EIA) (Figure 5). Patients with a negative screening test were relegated to periodic repeat screening whereas patients with positive results required a treponemal test to confirm a diagnosis of syphilis. The major limitations with using a nontreponemal test for initial screening include the personnel time required to perform a labor-intensive test, biologic false positives (i.e. pregnancy, medication use, and other conditions) and, as with all diagnostic tests for syphilis, the inability to detect early primary or latent infection.

Figure 5. Standard syphilis screening algorithm

Abbreviation: TP-PA =Treponema pallidum-Particle agglutination

[Source ¹¹ ]

Reverse Sequence Syphilis Screening Algorithm

Another option for syphilis screening is to use Treponema pallidum-specific enzyme immunoassays (EIAs) or chemiluminescence immunoassays (CIAs) as an initial screening test. In recent years, increasing numbers of clinical laboratories and blood banks have begun using treponemal EIA or chemiluminescence immunoassays (CIAs) as the initial screening laboratory test for syphilis. With this approach, a positive enzyme immunoassay (EIA) or chemiluminescence immunoassay (CIA) test is followed by further testing with a nontreponemal test—often referred to as reverse screening (Figure 6). In the reverse screening algorithm, negative treponemal results are relegated to follow-up screening as with the standard (traditional) algorithm. Positive treponemal results undergo a confirmatory nontreponemal test (i.e. RPR) to guide management. In the event of a positive EIA and a negative nontreponemal test, a second confirmatory treponemal test (TP-PA) is performed. If either of the confirmatory tests is positive and there is no history of prior, treated syphilis, the patient is diagnosed with syphilis ⁴¹. This ‘reverse screening algorithm’ has several advantages and disadvantages distinguishing it from the standard (traditional) screening algorithm. Advantages of the reverse sequence algorithm include improved detection of early primary and treated infection, low cost, and reduced laboratory time and effort (much less pipetting and circumventing the manual dilutions of nontreponemal testing).

Figure 6. Reverse Sequence Syphilis Screening Algorithm

Abbreviations:

• Treponema pallidum-specific enzyme immunoassay (EIA) or chemiluminescence immunoassay (CIA)
• VDRL = Venereal Disease Research Laboratory
• RPR = Rapid Plasma Reagin
• FTA-ABS = Fluorescent Treponemal Antibody Absorbed
• TP-PA =Treponema pallidum-Particle agglutination
• ELISA= Enzyme Linked Immunoassay

[Source ⁴¹ ]

Discordant Test Results Using Reverse Screening

In the scenario where a patient has a positive treponemal screening test (EIA), a negative nontreponemal test, and a positive second treponemal test (TP-PA), there are several possible scenarios: prior treated syphilis, early syphilis, untreated latent syphilis, or false-positive test. If the patient has received prior treatment for syphilis and has no evidence by history or examination for recent infection with Treponema pallidum, then the patient does not require further evaluation or management ¹¹. Patients without prior treatment and no evidence for recent infection are considered to have latent syphilis and require further evaluation and treatment. If recent infection possibly occurred, then repeat nontreponemal testing should take place 2 to 3 weeks later; if this repeat testing is positive the patient likely has early syphilis and if the test is negative then further evaluation is usually not needed.

Diagnosis of Latent Syphilis

Persons are diagnosed with latent syphilis when they have: (1) serologic evidence of Treponema pallidum infection, (2) no past diagnosis of syphilis, and (3) no active syphilis-related signs or symptoms. It is often difficult to determine the duration of infection in a patient with latent syphilis.

Laboratory evaluation for neurosyphilis

Neurologic involvement can occur during any stage of syphilis. Cerebrospinal fluid (CSF) abnormalities have been noted in 13% of patients with untreated primary syphilis and 25% to 40% of patients with untreated secondary syphilis ⁴². Although these CSF laboratory abnormalities are common in persons with early syphilis, no evidence exists to support variation from recommended treatment for syphilis at any stage in the absence of clinical neurologic findings, with the exception of tertiary syphilis. In addition to work-up of clinically suspected neurosyphilis, there are a number of additional indications to perform cerebrospinal fluid (CSF) evaluation.

