Communicable Disease Management Protocol

Syphilis
Communicable Disease Control Unit

Etiology
Syphilis is primarily a sexually transmitted infection (STI). Syphilis can also be acquired through congenital transmission to the newborn and blood transfusion, but these are much less common. It is a systemic disease caused by the spirochete Treponema pallidum subspecies pallidum (1). This is one of the clinically important spirochetes and is related to such agents as Borellia burgdorferi (the cause of Lyme Disease) and Leptospira (the cause of leptospirosis). Syphilis occurs exclusively in humans; there is no animal reservoir (2). Non-venereal treponemal infections cause pinta, yaws, and bejel. These diseases are endemic to some developing nations and are seen in developed nations primarily as a result of immigration. Serologic testing cannot distinguish syphilis from these endemic treponematoses (3).

presence of one or more typical lesions (chancres), and reactive treponemal serology, regardless of nontreponemal test reactivity, in individuals with no previous history of syphilis; OR presence of one or more typical lesions (chancres) and at least a four-fold (e.g., 1:8 to 1:32) increase in titre over the last known nontreponemal test in individuals with a past history of syphilis treatment.

Secondary Syphilis:
Identification of T. pallidum by darkfield microscopy, fluorescent antibody, or equivalent examination of mucocutaneous lesions and condyloma lata; OR presence of one or more typical mucocutaneous lesions, alopecia, loss of eyelashes and lateral third of eyebrows, iritis, generalized lymphadenopathy, fever, malaise, or splenomegaly; PLUS either a reactive serology (nontreponemal and treponemal); OR at least a four-fold (e.g.,1:8 to 1:32) increase in titre over the last known nontreponemal test.

Case Definitions (4)

Incubating Syphilis:
An asymptomatic person with a history of sexual exposure within the past 10-90 days to a partner with a confirmed diagnosis of infectious syphilis; PLUS either a reactive serology (nontreponemal and treponemal); OR at least a four-fold (e.g., 1:8 to 1:32) increase in titre over the last known nontreponemal test. Incubating syphilis is a subset of Early Latent Syphilis.

Early Latent Syphilis:

An asymptomatic person with reactive serology (nontreponemal and treponemal) who within the past one year had ONE of the following: 1) non-reactive serology; 2) symptoms suggestive of primary or secondary syphilis; or 3) exposure to a sexual partner with primary, secondary or early latent syphilis.

Primary Syphilis:
Identification of T. pallidum by darkfield microscopy, fluorescent antibody, or equivalent examination of material from a chancre or regional lymph node; OR
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Late Latent Syphilis:

An asymptomatic person with persistently reactive treponemal serology (regardless of nontreponemal serology reactivity) who does not meet the criteria for early latent disease and who has not been previously treated for syphilis.

radiographic evidence of congenital syphilis, whose mother is seropositive for syphilis without documented evidence of adequate treatment. NOTE: The national case definitions for syphilis are currently in the process of being revised. This protocol will be updated accordingly.

Neurosyphilis:
Reactive treponemal serology (regardless of nontreponemal serology reactivity) and ONE of the following: 1) reactive CSF-VDRL in non-bloody cerebrospinal fluid (CSF); 2) clinical evidence of neurosyphilis and CSF pleocytosis (particularly lymphocytes) in the absence of other known causes; or 3) clinical evidence of neurosyphilis and elevated CSF protein in the absence of other known causes. Neurosyphilis may be seen during primary or secondary syphilis stages and can occur at any time after initial infection.

Reporting Requirements
All positive syphilis tests (both nontreponemal and treponemal) are reportable by laboratory operators to the Communicable Disease Control Unit, Manitoba Health. Operators of Manitoba clinical laboratories detecting nontreponemal or treponemal antibodies must forward sera or cerebrospinal fluid positive for these antibodies to Cadham Provincial Laboratory. All cases and contacts are reportable by attending health care professionals to the Communicable Disease Control Unit, Manitoba Health.

Tertiary Syphilis other than Neurosyphilis:

Presence of reactive treponemal serology (regardless of nontreponemal test reactivity) together with characteristic abnormalities of the cardiovascular system, bone, skin or other structures, in the absence of other known causes of these abnormalities (T. pallidum is rarely seen in these lesions, although when present is diagnostic); AND no clinical or laboratory evidence of neurosyphilis.

Epidemiology
Reservoir: Humans Transmission: Approximately 90% of all syphilis is sexually transmitted. Exposure mainly occurs during oral, anal, or vaginal intercourse. Transmission occurs through direct contact with infectious exudates from moist skin lesions or mucus membranes of infected persons during sexual contact (1, 5). Primary, secondary, and early latent stages are considered infectious, with an estimated risk of transmission per partner of 60%. Early latent syphilis is considered infectious because of the 25% chance of relapse to secondary stage (6). Transmission from touching children with congenital syphilis, kissing, blood transfusion, sharing of needles and drug equipment, and accidental direct inoculation are extremely rare. Ulcerative STIs like syphilis promote HIV transmission and/or acquisition by augmenting HIV infectiousness and susceptibility. Syphilis increases the rate of HIV acquisition between two and four-fold and the risk of transmission of HIV between two and nine-fold (7).
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Congenital Syphilis:
Identification of T. pallidum by darkfield microscopy, fluorescent antibody, or equivalent examination of material from nasal discharges, skin lesions, placenta or umbilical cord, or autopsy material of a neonate (up to four weeks of age); OR reactive serology (treponemal and nontreponemal) from venous blood (not cord blood) in an infant/child with clinical, laboratory, or
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Pregnant women can transmit the infection transplacentally to the fetus at all stages during the course of untreated disease or during passage through the birth canal (8). The rate of vertical transmission is approximately 70-100% in untreated early syphilis. Transmission is more likely with primary and secondary infections and less likely during latent infections (9, 10, 11). Breastfeeding does not result in syphilis transmission unless an infectious lesion is present on the breast (12). Occurrence: The incidence of infectious syphilis in Canada and Manitoba was very low in the 1990s with most cases being imported rather than locally acquired. After achieving rates of 0.4-0.6/100,000 in Canada from 1994 to 2000, rates of infectious syphilis rose to 1.5/100,000 in 2002 and 3.5/100,000 in 2004 (6, 13). In the last few years, several provinces (British Columbia, Alberta, Ontario, Quebec, and Manitoba) have experienced local syphilis outbreaks (12). Since January of 2003, Manitoba has experienced an outbreak of locally acquired infectious syphilis. Most cases reside in the Winnipeg region affecting men in the 40-44 year old age group and females in the 30-34 year old age group (14). Risk factors identified in Winnipeg include heavy and frequent alcohol use; casual unprotected sex among heterosexuals; and unprotected sex in anonymous partnering venues (bathhouses, bars and internet chat lines) among men who have sex with men (MSM) (14, 15). Incubation Period: For a primary chancre, the incubation period is three days to three months, usually about three weeks (1). Refer to Table 1: Clinical Manifestations and Incubation Period for further details. Period of Communicability: Variable. Syphilis is infectious during primary, secondary, and early latent stages, and also in mucocutaneous recurrences. Congenital transmission is most likely during primary and secondary maternal syphilis, but can occur in the latent period.

