Communicable Disease Management Protocol
Syphilis
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).
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.
Primary Syphilis:
Identification of T. pallidum by darkfield
microscopy, fluorescent antibody, or equivalent
examination of material from a chancre or regional
lymph node;
OR
Communicable Disease Management Protocol – Syphilis
Communicable Disease Control Unit
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.
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.
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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.
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.
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.
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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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.
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.
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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 Communicable Disease Management Protocol
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.
Communicable Disease Management Protocol – Syphilis
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%.
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.
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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.
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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Communicable Disease Management Protocol
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 Hutchinson’s 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.
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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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 Monday-
Friday 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.
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
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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/µL compared to CD4+ counts >200
cells/µL. 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;
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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/µL 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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 Communicable Disease Management Protocol
• 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.
• 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
Communicable Disease Management Protocol – Syphilis
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 Canada’s Canadian
Guidelines on Sexually Transmitted
Infections, 2006 Edition (see Additional
Resources and References section).
• 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.
August 2007
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 Communicable Disease Management Protocol
– 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).
• 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 year’s 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.
August 2007
10
• Persons who require retreatment should be
retreated according to the schedules
recommended for syphilis of more than one
year’s 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.
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
Communicable Disease Management Protocol – Syphilis
 Communicable Disease Management Protocol

doses of benzathine penicillin G 2.4 mU IM one Management of Sexual Contacts

week apart. The effect of this regimen in (Partner Notification)
preventing fetal syphilis is not known.
• Rapid identification and investigation of sexual
• If there is a documented penicillin allergy,
partners/contacts is essential to locate persons
consultation with an infectious disease specialist
with early (primary, secondary, early latent) or
and an allergy specialist for testing and
incubating syphilis and provide them with
desensitization is recommended.
treatment to prevent further transmission.
• The mother should be monitored closely during
• Approximately 46%-60% of contactable sex
and after the pregnancy, and if an increase in a
partners of patients and pregnant women with
nontreponemal test titre occurs, she and her
infectious syphilis also have the infection (24,
infant must be retreated (3).
25).
• If the mother is >20 weeks gestation, an
• Transmission probability per partner is around
ultrasound should be performed and she should
60% (26).
be managed with an obstetrician/fetal-maternal
medicine specialist; if fetal abnormalities are • All sexual and perinatal contacts identified
identified, the mother should be hospitalized for within the following time periods should be
treatment and fetal monitoring (6). located, tested, and treated if serologically
reactive:
• All babies should be assessed at delivery by a
pediatrician, and if a maternal non-penicillin
regimen was used, consideration should be given Patient’s Stage Examine All Sexual and
to treating the baby empirically for congenital Perinatal Contacts Exposed
syphilis. Consultation with an infectious disease Primary Syphilis during the three months prior
specialist is advised. to the onset of chancre
and
Jarisch-Herxheimer reaction: up to and including the
interview date
• Patients should be made aware of this possible
reaction to penicillin therapy (6). Secondary Syphilis during the six months prior to
onset of clinical symptoms
• An acute febrile illness with headache, myalgia, and
and chills/rigors can occur within 8-12 hours of up to and including the
penicillin therapy, with resolution within 24 interview date
hours (6).
Early Latent Syphilis one year prior to diagnosis
• More common in early syphilis and not usually
clinically significant unless there is neurologic or Late Latent Syphilis Marital and long term sex
partners of patients with latent
ophthalmologic involvement or in pregnancy
syphilis should be evaluated
where it may cause fetal distress and premature clinically and serologically for
labour (6). syphilis and treated on the basis
• This kind of reaction is not an allergic reaction, of the evaluation findings.
and should not be treated with antihistamines. Children of persons with late
latent syphilis should be assessed
• Patients demonstrating a reaction can be treated as appropriate.
with antipyretics. More severe reactions can be
treated with corticosteroids (in consultation with Congenital Syphilis Assess mother and her sexual
partner(s).
a medical specialist).