Several studies have shown that among persons with HIV and syphilis, cerebrospinal fluid (CSF) abnormalities (mononuclear pleocytosis and elevated protein) are associated with a CD4 count of 350 cells/mm3 or less and/or a nontreponemal serologic test titer of greater than or equal to 1:32 ¹¹. Data are lacking regarding the benefits of a CSF examination in this setting. In general, persons with HIV infection tend to have more frequent CSF abnormalities in the absence of neurologic symptoms, and the presence of 20 or more white blood cells/mm³ might improve the specificity of probable neurosyphilis in this patient population ¹¹. When using a nontreponemal test to evaluate for neurosyphilis, the CSF VDRL is preferred over the CSF RPR test ⁴³. For more detailed information on the diagnosis of neurosyphilis including interpretation of CSF findings, consult the 2015 STD Treatment Guidelines ⁴⁴.

Diagnosis of syphilis in patients with HIV Coinfection

Syphilis and HIV infection frequently coexist. In general, the clinical course of syphilis in persons with HIV infection is similar to that in persons not infected with HIV. Although not common, unusual serologic responses among persons with HIV infection can occur. If the clinical suspicion of syphilis is high and the serologic tests for syphilis are negative, then use of other tests (e.g., biopsy of the lesion or rash) should be considered. Conventional therapy is usually effective. After appropriate therapy, persons with HIV infection more frequently demonstrate “high serofast” values of nontreponemal serologic tests (often defined as RPR greater than or equal to 1:8) ¹¹.

Diagnosis of syphilis in Infants and Children

The diagnosis of congenital syphilis is often difficult since maternal nontreponemal and treponemal IgG antibodies can be transferred through the placenta to the fetus. The decision to treat a neonate (aged fewer than 30 days) is based on: (1) identification of syphilis in the mother; (2) adequacy of maternal treatment; (3) clinical, laboratory, and radiographic evidence of disease in the neonate; and (4) comparison of maternal and neonatal nontreponemal serologic titer. Based on these factors, neonates are classified as: (1) proven or highly probable congenital syphilis, (2) possible congenital syphilis, (3) congenital syphilis less likely, or 4) congenital syphilis unlikely.

Reporting and Referral to Health Departments

Patients with primary, secondary or early latent syphilis, or syphilis of unknown duration with a high nontreponemal serologic test titer (greater than 1:32), should be referred to the local health department STD program for interview, partner elicitation, and partner follow-up. The follow-up of patients with early syphilis is a public health priority. Laws and regulations in all states require that persons diagnosed with syphilis be reported to public health authorities. Reporting can be provider-based or laboratory-based. Providers unsure of reporting requirements should seek advice from state or local health departments or STD programs. To locate a state health department, see the CDC resource tool Public Health Resources: State or Territorial Health Departments.

Treponema pallidum treatment

Penicillin G, administered parenterally, is the preferred drug for treating of all stages of syphilis. The preparation(s) of penicillin used (i.e., benzathine, aqueous procaine, or aqueous crystalline), the dosage, and the length of treatment depend on the stage and clinical manifestations of the disease. However, neither benzathine-procaine penicillin co-formulations nor oral penicillin preparations are considered appropriate for the treatment of syphilis ¹¹. Reports have identified the inappropriate use of combination benzathine-procaine penicillin (Bicillin C-R) instead of the standard benzathine penicillin G (Bicillin L-A) product ⁴⁵. Doctors, pharmacists, and purchasing agents should be aware of the similar names of these two products and avoid use of the inappropriate combination therapy agent for treating syphilis. It is important to understand that benzathine penicillin G is slowly released from the intramuscular site due to extremely low solubility and is also hydrolyzed to penicillin G; the combination of slow absorption and hydrolysis results in prolonged low serum levels of penicillin.

2015 STD Treatment Guidelines: Primary and Secondary Syphilis Treatment of Primary and Secondary Syphilis ⁴⁴

Recommended for Adults

• Benzathine penicillin G 2.4 million units IM in a single dose
  • Note: Available data demonstrate that use of additional doses of benzathine penicillin G, amoxicillin, or other antibiotics do not enhance efficacy when used to treat primary and secondary syphilis, regardless of HIV status.