Clinical Presentation and Natural History

Incubating Syphilis:
Persons with incubating syphilis are asymptomatic. They are identified through self-reporting or contact tracing after having been exposed to a confirmed syphilis case within the last 90 days. An early spirochetemia develops during this phase, which results in secondary invasion of virtually every bodily organ (3).

Primary Syphilis:
Primary syphilis most often presents as a single painless lesion (chancre) that develops at the site of inoculation. The chancre is most commonly found on the external genitalia. These lesions frequently go unnoticed, particularly among women and MSM, who cannot see vaginal or anal lesions. The ulcer is clean-based with a raised, indurated border. In men, the most common site affected is the penis, more specifically the coronal sulcus and glans. Anorectal chancres are common in MSM. In women, the most common locations for lesions are the labia majora, labia minora, fourchette, and perineum. Ulcers may also be found on the lip, in the mouth, and on fingers. The chancre usually resolves spontaneously in one to four months. Painless, firm regional lymphadenopathy, often associated with genital lesions, is common and occurs in up to 80% of patients. These clinical findings usually occur about three weeks after infection with T. pallidum. Variations in clinical presentation have been reported in HIV infected patients. These variations include multiple single chancres and chancres that may be slower to resolve (16).

Secondary Syphilis:
The most common feature is a skin rash, which is present in about 90% of cases. This rash may be macular, papular, papulosquamous, pustular, or non-specific. The rash of secondary syphilis is somewhat unique in that it involves the palms of the hands and soles of the feet. The rash usually resolves without scarring over several weeks. Hair loss can also be an important clue to the diagnosis.
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Condylomata lata are characteristic of secondary syphilis. They are large fleshy lesions that may form in warm moist areas such as the perineum and perianal skin, axillae, and beneath the breasts. These lesions are painless but highly infectious. The original genital chancre is still present in up to 30% of patients with secondary syphilis. Constitutional symptoms such as fevers, muscle aches, and weight loss are also common. There may be evidence of central nervous system involvement in a number of cases. Headache is present in about 30% of patients. Symptomatic meningitis may occur in up to 1-2% of cases; however asymptomatic meningitis is more common and can occur in up to 40%.

Tertiary Syphilis:
Tertiary syphilis is a slowly progressive, inflammatory disease that can affect any organ in the body to produce clinical illness 10-30 years after the initial infection. Tertiary syphilis refers to gummatous and cardiovascular syphilis, but not to all neurosyphilis. These forms of syphilis are now uncommon. Gummatous syphilis (late benign syphilis) Gumma or granulomatous-like lesions are indolent and most commonly found in the skeletal system, skin, and mucous membranes, but can develop in any organ. Lesions rarely cause incapacity or death, but when lesions occur in organs like the brain or heart, serious complications occur. Cardiovascular syphilis Cardiovascular syphilis results from destruction of the elastic tissue of the aorta which leads to ascending aortitis and the formation of aneurysms that, rarely, rupture. The ascending aorta is most often affected, with the potential complications of valve insufficiency and coronary artery stenosis. Approximately 11% of untreated patients progress to cardiovascular syphilis.

Latent Syphilis:
Left untreated, secondary syphilis may progress to a period of subclinical infection. During the latent stage of syphilis, skin lesions resolve and patients are asymptomatic. The only clue for the diagnosis of latent infection is a positive serologic test for syphilis. Latent syphilis is divided into early latent and late latent syphilis. Patients are classified as having early latent disease if they are asymptomatic and have acquired the infection within the past year. This stage can be established only in patients who have seroconverted within the past year, who have had symptoms of primary or secondary syphilis within the past year or who have had a sexual partner with primary, secondary or early latent syphilis within the past year. Patients who do not meet these criteria should be presumed to have late latent syphilis or latent syphilis of unknown duration. A patient with early latent syphilis is considered to be infectious due to the 25% risk of relapse to secondary syphilis. Early latent syphilis is infectious by sexual contact whereas late latent syphilis is not. However, a pregnant woman with late latent syphilis can infect her fetus in utero, and an infection can be transmitted via transfusion of contaminated blood.

Neurosyphilis:
Central nervous system (CNS) disease can occur during any stage of syphilis. A patient who has clinical evidence of neurologic involvement with syphilis (e.g., cognitive dysfunction, motor or sensory deficits, ophthalmic or auditory symptoms, cranial nerve palsies, and symptoms or signs of meningitis) should have a CSF examination (16). Neurosyphilis is divided into early (acute) neurosyphilis and late (chronic) neurosyphilis (3). Both early and late neurosyphilis can be divided into asymptomatic and symptomatic phases. The symptomatic phase of late neurosyphilis is further distinguished as meningovascular or parenchymatous neurosyphilis. Clinical overlap with combinations of meningovascular and parenchymatous features are common as this form of chronic meningitis involves every portion of the CNS (3).
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Asymptomatic neurosyphilis occurs in up to 40% of patients (3). Asymptomatic neurosyphilis is defined as patients who have no clinical manifestations of neurologic involvement but who have one or more of the following CSF abnormalities: elevated WBC count, elevated protein concentration, a decreased glucose concentration, or a positive nontreponemal test (e.g., VDRL). RPR is not recommended for CSF testing.