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 Communicable Disease Management Protocol

Presumptive or epidemiologic treatment of sex Follow-up and Serologic Response to

partners should be considered under the following Treatment
circumstances:
The adequacy of therapy can be determined with
• Persons who were exposed within three months serial RPR (or VDRL) tests; the same test in the
preceding the diagnosis of primary, secondary or same laboratory should be followed sequentially.
early latent syphilis in a sex partner might be Table 5: Monitoring of NTT of the appendix
infected, even if testing indicates seronegative reflects the minimum follow-up required for
status; therefore such persons should be treated serological testing.
presumptively.
Once treatment has been completed, serological
• Persons who were exposed more than three response can be used to evaluate adequacy of
months preceding the diagnosis of primary, treatment. The guidelines for determining adequate
secondary or early latent syphilis in a sex partner serologic response are found in Table 6: Adequate
should be treated presumptively if serologic test Serologic Response of the appendix.
results are not available immediately and the
opportunity for follow-up is uncertain.
Otherwise management should be dependent on
serologic results.
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.

August 2007 Communicable Disease Management Protocol – Syphilis

12
 Communicable Disease Management Protocol

Appendix
Table 1: Clinical Manifestations and Incubation Period (6)
Stage Clinical manifestations Incubation period
Primary Chancre, regional lymphadenopathy 3 weeks (3-90 days)
Secondary Rash, fever, malaise, generalized lymphadenopathy, 2-12 weeks (2 weeks-6 months)
mucous lesions, condylomata lata, alopecia,
meningitis, headaches, uveitis, retinitis
Latent Asymptomatic Early: <1 year
Late: ≥1 year
Tertiary
Cardiovascular syphilis Aortic aneurysm, aortic regurgitation, coronary 10-30 years
artery ostial stenosis
Neurosyphilis Ranges from asymptomatic to symptomatic with <2 years-20 years
headaches, vertigo, personality changes, dementia,
ataxia, presence of Argyll Robertson pupil
Gumma Tissue destruction of any organ; manifestations 1-46 years (most cases 15 years)
depend on site involved
Congenital
Early Fulminant disseminated infection, Onset <2 years
mucocutaneous lesions, osteochondritis, anemia,
hepatosplenomegaly, neurosyphilis
Late Interstitial keratitis, lymphadenopathy, Persistence >2 years after birth
hepatosplenomegaly, bone and joint involvement,
anemia, Hutchinson’s teeth, neurosyphilis

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

Screening test Confirmatory test Reference test Most likely condition
(RPR/VDRL) TP-PA FTA-ABS
NR NR R Early primary syphilis with compatible history and
clinical findings
R R R Infectious syphilis (primary, secondary, or early latent)
(dilutions (test not indicated especially if titre >1:8
can vary) if screening and OR
confirmatory tests Old treated syphilis (especially if titre <1:8)
are positive) OR
Follow-up of treated syphilis
OR
In persons from endemic countries, yaws (e.g.
Caribbean), pinta (e.g. Central America), or bejel
NR R R 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)
R NR NR Biological false positive (see Table 3 for possible causes
of a biologic false positive result)
Repeat testing in 3-4 weeks
R NR R Possible incubating or primary syphilis. Suspect
incubating or primary syphilis based on client history
and/or clinical findings
NR = non-reactive; R = reactive

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 Communicable Disease Management Protocol

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

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

Stage Diagnosis(sensitivity) Preferred Treatment Alternative treatment for penicillin
allergic patients
Primary Syphilis† • Darkfield microscopy Benzathine penicillin G • Doxycycline 100 mg po BID for 14
of skin lesion (80%) 2.4 million units IM, days
• Nontreponemal tests as a single dose (1.2 • Ceftriaxone 1g IM or IV once daily
(78-86%) million units into each for 10 days (to be used in
• Treponemal specific buttock) exceptional circumstances)
tests (76-84%)
Secondary • Darkfield microscopy Benzathine penicillin G Same as for Primary Syphilis
Syphilis† of skin lesions (80%) 2.4 million units IM,
• Nontreponemal tests as a single dose (1.2
(100%) million units into each
• Treponemal specific buttock)
tests (100%)
Latent Syphilis†
Early latent • Nontreponemal tests Early latent: Benzathine Early latent: Same as for Primary
(95-100%) penicillin G 2.4 million Syphilis
• Treponemal specific units IM, as a single
tests (97-100%) dose (1.2 million units
into each buttock)
Late latent or Late latent: Benzathine Late latent:
unknown penicillin G 2.4 million • Strongly consider penicillin
duration units IM once weekly desensitization
for 3 weeks • 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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 Communicable Disease Management Protocol