Recommended for Infants and Children

• Benzathine penicillin G 50,000 units/kg IM, up to the adult dose of 2.4 million units in a single dose
  • Note: Infants and children aged ≥1 month with primary or secondary syphilis should be managed by a pediatric infectious disease specialist and evaluated for sexual abuse (e.g., through consultation with child-protection services)

Jarisch-Herxheimer Reaction

The Jarisch-Herxheimer reaction is a self-limited reaction associated with initiation of anti-treponemal therapy that most often occurs in persons treated for early syphilis, presumably because bacterial burdens are higher during these stages. The Jarisch-Herxheimer reaction is characterized by fever, malaise, nausea, vomiting, and less frequently, chills and exacerbation of a secondary syphilis rash ⁴⁶. This reaction almost always occurs within 24 hours after initiating antimicrobial therapy and usually resolves within 24 hours. For patients who develop a Jarisch-Herxheimer reaction, the clinician should clarify this reaction is not an allergic reaction to penicillin. It occurs more frequently after treatment with penicillin and treatment of early syphilis, especially at the secondary stage. Antipyretics can be used to manage symptoms associated with the Jarisch-Herxheimer reaction, but they do not prevent this reaction.

Follow-Up

Clinical and serologic evaluation should be performed at 6 and 12 months after treatment; more frequent evaluation might be prudent if follow-up is uncertain or if repeat infection is a concern. Serologic response (i.e., titer) should be compared with the titer at the time of treatment. However, assessing serologic response to treatment can be difficult, and definitive criteria for cure or failure have not been well established. In addition, nontreponemal test titers might decline more slowly for persons previously treated for syphilis ⁴⁷.

Persons who have signs or symptoms that persist or recur and those with at least a fourfold increase in nontreponemal test titer persisting for >2 weeks likely experienced treatment failure or were re-infected. These persons should be retreated and reevaluated for HIV infection. Because treatment failure usually cannot be reliably distinguished from reinfection with Treponema pallidum, a CSF analysis also should be performed; treatment should be guided by CSF findings.

Failure of nontreponemal test titers to decline fourfold within 6–12 months after therapy for primary or secondary syphilis might be indicative of treatment failure. However, clinical trial data have demonstrated that 15%–20% of persons with primary and secondary syphilis treated with the recommended therapy will not achieve the fourfold decline in nontreponemal titer used to define response at 1 year after treatment ⁴⁷. Serologic response to treatment appears to be associated with several factors, including the person’s stage of syphilis (earlier stages are more likely to decline fourfold and become negative) and initial nontreponemal antibody titers (lower titers are less likely to decline fourfold than higher titers) ⁴⁷. Optimal management of persons who have less than a fourfold decline in titers after treatment of syphilis is unclear. At a minimum, these persons should receive additional clinical and serologic follow-up and be evaluated for HIV infection. If additional follow-up cannot be ensured, retreatment is recommended. Because treatment failure might be the result of unrecognized CNS infection, CSF examination can be considered in such situations.

For retreatment, weekly injections of benzathine penicillin G 2.4 million units IM for 3 weeks is recommended, unless CSF examination indicates that neurosyphilis is present (see Neurosyphilis). Serologic titers might not decline despite a negative CSF examination and a repeated course of therapy ⁴⁸. In these circumstances, although the need for additional therapy or repeated CSF examinations is unclear, it is not generally recommended.

Primary and Secondary Syphilis

Parenteral penicillin G is effective in resolving clinical symptoms associated with primary and secondary syphilis and prevents late sequelae in those who receive appropriate treatment. The recommended regimen in the 2015 STD Treatment Guidelines for adults with primary and secondary syphilis is benzathine penicillin G given as 2.4 million units intramuscular (IM) in a single dose; for infants and children, the dose is 50,000 units/kg, with a maximum of 2. 4 million units ¹¹. The few available studies exploring optimal dosing regimens did not find any benefit from additional doses of penicillin or with combination therapy that included other antibiotics ⁴⁹.