Syphilis in Pregnancy and Congenital Syphilis:

Syphilis can be transmitted transplacentally to the fetus at all stages during the course of untreated maternal disease from incubating syphilis to primary, secondary, tertiary, and latent disease (16). Syphilis can also be transmitted during passage through the birth canal when the newborn infant contacts a genital lesion (8). Breastfeeding does not result in transmission of syphilis unless an infectious lesion is present on the breast. Pregnancy has no known effect on the clinical course of syphilis. The rate of vertical transmission in untreated women is 70-100% in primary syphilis, 40% for early latent syphilis, and 10% for latent disease. The longer the interval between infection and pregnancy, the more benign is the outcome in the infant. All pregnant women should be screened for syphilis (with a nontreponemal test) and other STIs (including HIV) on their first prenatal visit. High seroconversion rates for both syphilis and HIV in high risk populations during pregnancy has led some experts to suggest repeat screening of women during late pregnancy and delivery (17). Syphilis in pregnancy can cause widespread complications for both the infected mother and fetus. At least two-thirds of all babies born to untreated women with syphilis are infected (10). If evidence of syphilis is present, treatment should be initiated immediately according to the stage of the disease. Efficacy of syphilis treatment in pregnancy considers resolution of maternal infection and prevention of congenital syphilis.

Clinical manifestations of congenital syphilis are divided into early (appear within the first two years of life) and late (after first two years of life) stages. Late congenital syphilis usually manifests near puberty. Most clinical signs of early congenital syphilis develop within the first three months of life. Snuffles or persistent rhinitis is one of the earliest clinical manifestations occurring in 4-22% of infants. The nasal discharge may be profuse, purulent, or blood tinged and is highly infectious. Hepatomegaly with or without splenomegaly occurs in 33-100% of patients. Asymptomatic central nervous system involvement manifesting in CSF abnormalities of lymphocytosis, elevated protein levels, and positive serologic tests occur in up to 80% of infected infants. Symptomatic neurosyphilis develops rarely. Bone lesions develop within eight months of birth in early congenital syphilis. Late manifestations of congenital syphilis include Hutchinsons triad of interstitial keratitis, peg shaped upper incisors, and eighth cranial nerve deafness. The hearing loss can be sudden and usually occurs at eight to 10 years of age. The optimal treatment of an infant born with congenital syphilis is not known.

HIV and Syphilis:

Coinfection is common as both syphilis and HIV are sexually transmitted infections. The two diseases can affect each other in several ways. As with other ulcer-causing infections, syphilis can enhance the acquisition of HIV. Syphilis in the HIV-infected individual can be highly aggressive. Patients can progress from primary to tertiary syphilis over several years, as opposed to several decades in individuals not infected with HIV. Despite this progression, the conventional staging of syphilis is similar with HIV coinfection. Although patients with syphilis and HIV coinfection have shown no distinctive or unique features from those without concurrent HIV infection, they are at increased risk to manifest a more protracted and malignant course. This includes greater constitutional symptoms, greater organ involvement, atypical and florid skin rashes, multiple genital ulcers, concomitant chancre during
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the second stage, and a significant predisposition to develop symptomatic neurosyphilis, especially uveitis (3). Coinfected patients should be managed in consultation with an infectious disease specialist or physician knowledgeable in HIV/AIDS.

Diagnosis of Syphilis
Diagnosis of syphilis is based on history, physical examination, and laboratory investigation. It is essential that the stage of syphilis be accurately assessed and documented in order to ensure appropriate management of cases and contacts.

two types of serologic tests for syphilis; nonspecific nontreponemal antibody tests (VDRL and RPR) and specific treponemal antibody tests (FTA-ABS and TP-PA). To establish a diagnosis of syphilis, both types of serologic tests are usually necessary. It should be emphasized that serologic test results for syphilis on rare occasions may be negative in active cases, especially in older patients, or very early in primary infections. All clinical serology testing and screening for syphilis are performed at the Cadham Provincial Laboratory. Samples are routinely tested MondayFriday within 24 hours of being received. Contact the Serology section at CPL at (204) 945-6123 for questions about testing and (204) 945-6805 to order CPL requisitions forms. After hours testing is conducted for transplant and other emergent purposes. An appropriate sample is 5-10 ml of blood collected in a red-stoppered tube which should be sent to CPL with a request for serum for VDRL. The CPL lab requisition should also provide information on the reason for testing (sexual contact to case, genital ulcer, clinical findings, etc). It is extremely important to include the relevant history on the lab requisition. Routine screening of umbilical cord blood is NOT recommended for serological testing where a diagnosis of congenital syphilis is considered. Testing of maternal serum is preferred to testing infant serum because infant serum can be nonreactive if maternal serology is low titre or if the infection was late in pregnancy. Cord blood that is contaminated with maternal blood may lead to a false positive test result. Contact CPL at 945-7582 or 945-7545 if further diagnostic strategies are sought. See Table 2: Interpretation of Serologic Tests for Syphilis.

Darkfield Microscopy & Direct or Indirect Fluorescent Antibody Test (DFA/IFA):

Darkfield microscopy and DFA/IFA testing of lesion exudates or tissues are the definitive methods for diagnosing early syphilis when an active chancre, mucous patch, or condyloma latum is present. It is also useful for testing nasal discharge in a neonate with snuffles. Darkfield microscopy is often not practical (it is not available in most labs including CPL) as it requires a skilled technician on-site. In addition, specimens must be appropriately collected and quickly examined within 5-20 minutes of collection. Positive tests on these materials for immunofluorescent (DFA) testing are diagnostic. Samples collected from serous exudates from a chancre or secondary skin or mucous membrane lesions for DFA testing should be submitted on a slide and sent to CPL. CPL requests an additional dry Dacron swab be collected for nucleic acid amplification testing (NAAT), and transported in a dry sterile urine container. NAAT is used for syphilis subtyping and not for diagnosis. Prior arrangements are generally not required.

