INTRODUCTION

Section 2 of 10
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Background: Syphilis is an infectious disease caused by the spirochete

Treponema pallidum. It almost always is transmitted by sexual contact with
infectious lesions, but it also can be transmitted in utero and via blood
transfusion.

Syphilis has a myriad of presentations and can mimic many other infections and
immune-mediated processes in advanced stages. The complex and variable
manifestations of the disease prompted Sir William Osler to remark that, "The
physician who knows syphilis knows medicine."

Pathophysiology: T pallidum is a delicate spiral bacterium 6-15 micrometers

long by 0.25 micrometers in diameter. It can survive only briefly outside of the
body; thus transmission almost always requires direct contact with the infectious
lesion(s).

T pallidum penetrates abraded skin or intact mucous membranes easily and

disseminates rapidly, although asymptomatically, via the blood vessels and
lymphatics.

The prominent histologic features of the human response to the presence of T

pallidum are vascular changes with associated endarteritis and periarteritis.

The initial lesion of primary syphilis develops at the site of transmission after an
incubation period of 10-90 days, with a mean of about 21-28 days, and then heals
spontaneously in 3-7 weeks.

Secondary syphilis develops about 4-10 weeks after the appearance of the
primary lesion and has a wide range of presentations. The most common
systemic manifestations include malaise, fever, myalgias, and arthralgias with a
generalized body rash and lymphadenopathy.

Symptomatic secondary syphilis usually resolves without treatment. The disease

then enters a latent stage that may be divided into early and late latent phases.
Early latent syphilis encompasses the first 1-2 years of the disease and is marked
by occasional relapses of active secondary lesions. During late latent syphilis, the
patient remains asymptomatic and generally noninfectious. About one third of
untreated patients develop tertiary syphilis, which involves a latency period
lasting years to decades and manifests as gummatous or cardiovascular syphilis
or neurosyphilis.

Congenital syphilis is not addressed in this article.

Frequency:

 In the US: Incidence of primary and secondary syphilis was about 100,000
cases in 1940, prior to the introduction of antibiotics. Incidence declined
steadily with antibiotic therapy to less than 10,000 cases by 1956. Over the
next 25 years, the incidence of syphilis rose to about 35,000 by the early
1980s and then began to decrease again because of safer sexual
practices associated with the AIDS epidemic of the 1980s. Recently, the
incidence has increased as a result of intravenous (IV) drug and crack
cocaine abuse, as well as illegal prostitution, to an incidence of over
45,000 cases in 1990. The incidence of syphilis steadily declined through
the 1990s; only 16,500 cases were reported in 1995.

Mortality/Morbidity:

 T pallidum is sensitive to the penicillins and is easily treatable in the early

stages.

 The morbidity of primary and secondary syphilis ranges from the

annoyance of the primary lesion to the more significant constitutional
systemic symptoms of secondary syphilis.

 Tertiary syphilis is associated with serious illness and disability; death may
result in approximately 20% of untreated patients.

Sex: Men have a higher incidence than women. A recent study by Garfinkel et al
indicates that among ED patients, women with suspected sexually transmitted
diseases (STDs) are screened less often for syphilis than men. This raises
concerns about underdiagnosis in women.

Age: Syphilis is most common during the years of peak sexual activity.

 Most new cases occur in both men and women aged 15-39 years, with the
highest infection rates in persons aged 20-29 years.

 Since latent syphilis can persist for years or decades, the manifestations of
tertiary syphilis often occur much later in life.

CLINICAL Section 3 of 10
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History: Since the manifestations of syphilis (particularly advanced syphilis) are
nonspecific and may masquerade as many other diseases, the physician must
keep a high index of suspicion regarding the possible diagnosis of syphilis during
the workup.

The clinician should carefully reconstruct the time course and description of all
symptoms and lesions and obtain a complete sexual history, including information
about condom use and the number and symptomatology of all partners.

 Primary syphilis

o Genital chancre - "Painless" until examined, then may be tender

o Frequently solitary, may be multiple

o Rash - Bilaterally symmetric

o Patchy alopecia

 Secondary syphilis

o Asymptomatic

o Positive serology

 Tertiary syphilis

o Mental status may be altered.

o Patients may have symptoms related to the cardiovascular,

musculoskeletal, or central nervous systems.

o Serologic findings are often negative.

Physical: Conduct the physical examination with the manifestations of primary,

secondary, and tertiary syphilis in mind. The lesions and exanthem of primary and
secondary syphilis are infectious, thus, gloves must be worn.