Treatment of primary or secondary syphilis in penicillin-allergic patients

Treatment of primary and secondary syphilis for patients with documented allergy to penicillin is a topic with limited available data. Small studies and clinical experience suggest that regimens of doxycycline (100 mg orally twice daily for 14 days) or tetracycline (500 mg four times daily for 14 days) are acceptable alternatives for nonpregnant, penicillin-allergic persons who have primary or secondary syphilis ⁵⁰. Doxycycline is preferable to tetracycline because tetracycline can cause gastrointestinal side effects and requires more frequent dosing. In addition, ceftriaxone (1-2 g daily either IM or IV for 10 to 14 days) is considered effective for treating primary and secondary syphilis, but the optimal dose and duration of ceftriaxone in this setting remains unknown ⁵¹. Azithromycin as a single 2 g oral dose has been effective for treating primary and secondary syphilis, but concerns for emerging macrolide resistance led the CDC to recommend avoiding azithromycin for first-line syphilis treatment and, if used, it should only be considered when treatment with penicillin or doxycycline is not feasible ⁵². Further, azithromycin to treat syphilis should not be used in any circumstance to treat MSM, persons with HIV infection, or pregnant women. Any person receiving any of the alternative therapies for the treatment of syphilis should have careful clinical and serologic follow-up. Persons with a penicillin allergy for whom concern exists with adherence or follow-up should undergo penicillin desensitization and then receive treatment with benzathine penicillin G.

Latent Syphilis

The treatment of patients with latent syphilis requires appropriate classification into early latent syphilis (acquired less than 1 year ago as detailed above) or late latent syphilis (acquired longer than 1 year ago), or undetermined duration. The goals of treating patients with latent syphilis are to prevent development of late manifestations of infection (tertiary/neurosyphilis), as well as to prevent transmission to the fetus by infected pregnant women. Early latent syphilis is treated with a single dose of benzathine penicillin G 2.4 million units IM; late latent syphilis is treated with benzathine penicillin G 7.2 million units total split into three weekly IM injections of 2.4 million units ¹¹. There are limited data comparing the efficacy of specific regimens or duration, but available data do not suggest any added benefit of additional antibiotics. Alternative therapies for treatment of latent syphilis have not been well studied.

Treatment of latent syphilis in penicillin-allergic patients

For penicillin-allergic, nonpregnant patients with early latent syphilis, the treatment approach should be the same as penicillin-allergic patients with primary or secondary syphilis. For penicillin-allergic patients with late latent syphilis, the only acceptable treatment alternatives are doxycycline (100 mg orally twice daily) or tetracycline (500 mg orally four times daily), each for 28 days ¹¹. Ceftriaxone may be a reasonable option in this setting, but the optimal number of doses or schedule has not been determined and use of ceftriaxone to treat latent syphilis should involve consultation with a syphilis expert. All patients treated with alternative regimens require close serologic and clinical follow-up, especially in persons with HIV infection. Patients for whom adherence and follow-up is a concern should be desensitized and treated with benzathine penicillin G if possible.

Neurosyphilis

Involvement of the central nervous system (brain and spinal cord) can occur during any stage of syphilis, which makes it essential that any patient receiving treatment for primary, secondary, or latent infection be evaluated for clinical evidence of neurologic involvement. If signs or symptoms of neurologic involvement are noted, a cerebrospinal fluid (CSF) examination should be performed ⁴². The recommended regimen for both neurosyphilis and ocular syphilis is aqueous crystalline penicillin G 18-24 million units per day, given as 3-4 million units intravenously (IV) every 4 hours (or as continuous infusion), for a total of 10 to 14 days ¹¹. If adherence to therapy can be ensured, an acceptable alternative regimen is procaine penicillin G 2.4 million units IM once daily with probenecid 500 mg orally four times a day. Both agents are given for 10 to 14 days. It is important to note that some experts believe the duration of neurosyphilis therapy is not sufficient for treatment of late latent syphilis. Therefore, benzathine penicillin G 2.4 million units IM once per week for up to 3 weeks can be considered after completion of a neurosyphilis regimen in order to provide a comparable total duration of therapy. In addition, systemic corticosteroids have been used by some experts or specialists as adjunctive therapy for otologic syphilis, but data are insufficient to support the use of systemic corticosteroid therapy for otologic syphilis or any other form of syphilis.

Treatment of neurosyphilis in penicillin-allergic patients

Limited data suggest that ceftriaxone 2 g daily either IM or IV for 10 to 14 days can be used as an alternative treatment for persons with neurosyphilis ¹¹. Other regimens have not been adequately studied for use in patients with neurosyphilis.