Serology:
Serologic tests for syphilis are essential for diagnosis of individuals, for following the efficacy of therapy, and for screening purposes. They detect antibodies formed during the course of syphilitic infection. A presumptive diagnosis is possible with the use of
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Nontreponemal Tests (VDRL and RPR):

Syphilitic infection leads to the production of nonspecific antibodies (IgM and IgG) directed against a lipoidal antigen resulting from the interaction of host tissues with T. pallidum or from T. pallidum itself. This antibody-antigen reaction is the basis of nontreponemal tests such as the
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Venereal Disease Research Laboratory slide test (VDRL) and the rapid plasma reagin test (RPR). The RPR test is more sensitive than the VDRL. CPL uses the rapid plasma reagin card test (RPR). After adequate treatment of syphilis, nontreponemal tests (NTT) eventually become nonreactive. However, even with sufficient treatment, patients sometimes have a persistent low-level positive nontreponemal test referred to as a serofast conversion. Nontreponemal test titres of persons who have been treated for latent or late stages of syphilis or who have become reinfected do not decrease as rapidly as do those of persons in the early stages of their first infection. In fact these persons may remain serofast for life. VDRL and RPR become positive one to four weeks after the appearance of the primary chancre or six weeks after exposure. Biologic false positive reactions occur at a rate of 1-2% in the general population. Acute false positive tests lasting less than six months can occur following a febrile illness or immunization. As a rule, 90% of false positive titres are less than 1:8, but low titres are also seen in latent infection. False positive rates in pregnancy are similar to the general population. More than 10% of IDU may have false positive results (18). HIV infection has not been associated with increased false positive NTT in individuals at low risk of IDU. Causes of acute and chronic biologic false positive reactions in NTT are listed in Table 3 of the appendix. Serial nontreponemal tests are useful to determine the stage of the disease; a four-fold rise in titre may indicate recent infection, reinfection in an adequately treated person, or relapse in an inadequately treated person. Adequate treatment of infectious syphilis is indicated by a four-fold or greater decline in titre within one year. Titres should generally become non-reactive or weakly reactive within one year following treatment of primary syphilis and within two years after treatment for secondary syphilis. Treatment of late latent or late syphilis usually has little or no effect on the titre and should not be used to gauge the adequacy of the treatment. Titres tend to become

lower with time, but serum frequently remains reactive, usually in low titre. As with all quantitative serologic tests, only a four-fold or greater change in titre is meaningful.

Specific Treponemal Tests:

These tests measure antibodies against specific T. pallidum antigens and are used primarily to confirm the diagnosis of syphilis in patients with a reactive nontreponemal test. The principal specific treponemal antibody tests performed in most laboratories are the T. pallidum particle agglutination tests (TP-PA) and fluorescent treponemal antibody-absorption test (FTA-ABS). Most patients who have reactive treponemal tests will have reactive tests for the remainder of their lives, regardless of treatment or disease activity. However, reversion to a nonreactive status may occur in up to 10% of patients, especially in those who are treated early (3). Treponemal test antibody titres correlate poorly with disease activity and should not be used to assess treatment response. False positive results can occur especially when the FTA-ABS test is used in patients with Lyme disease, HIV, pregnancy, drug addiction, toxoplasmosis, H. pylori, autoimmune disorders like lupus and rheumatoid arthritis, and in persons with other treponemal diseases such as yaws, pinta or bejel. Confirmatory Test: The TP-PA test is a specific treponemal test for the serologic detection of antibodies to various species and subspecies of treponemes. Reports from CPL refer to the TP-PA as a confirmatory test result. Reference Test: The FTA-ABS test is an indirect immunofluorescent antibody test using T. pallidum from rabbit testis as the antigen. Its interpretation is subjective and requires great attention to detail. Its principal use is to verify the diagnosis of syphilis. Reports from CPL refer to this as the reference test.

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Tests for Neurosyphilis:

No single test is diagnostic for neurosyphilis; the CSF-VDRL is highly specific but it is insensitive; as low as 30%. Most other tests are both insensitive and nonspecific and must be interpreted in relation to other test results and the clinical assessment. Diagnosis of neurosyphilis usually depends on the combination of patient history, physical examination, reactive serologic test results, and abnormalities of CSF (cell count, protein, or a reactive CSF-VDRL). The CSF leukocyte count is usually elevated (>5 WBC/mm3) in patients with neurosyphilis. The CSF leukocyte count can also be used as a sensitive measure of the effectiveness of therapy. A positive CSF-VDRL result in the appropriate clinical setting establishes the diagnosis of neurosyphilis although serum antibody contamination is possible. A negative CSF-VDRL does not rule out the possibility of neurosyphilis. Normalization of CSF markers is affected by the stage of syphilis at which treatment is initiated and pretreatment levels of particular CSF markers. In patients without HIV infection treated with penicillin regimens, the CSF pleocytosis and VDRL titre normalize within one year. Reversion of pleocytosis is more likely when pretreatment CSF WBC counts are high. CSF-VDRL normalization is less likely when pretreatment CSF-VDRL titres are high. In HIV-infected patients, CSF WBC count, protein, and VDRL may be slow to normalize. CSF-VDRL titres are less likely to normalize after treatment when CD4+ counts are <200 cells/L compared to CD4+ counts >200 cells/L. Therefore in HIV-infected patients, it is not possible to exclude treatment failure and more intensive regimens may be required. Examination of CSF should be considered in the following circumstances: 1. Congenital syphilis; 2. Neurologic, ophthalmic, or otologic signs and symptoms; 3. Tertiary syphilis; 4. Previously treated patients who fail to achieve an adequate serologic response;

5. HIV coinfection with late latent or syphilis of unknown duration; 6. Where HIV coinfection exists, a lumbar puncture (LP) is strongly recommended when neurological signs or symptoms are present, VDRL/RPR 1:32 dilutions, CD4+ counts <350 cells/L or treated syphilis with suboptimal decline in VDRL/RPR titre. Some experts recommend a LP for all syphilis cases with HIV coinfection. A LP may be considered in other patients on a case by case basis.