 Primary syphilis

o The chancre of primary syphilis usually begins as a single, painless

papule that rapidly becomes eroded and indurated. The ulcer has a
cartilaginous consistency at the edge and base.

o Chancres usually are located on the penis in heterosexual men, but

 in homosexual men may be found in the anal canal, mouth, or
external genitalia. Common primary sites in women include the
cervix and labia.

o Atypical primary lesions are common and may manifest as a

papular lesion without subsequent ulceration or induration.

o The primary lesion usually is associated with regional

lymphadenopathy that may be unilateral or bilateral. Inguinal
adenitis is usually discrete, firm, mobile, and painless, without
overlying skin changes.

 Secondary syphilis

o Secondary syphilis may present in many different ways but usually

includes a localized or diffuse mucocutaneous rash and generalized
nontender lymphadenopathy. The exanthem may be macular,
papular, pustular, or mixed.

o Typical early lesions are round, discrete, nonpruritic, and symmetric

macules distributed on the trunk and proximal extremities. Red
papular lesions also may appear on the palms, soles, face, and
scalp and may become necrotic. Patchy and nonpatchy alopecia
may occur. In intertriginous areas, papules may coalesce to form
highly infectious lesions called condylomata lata.

o Mucous patches are superficial mucosal erosions, usually painless,

that may develop on the tongue, oral mucosa, lips, vulva, vagina,
and penis.

o Constitutional symptoms of secondary syphilis include malaise, sore

throat, headache, fever, anorexia, and, rarely, meningismus.

o Other, less common, manifestations of secondary syphilis include

gastrointestinal involvement, hepatitis, nephropathy, proctitis,
arthritis, and optic neuritis.

 Symptomatic tertiary syphilis is the result of a chronic, progressive

inflammatory process that eventually produces clinical symptoms years to
decades after the initial infection.

 Gummatous syphilis manifests as coalescent granulomatous lesions that

usually affect skin, bone, and mucous membranes, but may involve any
organ system. The lesions often cause local destruction of the affected
organ system.
  Cardiovascular syphilis results from endarteritis of the aorta, subsequent
medial necrosis, aortitis, and aneurysm formation. Other large arteries may
be affected as well.

 Neurosyphilis may be asymptomatic or symptomatic. In asymptomatic

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

o Symptomatic neurosyphilis may manifest as syphilitic meningitis,

meningovascular syphilis, or parenchymatous neurosyphilis.

o Syphilitic meningitis usually develops within several years of initial

infection, and patients present with typical symptoms of meningitis,
including headache, nausea and vomiting, and photophobia, but are
typically afebrile. Patients may exhibit cranial nerve abnormalities.

o Meningovascular syphilis manifests 5-10 years after infection and is

the result of endarteritis, which affects small blood vessels of the
meninges, brain, and spinal cord. Patients may present with CNS
vascular insufficiency or outright stroke.

o Parenchymatous neurosyphilis results from direct parenchymal

CNS invasion by T pallidum and is usually a late development (15-
20 years after primary infection).

o Patients present with ataxia, incontinence, paresthesias, and loss of

position, vibratory, pain, and temperature sensations. Paresis and
dementia, with changes in personality and intellect, may develop.

DIFFERENTIALS Section 4 of 10
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Chancroid
Condyloma Acuminata
Herpes Simplex
Lymphogranuloma Venereum
Pityriasis Rosea
Psoriasis
Stevens-Johnson Syndrome
Warts, Genital

Other Problems to be Considered:

Primary genital syphilitic lesion
Herpes simplex (primary and recurrent infection)
Chancroid
Traumatic superinfected lesions
Carcinoma
Mycotic infection
Granuloma inguinale
Lichen planus
Psoriasis
Fungal infection
Venereal chlamydial infections

Cutaneous eruption of secondary syphilis

Drug eruptions
Pityriasis rosea
Psoriasis
Lichen planus
Viral exanthem

WORKUP Section 5 of 10
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Lab Studies:

 T pallidum cannot be cultivated in vitro and is too small to be seen under the
light microscope. Therefore, direct visualization of the organism by darkfield
microscopy, immunofluorescent staining, or serologic testing is necessary for
diagnosis of syphilis.

o Darkfield microscopic diagnosis of oral lesions should be avoided

because of the difficulty in distinguishing T pallidum morphologically
from Treponema macrodentium and Treponema microdentium, 2
nonpathologic treponemes found in the mouths of healthy individuals.

o A positive darkfield examination is the only means of making an

absolute diagnosis of syphilis.