Stage Diagnosis(sensitivity) Preferred Treatment Alternative treatment for penicillin

Tertiary Syphilis • Nontreponemal tests Benzathine penicillin
(71-73%) G 2.4 million units IM
• Treponemal specific once weekly for 3 weeks
tests (94-96%)
Neurosyphilis Crystalline penicillin G • Strongly consider penicillin
3-4 million units IV every
4 hrs (18-24 million units/
day) for 10-14 days • Ceftriaxone 2 g IV/IM daily for 10-
Alternative regimen:
IM procaine penicillin
G, 2.4 million units once
daily with oral probenecid,
500 mg QID both for
10-14 days
Pregnant Women Benzathine penicillin G
Primary 2.4 million units IM as
Secondary†† a single dose (1.2 million
Early latent units into each buttock)
Pregnant Women Benzathine penicillin G
Late latent 2.4 million units IM
syphilis once weekly for 3 weeks
Latent syphilis
of unknown
duration
Cardiovascular
syphilis and
other tertiary
syphilis not
involving
the central
nervous system
Congenital Early (<1 month of age):
Syphilis 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
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)
desensitization followed by
treatment with penicillin
14 days
• 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
• No data are available to recommend
penicillin alternatives in the case
of penicillin allergy

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 Communicable Disease Management Protocol

Stage Diagnosis(sensitivity) Preferred Treatment Alternative treatment for penicillin

allergic patients
Late (≥1 month of age): • If no neurologic involvement and
Crystalline penicillin G normal CSF: benzathine penicillin
50,000 units/kg IV every G 50,000 units/kg IM (max 2.4
6 hours for 10-14 days million units) weekly for 3 successive
weeks
• No data are available to recommend
penicillin alternatives in the case of
penicillin allergy
Epidemiologic Benzathine penicillin G Azithromycin alone should not be
treatment of 2.4 million units IM, as a used as a treatment option for early or
sexual contacts single dose (1.2 million incubating syphilis as azithromycin
in the preceding units into each buttock) resistance has been reported and is
90 days to increasing. Under exceptional
primary, circumstances, the use of azithromycin
secondary, and 2g stat dose may be considered for
early latent suspect syphilis cases (at the time that
syphilis 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.

† 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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 Communicable Disease Management Protocol

Table 5: Monitoring of NTT (6)

Stage of Syphilis NTT Monitoring intervals
Primary, secondary, and early latent syphilis 1, 3, 6, and 12 months following treatment
Late latent and tertiary syphilis 12 and 24 months following treatment
Neurosyphilis 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
HIV-infected
Early syphilis 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
Late syphilis 1, 3, 6, 12, 18, and 24 months after treatment and annually
thereafter
Babies born to mothers with reactive 3 and 6 months after birth; repeat nontreponemal and
syphilis serology* treponemal tests at 12 and 18 months if test is reactive at
6 months
Congenital syphilis* 0, 3, 6, 12, and 18 months after birth

*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 One would expect to see
Primary syphilis 4-fold decrease at 6 months*
8-fold decrease at 12 months
16-fold decrease at 24 months
Secondary syphilis 8-fold and 16-fold decrease at 6 and 12 months respectively
Early latent syphilis 4-fold decrease by 12 months
HIV-infected
Early syphilis 4-fold decrease 6-12 months following treatment
Late latent syphilis or syphilis of unknown duration 4-fold decrease 12-24 months following treatment

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

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 Communicable Disease Management Protocol
Additional Resources
Public Health Agency of Canada’s 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.
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