Tests for congenital syphilis:

Venous samples should be obtained from both mother and baby for serology (treponemal and nontreponemal tests). Cord blood is not suitable for testing. The interpretation of reactive antibodies in the neonate must take into consideration the maternal history, including stage of syphilis, history of treatment, and syphilis serology results. Placenta, neonatal nasal discharge, or skin lesions may be examined by darkfield microscopy or DFA/IFA for T. pallidum. CSF examination should be performed on all infants with suspected congenital syphilis. Long bone x-rays should also be performed.

Key Investigations
Interview case for history of exposure, risk behaviours, sexual contacts, adequacy of treatment, and promotion of safer sex practices. Interview sexual contacts and provide epidemiological treatment if indicated (see Management of Sexual Contacts section), with risk assessment and promotion of safer sex practices.

Control
Management of Cases:
Close collaboration between Public Health and Primary Care in addition to timely completion and return of NSTD forms are crucial to ensure there is sufficient information to identify and locate sexual contacts in a timely manner.
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Seroreactive persons should be expeditiously evaluated. This evaluation should include a history and physical examination, laboratory testing, risk assessment, and promotion of safer sex practices. All persons with syphilis should be counseled concerning the risks of HIV infection and other STIs and testing for these infections should be offered. Cases with infectious syphilis (primary, secondary, and early latent) should be interviewed for sexual contacts (see Management of Sexual Contacts section). The following principles of case management apply: Treat all cases of infectious syphilis immediately; Interview cases within one working day whenever possible; Evaluate cases within one week after treatment to document clinical response.

provincial and federal requirement. Bicillin L-A is provided to Manitoba Health through the Special Access Programme (SAP) of the Therapeutic Products Directorate (TPD) at Public Health Agency of Canada. The product monograph will be provided with the Bicillin L-A medication in 2 ml TUBEX sterile cartridge-needle units containing 1.2 mU of benzathine penicillin G. The dosage, administration, contraindications, and precautions sections should be reviewed thoroughly prior to use. Refer to Table 4: Diagnosis and Treatment of Syphilis by Stage for the specific management of syphilis by stage. Additional resources include Public Health Agency of Canadas Canadian Guidelines on Sexually Transmitted Infections, 2006 Edition (see Additional Resources and References section).

Manitoba Health provides free drugs for STI treatment to practitioners in the provincial jurisdiction.

Treatment:
Penicillin G, administered parenterally is the preferred drug for treatment of all stages of syphilis. Injectable benzathine penicillin G (Bicillin L-A) is available for the treatment of incubating, primary, secondary, latent, and tertiary syphilis. Orders can be made by contacting the CDC Unit of Manitoba Health at 788-6737. The CDC Unit will fax or mail out the STI Medication Order form which must be completed and faxed back to the Unit (CDC Unit confidential fax 948-3044). After administration of the medication, the STI Medication Administration form and Adverse Drug Reactions form (as appropriate) must also be completed and faxed back to Manitoba Health. Appropriate documentation of administration and adverse reactions is both a
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Crystalline penicillin G is recommended for the treatment of neurosyphilis as treponemicidal levels of benzathine penicillin G are not reliably achieved in the CSF. Expert opinion suggests the alternative use of doxycycline for the treatment of early syphilis and late latent syphilis for nonpregnant adults who are penicillin allergic (6). However, treatment failures have been documented with the use of doxycycline. Because penicillin G is the most reliable treatment for all stages of syphilis, desensitization of patients should be considered. This can be done orally or intravenously and in consultation with an infectious disease specialist and/or allergy specialist. Protocols for oral desensitization are found in the Canadian Guidelines on Sexually Transmitted Infections, 2006 Edition (see Additional Resources and References section) (6). Azithromycin monotherapy should not be used as a treatment option for early or incubating syphilis as azithromycin resistance has been reported and is increasing.

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In exceptional circumstances, azithromycin may be considered for suspect syphilis cases (at the time that serology is performed) only if benzathine penicillin G is not readily available, with the understanding that the patient will require benzathine penicillin G if their serology confirms that they have syphilis. This may include the epidemiologic treatment of incubating syphilis of sexual contacts in the preceding 90 days to primary, secondary, or early latent syphilis pending the results of serologic tests where follow-up is assured. A single 2 gram oral dose is indicated in this circumstance (6).

Persons who require retreatment should be retreated according to the schedules recommended for syphilis of more than one years duration. In general, a person should be retreated only once, since they may maintain stable, low titres when nontreponemal tests are used. All cases of infectious syphilis should abstain from sexual activity until they and their sex partners are appropriately treated and clinical signs are no longer present. Cases in hospital should be managed with appropriate infection control precautions.

Syphilis in HIV-infected persons:

Because of the concurrent immune dysfunction and the propensity for developing more severe disease, some experts feel that coinfected persons should be treated with a course of antibiotics similar to those used for late latent syphilis (6). However, limited data suggest that there is no difference between standard and prolonged regimens (23). Treatment failures with ceftriaxone, doxycycline, and azithromycin have been reported so use of these agents is discouraged in HIV-infected persons. Desensitization for penicillin allergic patients is strongly recommended. Consultation with an infectious disease specialist or physician knowledgeable in HIV/AIDS is strongly recommended.

Ceftriaxone can be used as an alternative for the treatment of neurosyphilis in penicillin allergic patients and under exceptional circumstances in early syphilis (19, 20, 21, 22). Therapeutic regimens other than penicillin have not been well studied, especially in patients with syphilis of longer than one years duration; therefore, careful follow-up is mandatory. Consultation with an infectious disease specialist is advised if regimens other than penicillin are considered. Persons for whom there is documentation of recommended treatment for syphilis in the past need not be treated again unless there is clinical or serologic evidence of reinfection such as lesions positive for syphilis as detected by direct fluorescence antigen (DFA) or a four-fold rise in titre when a nontreponemal test is used. Retreatment should be considered when: clinical signs or symptoms of syphilis persist or recur; there is a four-fold increase in titre with a nontreponemal test; or a nontreponemal test showing a high titre initially fails to show a four-fold decrease within a year following treatment.