 A negative darkfield examination does not rule out the diagnosis; and the
lesion should be reexamined the following day.

 The nontreponemal tests, VDRL and rapid plasma reagent (RPR), have
sensitivities approaching 80% in patients with symptomatic primary syphilis
and virtually 100% in patients with secondary syphilis.

o A positive VDRL should be quantified and titers followed at regular

 intervals after treatment.

o Most patients have nonreactive nontreponemal tests within several

years after successful treatment for syphilis, but a significant number
have persistently positive tests and are said to be serofast.
Unfortunately, the specificities of the VDRL and RPR tests are only
fair.

o False-positive results may result after immunizations, in acute viral or

bacterial infection, or during pregnancy.

o Patients with a reactive VDRL or RPR should have the result

confirmed by specific treponemal testing. These tests include the
fluorescent treponemal antibody absorption (FTA-ABS) and the
microhemagglutination assay for T pallidum (MHA-TP).

 Primary syphilis

o Serology and darkfield microscopy or immunofluorescent staining

confirms the diagnosis of syphilis.

o Little indication exists for other routine laboratory studies in the

evaluation of the lesion of primary syphilis.

 Secondary syphilis

o The manifestations of secondary syphilis may mimic many other

diseases, and laboratory evaluation should reflect the particular
presentation and the concerns of the physician.

o A complete blood count (CBC), electrolytes, erythrocyte

sedimentation rate (ESR), blood cultures, and other laboratory studies
may be appropriate, depending on the presentation of the patient.

 Tertiary syphilis

o Serology and darkfield microscopy are used in diagnosis.

o Evaluation of neurosyphilis requires a lumbar puncture and evaluation

of the CSF. Order routine laboratory studies as necessary.

TREATMENT Section 6 of 10
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Emergency Department Care: Base ED care on the symptoms of the individual

patient. Most patients need only supportive care in the ED; however, a patient
presenting with advanced neurosyphilis may require emergent intervention,
including possible intubation. The current treatment for syphilis, from the Centers
for Disease Control and Prevention 1993 STD treatment guidelines, is as follows;
for dosage information, see Medication section.

 Primary, secondary, and early latent syphilis (<1 y duration)

o Recommended treatment - Single dose of benzathine penicillin G, 2.4

million U IM

o Alternative treatments (only for nonpregnant, penicillin-allergic

patients) - 2-week course of doxycycline 100 mg PO bid, tetracycline
500 mg PO qid, or erythromycin base 500 mg PO qid

 Late latent syphilis (>1 y duration), syphilis of undetermined duration, and

late syphilis

o Recommended treatment - Benzathine penicillin G, 2.4 million U IM

once weekly for 3 consecutive weeks
o Alternative treatment - Doxycycline 100 mg PO bid or tetracycline 500
mg PO qid daily for 4 weeks

 Neurosyphilis

o Recommended treatment - Aqueous crystalline penicillin G, 2-4

million U IV q4h for 10-14 days
o Alternative treatment - Procaine penicillin, 2.4 million U IM qd, plus
probenecid 500 mg PO qid for 10-14 days

 Inform the patient of the possibility of a Jarisch-Herxheimer reaction that

may occur at the outset of treatment.

o Patients may develop transient fever and symptoms such as malaise,

chills, headache, and myalgias.
o Existing lesions may intensify temporarily.

o The reaction is quite common, develops within several hours after

beginning antibiotic treatment, and usually clears within 24 hours.

The goal of pharmacotherapy is to eradicate the causative organism of syphilis,

T pallidum. The drug of choice is parenteral penicillin G for all stages of syphilis.
Penicillin G benzathine is the only penicillin effective for single-dose therapy.
Since T pallidum resistance to penicillin has not emerged, the primary need for
alternative drugs in treating syphilis is reserved for penicillin-allergic patients.
Alternative regimens recommended for penicillin-allergic patients are
doxycycline, tetracycline, and erythromycin.

Although neither the tetracyclines nor erythromycin has been evaluated as

extensively as penicillin G in the treatment of syphilis, some evidence suggests
higher treatment failure rates in erythromycin-treated patients. Alternative
treatment regimens should be used only in cases of documented penicillin
allergy.