Tertiary Syphilis

The recommended regimen for tertiary syphilis (not neurosyphilis) is benzathine penicillin G 7.2 million units total split into three weekly IM injections of 2.4 million units ¹¹. All persons diagnosed with tertiary syphilis should undergo a cerebrospinal fluid (CSF) examination prior to starting therapy. This is done because of the high rates of clinically inapparent neurosyphilis in patients with tertiary syphilis. Patients with tertiary syphilis have potential for a wide variety of sequelae and should be managed in consultation with a syphilis expert. Patients diagnosed with tertiary syphilis who have a documented penicillin allergy also should be treated in consultation with a syphilis expert; for these patients, there is no alternative therapy suggested in the STD Guidelines ¹¹.

Syphilis in persons with HIV infection

Available data suggest that persons with HIV infection who have early syphilis may have an increased risk of developing neurologic complications ⁵³. The extent of this increased risk has not been clarified and current CDC guidelines do no recommend routinely performing cerebrospinal fluid (CSF) examination in persons with HIV infection diagnosed with syphilis, but all persons with HIV infection and syphilis should undergo careful neurologic examination and those with abnormal findings should promptly undergo lumbar puncture for cerebrospinal fluid (CSF) examination ¹¹. There is no evidence that more intensive syphilis treatment improves outcomes or prevents neurosyphilis in persons with HIV infection who have early syphilis ⁵⁴. The recommended regimens for the treatment of syphilis in persons with HIV infection are the same as for persons without HIV infection ¹¹. Initiation of antiretroviral therapy for HIV infection concurrently with syphilis treatment has been shown to reduce serologic failure rates for syphilis ⁵⁵.

Syphilis in Pregnancy

All pregnant women diagnosed with syphilis should receive treatment according to stage of infection and whether there is any evidence of neurologic disease. Erythromycin is no longer an acceptable alternative drug for penicillin-allergic patients. Patients who are skin-test-reactive to penicillin should be desensitized in the hospital and treated with penicillin ¹¹. Some experts recommend giving a second dose of benzathine penicillin G 2.4 million units IM 1 week after the initial dose for pregnant women who have primary, secondary, or early latent infection. Treatment of the mother during the last month of pregnancy or with a drug other than penicillin is not considered adequate treatment for the fetus. Pregnant women should be informed that treatment for syphilis may precipitate early labor and that they should notify an obstetrician if problems develop.

Infants and children with syphilis

The regimen for proven or highly probable and possible congenital syphilis is either aqueous crystalline penicillin G 100,000–150,000 units/kg/day, administered as 50,000 units/kg/dose IV every 12 hours during the first 7 days of life and every 8 hours thereafter for a total of 10 days; or procaine penicillin G 50,000 units/kg/dose IM in a single daily dose for 10 days. Neonates classified as possible congenital syphilis have the additional option of receiving treatment with benzathine penicillin G 50,000 units/kg IM in a single dose. The single dose regimen is only acceptable if all elements of the neonate’s lab work-up were performed and unequivocally normal. In addition, follow-up must be assured. Neonates with disease classified as “congenital syphilis less likely” should be given benzathine penicillin G 50,000 units/kg/dose intramuscularly in a single dose. Neonates for whom congenital syphilis is deemed unlikely do not require therapy but should be followed to ensure that their nontreponemal titer returns to nonreactive (as mother’s antibodies are lost). For additional details regarding the diagnosis and management of congenital syphilis, refer to the 2015 STD Treatment Guidelines for information on the management of congenital and acquired syphilis in infants and children or the American Academy of Pediatrics’ Red Book ¹¹. Diagnosis and treatment of congenital syphilis is complex and challenging and should be done in consultation with a congenital syphilis expert. Notably, infants and children with a history of penicillin allergy or who develop signs of allergic reaction during treatment with penicillin present a unique challenge and should be managed with close follow-up and consultation with a syphilis expert.

Follow-Up

The follow-up of patients with syphilis is extremely important to document response to therapy and to reevaluate for reinfection. The following are general recommendations for follow-up after treatment.