Syphilis in Pregnancy:
Pregnant patients should receive penicillin, following dosage schedules appropriate for the stage of syphilis as recommended for nonpregnant patients. Despite the administration of the recommended penicillin regimen, as many as 14% will have fetal deaths or deliver infants with clinical evidence of congenital syphilis. The Canadian Guidelines on Sexually Transmitted Infections, 2006 Edition suggests that women with secondary syphilis in late pregnancy receive two
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doses of benzathine penicillin G 2.4 mU IM one week apart. The effect of this regimen in preventing fetal syphilis is not known. If there is a documented penicillin allergy, consultation with an infectious disease specialist and an allergy specialist for testing and desensitization is recommended. The mother should be monitored closely during and after the pregnancy, and if an increase in a nontreponemal test titre occurs, she and her infant must be retreated (3). If the mother is >20 weeks gestation, an ultrasound should be performed and she should be managed with an obstetrician/fetal-maternal medicine specialist; if fetal abnormalities are identified, the mother should be hospitalized for treatment and fetal monitoring (6). All babies should be assessed at delivery by a pediatrician, and if a maternal non-penicillin regimen was used, consideration should be given to treating the baby empirically for congenital syphilis. Consultation with an infectious disease specialist is advised.

Management of Sexual Contacts (Partner Notification)

Rapid identification and investigation of sexual partners/contacts is essential to locate persons with early (primary, secondary, early latent) or incubating syphilis and provide them with treatment to prevent further transmission. Approximately 46%-60% of contactable sex partners of patients and pregnant women with infectious syphilis also have the infection (24, 25). Transmission probability per partner is around 60% (26). All sexual and perinatal contacts identified within the following time periods should be located, tested, and treated if serologically reactive:
Patients Stage Primary Syphilis Examine All Sexual and Perinatal Contacts Exposed during the three months prior to the onset of chancre and up to and including the interview date during the six months prior to onset of clinical symptoms and up to and including the interview date Marital and long term sex partners of patients with latent syphilis should be evaluated clinically and serologically for syphilis and treated on the basis of the evaluation findings. Children of persons with late latent syphilis should be assessed as appropriate. Assess mother and her sexual partner(s).

Jarisch-Herxheimer reaction:
Patients should be made aware of this possible reaction to penicillin therapy (6). An acute febrile illness with headache, myalgia, and chills/rigors can occur within 8-12 hours of penicillin therapy, with resolution within 24 hours (6). More common in early syphilis and not usually clinically significant unless there is neurologic or ophthalmologic involvement or in pregnancy where it may cause fetal distress and premature labour (6). This kind of reaction is not an allergic reaction, and should not be treated with antihistamines. Patients demonstrating a reaction can be treated with antipyretics. More severe reactions can be treated with corticosteroids (in consultation with a medical specialist).
Secondary Syphilis

Early Latent Syphilis one year prior to diagnosis Late Latent Syphilis

Congenital Syphilis

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Presumptive or epidemiologic treatment of sex partners should be considered under the following circumstances: Persons who were exposed within three months preceding the diagnosis of primary, secondary or early latent syphilis in a sex partner might be infected, even if testing indicates seronegative status; therefore such persons should be treated presumptively. Persons who were exposed more than three months preceding the diagnosis of primary, secondary or early latent syphilis in a sex partner should be treated presumptively if serologic test results are not available immediately and the opportunity for follow-up is uncertain. Otherwise management should be dependent on serologic results.

Follow-up and Serologic Response to Treatment

The adequacy of therapy can be determined with serial RPR (or VDRL) tests; the same test in the same laboratory should be followed sequentially. Table 5: Monitoring of NTT of the appendix reflects the minimum follow-up required for serological testing. Once treatment has been completed, serological response can be used to evaluate adequacy of treatment. The guidelines for determining adequate serologic response are found in Table 6: Adequate Serologic Response of the appendix.

Syphilis of Unknown Duration:

For purposes of partner notification and presumptive treatment of exposed sex partners, patients with syphilis of unknown duration who have high nontreponemal titres (i.e., RPR or VDRL 1:32) should be assumed to have early latent syphilis and be managed accordingly.

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Appendix
Table 1: Clinical Manifestations and Incubation Period (6)
Stage Primary Secondary Clinical manifestations Chancre, regional lymphadenopathy Rash, fever, malaise, generalized lymphadenopathy, mucous lesions, condylomata lata, alopecia, meningitis, headaches, uveitis, retinitis Asymptomatic Incubation period 3 weeks (3-90 days) 2-12 weeks (2 weeks-6 months)

Latent Tertiary Cardiovascular syphilis Neurosyphilis

Early: <1 year Late: 1 year 10-30 years <2 years-20 years

Aortic aneurysm, aortic regurgitation, coronary artery ostial stenosis Ranges from asymptomatic to symptomatic with headaches, vertigo, personality changes, dementia, ataxia, presence of Argyll Robertson pupil Tissue destruction of any organ; manifestations depend on site involved Fulminant disseminated infection, mucocutaneous lesions, osteochondritis, anemia, hepatosplenomegaly, neurosyphilis Interstitial keratitis, lymphadenopathy, hepatosplenomegaly, bone and joint involvement, anemia, Hutchinsons teeth, neurosyphilis

Gumma Congenital Early

1-46 years (most cases 15 years)

Onset <2 years

Late

Persistence >2 years after birth

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Table 2: Interpretation of Serologic Tests for Syphilis (6)

Screening test (RPR/VDRL) NR R (dilutions can vary) Confirmatory test TP-PA NR R Reference test FTA-ABS R R (test not indicated if screening and confirmatory tests are positive) Most likely condition Early primary syphilis with compatible history and clinical findings Infectious syphilis (primary, secondary, or early latent) especially if titre >1:8 OR Old treated syphilis (especially if titre <1:8) OR Follow-up of treated syphilis OR In persons from endemic countries, yaws (e.g. Caribbean), pinta (e.g. Central America), or bejel Usually treated syphilis OR Late latent of unknown duration if no history of confirmed treatment OR In persons from endemic countries, yaws (e.g. Caribbean), pinta (e.g. Central America), or bejel OR Early infection (primary syphilis) Biological false positive (see Table 3 for possible causes of a biologic false positive result) Repeat testing in 3-4 weeks Possible incubating or primary syphilis. Suspect incubating or primary syphilis based on client history and/or clinical findings