• Patients treated for primary or secondary syphilis should be reexamined clinically and serologically 6 months and 12 months following treatment.
• Patients with latent syphilis should be followed up clinically and serologically at 6, 12, and 24 months.
• Persons with HIV infection should be evaluated more frequently; for primary or secondary syphilis at 3, 6, 9, 12, and 24 months and for latent syphilis at 6, 12, 18, and 24 months.
• If cerebrospinal fluid (CSF) pleocytosis was present initially, a CSF examination should be repeated every 6 months until the CSF cell count is normal. If the cell count has not decreased after 6 months, or if the CSF cell count or protein is not normal after 2 years, retreatment should be considered.
• Follow-up titers should be compared to the maximum or baseline nontreponemal titer obtained prior to treatment.

Treatment Failure

A key reason for close follow-up of patients treated for syphilis is to monitor signs, symptoms, or serologic changes that indicate possible treatment failure. There are no well-established, definitive criteria for treatment failure. Treatment failure cannot usually be differentiated from reinfection and thus persons suspected to have treatment failure or reinfection should be retested for HIV and should have a cerebrospinal fluid (CSF) evaluation for neurosyphilis (regardless of symptoms or prior CSF findings). Indications of probable treatment failure or reinfection include the following:

• A patient has persistent or recurring signs or symptoms.
• Patient testing shows sustained fourfold increase in nontreponemal titer. These patients should be retreated and reevaluated for HIV infection. Because treatment failure may be a result of unrecognized central nervous system (CNS) infection, cerebrospinal fluid (CSF) examination should be considered.
• Failure of nontreponemal titers to decline fourfold within twelve months after therapy for primary or secondary syphilis may be indicative of treatment failure. Additional clinical and serological follow-up is necessary since the optimal management is unclear. Examination of cerebrospinal fluid (CSF) can be considered in these instances.[65] If follow-up cannot be ensured, retreatment is recommended.

When patients are retreated for primary, secondary, or latent syphilis (assuming no evidence of neurosyphilis), the recommended regimen is weekly injections of benzathine penicillin G 2.4 million units IM for 3 weeks. If neurosyphilis is diagnosed, aqueous crystalline penicillin G 18-24 million units per day is given as 3 to 4 million units IV every 4 hours (or as continuous infusion), for a total of 10 to 14 days ¹¹. Refer to the 2015 STD Treatment Guidelines ⁴⁴ for more detailed information on assessment and management of probable treatment failure.

Partner Management and Public Health Measures

In general, the transmission of Treponema pallidum between sex partners only occurs when the person with syphilis has mucocutaneous lesions. In general, all persons who have sexual contact with a person diagnosed with primary, secondary, or early latent syphilis infection should undergo evaluation and testing for syphilis. Potential treatment for syphilis depends on the circumstances, as recommended in the 2015 STD Treatment Guidelines and outlined below ¹¹.

• Persons who have had sexual contact with a person who receives a diagnosis of primary, secondary, or early latent syphilis within 90 days preceding the diagnosis should be treated presumptively for early syphilis, even if serologic test results are negative.
• Persons who have had sexual contact with a person who receives a diagnosis of primary, secondary, or early latent syphilis greater than 90 days before the diagnosis should be treated presumptively for early syphilis if serologic test results are not immediately available and the opportunity for follow-up is uncertain. If serologic tests are negative, no treatment is needed. If serologic tests are positive, treatment should be based on clinical and serologic evaluation and stage of syphilis.
• In some areas or populations with high rates of syphilis, health departments recommend notification and presumptive treatment of sex partners of persons with late latent syphilis who have high nontreponemal serologic test titers (i.e., greater than 1:32), because high titers might be indicative of early syphilis. These partners should be managed as if the index case had early syphilis.
• Long-term sex partners of persons who have late latent syphilis should be evaluated clinically and serologically for syphilis and treated based on these findings.
• Certain sex partners of persons with syphilis are considered at risk for infection and should be confidentially notified of the exposure and the need for evaluation. These include partners who have had sexual contact within 3 months plus the duration of symptoms for persons who receive a diagnosis of primary syphilis, 6 months plus duration of symptoms for those with secondary syphilis, and 1 year for persons with early latent syphilis.

Expedited Partner Therapy

There is insufficient data to support the use of expedited partner therapy in management of syphilis contacts. Accordingly, use of expedited partner therapy is not recommended for sexual contacts of persons diagnosed with syphilis. Transmission of Treponema pallidum is highly unlikely in persons when more than 1 year has elapsed since the time of infection.

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