NR

NR

NR

NR

NR = non-reactive; R = reactive

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Table 3: Causes of Biologic False Positive Syphilis Nontreponemal Test Serology (RPR/VDRL)
Acute Hepatitis Viral pneumonia Measles Malaria Pregnancy Infectious mononucleosis Chicken pox Other viral infections Immunizations Drug use Lab/technical error Chronic Connective tissue/autoimmune diseases Immunoglobulin abnormalities Narcotic addiction Aging Leprosy Malignancy

Table 4: Diagnosis and Treatment of Syphilis by Stage (6, 27)

Stage Primary Syphilis Diagnosis(sensitivity) Darkfield microscopy of skin lesion (80%) Nontreponemal tests (78-86%) Treponemal specific tests (76-84%) Darkfield microscopy of skin lesions (80%) Nontreponemal tests (100%) Treponemal specific tests (100%) Nontreponemal tests (95-100%) Treponemal specific tests (97-100%) Preferred Treatment Benzathine penicillin G 2.4 million units IM, as a single dose (1.2 million units into each buttock) Benzathine penicillin G 2.4 million units IM, as a single dose (1.2 million units into each buttock) Alternative treatment for penicillin allergic patients Doxycycline 100 mg po BID for 14 days Ceftriaxone 1g IM or IV once daily for 10 days (to be used in exceptional circumstances) Same as for Primary Syphilis

Secondary Syphilis

Latent Syphilis Early latent

Late latent or unknown duration

Early latent: Benzathine penicillin G 2.4 million units IM, as a single dose (1.2 million units into each buttock) Late latent: Benzathine penicillin G 2.4 million units IM once weekly for 3 weeks

Early latent: Same as for Primary Syphilis

Late latent: Strongly consider penicillin desensitization Doxycycline 100 mg po BID for 28 days Ceftriaxone 1g IM or IV once daily for 10 days (to be used in exceptional circumstances)
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Stage Tertiary Syphilis

Diagnosis(sensitivity) Nontreponemal tests (71-73%) Treponemal specific tests (94-96%)

Preferred Treatment Benzathine penicillin G 2.4 million units IM once weekly for 3 weeks

Alternative treatment for penicillin allergic patients Strongly consider penicillin desensitization Doxycycline 100 mg po BID for 28 days Ceftriaxone 1g IM or IV once daily for 10 days (to be used in exceptional circumstances)

Neurosyphilis

Crystalline penicillin G Strongly consider penicillin 3-4 million units IV every desensitization followed by 4 hrs (18-24 million units/ treatment with penicillin day) for 10-14 days Ceftriaxone 2 g IV/IM daily for 10Alternative regimen: 14 days IM procaine penicillin G, 2.4 million units once daily with oral probenecid, 500 mg QID both for 10-14 days Benzathine penicillin G 2.4 million units IM as a single dose (1.2 million units into each buttock) There is no satisfactory alternative to penicillin for the treatment of syphilis in pregnancy; insufficient data exists to recommend ceftriaxone in pregnancy Strongly consider penicillin desensitization There is no satisfactory alternative to penicillin for the treatment of syphilis in pregnancy; insufficient data exists to recommend ceftriaxone in pregnancy Strongly consider penicillin desensitization

Pregnant Women Primary Secondary Early latent

Pregnant Women Late latent syphilis Latent syphilis of unknown duration Cardiovascular syphilis and other tertiary syphilis not involving the central nervous system Congenital Syphilis

Benzathine penicillin G 2.4 million units IM once weekly for 3 weeks

Early (<1 month of age): Crystalline penicillin G 50,000 units/kg IV every 12 hours for the first week of life and every 8 hours thereafter for a total of 10 days of therapy

No data are available to recommend penicillin alternatives in the case of penicillin allergy

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Stage

Diagnosis(sensitivity)

Preferred Treatment Late (1 month of age): Crystalline penicillin G 50,000 units/kg IV every 6 hours for 10-14 days

Alternative treatment for penicillin allergic patients If no neurologic involvement and normal CSF: benzathine penicillin G 50,000 units/kg IM (max 2.4 million units) weekly for 3 successive weeks No data are available to recommend penicillin alternatives in the case of penicillin allergy Azithromycin alone should not be used as a treatment option for early or incubating syphilis as azithromycin resistance has been reported and is increasing. Under exceptional circumstances, the use of azithromycin 2g stat dose may be considered for suspect syphilis cases (at the time that serology is performed) only if benzathine penicillin G is not readily available, with the understanding that the patient will require benzathine penicillin G if their serology confirms that they have syphilis.

Epidemiologic treatment of sexual contacts in the preceding 90 days to primary, secondary, and early latent syphilis

Benzathine penicillin G 2.4 million units IM, as a single dose (1.2 million units into each buttock)

Some experts recommend three weekly doses (total of 7.2 million units) of benzathine penicillin G in HIV-infected individuals however limited data suggest that there is no difference between standard and prolonged regimens (6, 23). Some experts recommend a second dose (2.4 million units) benzathine penicillin G one week after initial dose especially in third trimester or with secondary syphilis (6).

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Table 5: Monitoring of NTT (6)

Stage of Syphilis Primary, secondary, and early latent syphilis Late latent and tertiary syphilis Neurosyphilis NTT Monitoring intervals 1, 3, 6, and 12 months following treatment 12 and 24 months following treatment 6, 12, and 24 months following treatment. A lumbar puncture and CSF analysis should be repeated every 6 months until the cell count has normalized Re-examine 1-2 weeks after treatment and follow serologically and clinically at 1, 3, 6, 9, 12, 24 months after treatment and annually thereafter 1, 3, 6, 12, 18, and 24 months after treatment and annually thereafter 3 and 6 months after birth; repeat nontreponemal and treponemal tests at 12 and 18 months if test is reactive at 6 months 0, 3, 6, 12, and 18 months after birth

HIV-infected Early syphilis Late syphilis Babies born to mothers with reactive syphilis serology* Congenital syphilis*

*NTT titres should decline by 3 months of age and be non-reactive by 6 months if the infant was not infected. If the titres are stable or increase after 6-12 months of age, the child should be evaluated (including CSF examination) and treated for congenital syphilis. Passively transferred treponemal antibodies can be present in an infant up to 15 months; a reactive treponemal test after 18 months is diagnostic of congenital syphilis. Table 6: Adequate Serologic Response (6)
Following treatment of Primary syphilis One would expect to see 4-fold decrease at 6 months* 8-fold decrease at 12 months 16-fold decrease at 24 months 8-fold and 16-fold decrease at 6 and 12 months respectively 4-fold decrease by 12 months 4-fold decrease 6-12 months following treatment 4-fold decrease 12-24 months following treatment

Secondary syphilis Early latent syphilis HIV-infected Early syphilis Late latent syphilis or syphilis of unknown duration

*e.g., a change from 1:32 dilutions (32 DL) to 1:8 dilutions (8 DL)

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Additional Resources
Public Health Agency of Canadas Sexual Health and Sexually Transmitted Infections Website available at: www.phac-aspc.gc.ca/std-mts/ syphilis_e.html. Public Health Agency of Canada. Canadian Guidelines on Sexually Transmitted Infections 2006 Edition. Available at: www.phac-aspc.gc.ca/std-mts/ sti_2006/pdf/sti2006_e.pdf. Centers for Disease Control and Prevention (CDC) Sexually Transmitted Disease (Syphilis) Website available at: www.cdc.gov/std/syphilis/default.htm. Centers for Disease Control and Prevention (CDC) 2002 Sexually Transmitted Disease Treatment Guidelines available at: www.cdc.gov/STD/ treatment/. Department of Reproductive Health and Research (RHR), World Health Organization. Guidelines for the management of sexually transmitted infections available at: www.who.int/reproductive-health/ publications/rhr_01_10_mngt_stis/index.html.

References
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6. Public Health Agency of Canada. Canadian Guidelines on Sexually Transmitted Infections 2006 Edition. Available at: www.phac-aspc. gc.ca/std-mts/sti_2006/pdf/sti2006_e.pdf. Accessed July 4, 2007. 7. Fleming DT, Wasserheit JN. From Epidemiologic Synergy to Public Health Practice: The Contribution of Other STD to Sexual Transmission of HIV Infection. Sexually Transmitted Infections 1999;75(2):3-17. 8. Tsui AO et al. (eds.). Reproductive Health in Developing Countries. Expanding Dimensions, Building Solutions, National Academy Press, Washingtom, 1997. 9. Schulz KF et al. Congenital syphilis. In: Sexually Transmistted Diseases 2nd ed. McGrawHill Inc New York,1990; 821-42. 10.Zenker PN, Rolfs RT. Treatment of Syphilis 1989. Reviews of Infectious Disease 1990;12(6):S590-S605. 11.Brocklehurst P. Update on the Treatment of Sexually Transmitted Infections in Pregnancy-1. International Journal of STD & AIDS 1999; 10:571-580. 12.Genc M, Ledger WJ. Syphilis in Pregnancy. Sexually Transmitted Infections 2000; 76:73-79. 13.Public Health Agency of Canada. 2004 Canadian Sexually Transmitted Infections Surveillance Report. Canada Communicable Disease Report. 2007; 33(S1): 1-69. 14.Manitoba Health. The Descriptive Epidemiology of Sexually Transmitted Infections and Blood-borne Pathogens in Manitoba 2002-2003. 2005. Available at: www.gov.mb.ca/health/publichealth/cdc/ surveillance/desti.pdf. 15.Unpublished Data. Winnipeg Regional Health Authority, 2005. 16.Centers for Disease Control and Prevention. Sexually Transmitted Diseases Treatment Guidelines 2002. Morbidity and Mortality Weekly Report 2002; 51:18-28.

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17.Qolohle DC et al. Serological Screening for Sexually Transmitted Infections in Pregnancy: Is There Any Value in Re-screening for HIV and Syphilis at the Time of Delivery? Genitourinary Medicine 1995; 71:65-67. 18.Larsen SA, Pope V, Johnson RE, Kennedy EJ (eds). A Manual of Tests for Syphilis 9th edition. American Public Health Association, Washington, 1998. 19.Hook E, Roddy R, Handsfield H. Ceftriaxone for Early and Incubating Syphilis. The Journal of Infectious Diseases 1988; 158:881-4. 20.Moorthy T, Lee C, Kim K, Tan T. Ceftriaxone for the Treatment of Primary Syphilis in Men: a Preliminary Study. Sexually Transmitted Diseases 1987; 14:116-18. 21.Schofer H, Vogt HJ, Milbradt R. Ceftriaxone for the Treatment of Primary and Secondary Syphilis. Chemotherapy 1989; 35:140-145. 22.Katsambas A, Adonious C, Katsarou A, Kerkidou A, Stratigos J. Comparative Study of Ceftriaxone and Benzathine Penicillin G in the Treatment of Primary and Secondary Syphilis. Chemiotherapia 1987; 6:549-50.

23.Zetola, NM, Klausner. Syphilis and HIV Infection: An Update. Clinical Infectious Diseases 2007; 44:1222-1228. 24.Schober PC, Gabriel G, White P et al. How Infectious is Syphilis? British Journal Venereal Disease 1983; 59(4):217-9. 25.Phaosavasdi S et al. Treatment of Sexual Contacts of Syphilitic Pregnant Women. Journal of the Medical Association of Thailand 1989; 72(3):132-7. 26.Garnett GP, Aral SO, Hoyle DV, Cates W Jr, Anderson RM. The Natural History of Syphilis. Implications for the Transmission Dynamics and Control of Infection. Sexually Transmitted. Diseases 1997; 24:185-200. 27.Brown DL, Frank JE. Diagnosis and Management of Syphilis. American Family Physician 2003; 68:283-90.

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