Drug Category: Antibiotics -- Empiric antimicrobial therapy must be

comprehensive and should cover all likely pathogens in the context of the clinical setting.

Penicillin G benzathine (Bicillin) -- Interferes with

synthesis of cell wall mucopeptide during active
Drug Name
multiplication, resulting in bactericidal activity against
susceptible microorganisms.
Disease for <1 year: 2.4 million U IM once in 2
injection sites
Adult Dose
Disease for >1 year: 2.4 million U in 2 injection sites
weekly for 3 doses
Disease for <1 year: 50,000 U/kg IM once; not to
exceed 2.4 million U
Pediatric Dose
Disease for >1 year: 50,000 U/kg IM weekly for 3
doses; not to exceed 2.4 million U per dose
Contraindications Documented hypersensitivity
Probenecid can increase effectiveness by decreasing
Interactions
clearance; tetracyclines can decrease effectiveness
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions Caution in impaired renal function
Doxycycline (Vibramycin, Doryx) -- Inhibits protein
synthesis and thus bacterial growth by binding with
Drug Name
30S and possibly 50S ribosomal subunits of
susceptible bacteria.
Adult Dose 300 mg/d PO in divided doses for 10 d
Pediatric Dose <8 years: Not recommended
>8 years: 2-5 mg/kg/d PO in 1-2 divided doses; not to
exceed 200 mg/d
<100 lbs (45 kg): 2 mg/lb/d (4.4 mg/kg/d) divided bid
 >100 lbs (45 kg): Administer as in adults
Documented hypersensitivity; severe hepatic
Contraindications
dysfunction
Antacids containing aluminum, calcium, magnesium,
iron, or bismuth subsalicylate decrease bioavailability;
can increase hypoprothrombinemic effects of
Interactions
anticoagulants; can decrease effects of oral
contraceptives, causing breakthrough bleeding and
increased risk of pregnancy
Pregnancy D - Unsafe in pregnancy
Photosensitivity may occur with prolonged exposure to
sunlight or tanning equipment; reduce dose in renal
impairment; consider drug serum level determinations
in prolonged therapy; exposure during tooth
Precautions
development (last half of pregnancy through age 8 y)
can cause permanent discoloration of teeth;
Fanconilike syndrome may occur with outdated
tetracyclines
Tetracycline (Sumycin) -- Inhibits bacterial protein
Drug Name synthesis by binding with 30S and possibly 50S
ribosomal subunit(s) of susceptible bacteria.
250-500 mg PO q6h
Mild to moderately severe infections: 500 mg PO bid
Adult Dose
or 250 mg qid for 7-14 d
Severe infections: 500 mg qid for 7-14 d
<8 years: Not recommended
Pediatric Dose
>8 years: 10-20 mg/lb (25-50 mg/kg) PO qid
Documented hypersensitivity; severe hepatic
Contraindications
dysfunction
Antacids containing aluminum, calcium, magnesium,
iron, or bismuth subsalicylate decrease bioavailability;
can decrease effects of oral contraceptives, causing
Interactions
breakthrough bleeding and increased risk of
pregnancy; can increase hypoprothrombinemic effects
of anticoagulants
Pregnancy D - Unsafe in pregnancy
Precautions Photosensitivity may occur with prolonged exposure to
sunlight or tanning equipment; reduce dose in renal
impairment; consider drug serum level determinations
in prolonged therapy; exposure during tooth
development (last half of pregnancy through age 8 y)
can cause permanent discoloration of teeth;
 Fanconilike syndrome may occur with outdated
tetracyclines
Erythromycin (Erythrocin, E-Mycin, EES) -- Indicated
Drug Name for treatment of infections caused by susceptible
strains including T pallidum.
250 mg stearate/base (or 400 mg ethylsuccinate) PO
q6h 1 h ac, or 500 mg q12h
Adult Dose
Alternatively, use 333 mg q8h; increase up to 4 g/d
depending on severity of infection
30-50 mg/kg/d (15-25 mg/lb/d) PO in divided doses;
Pediatric Dose
for severe infections, double dose
Contraindications Documented hypersensitivity; hepatic impairment
May increase toxicity of theophylline, digoxin,
carbamazepine, and cyclosporine; may potentiate
Interactions
anticoagulant effects of warfarin; lovastatin and
simvastatin increase risk of rhabdomyolysis
Pregnancy B - Usually safe but benefits must outweigh the risks.
Caution in liver disease; estolate formulation may
cause cholestatic jaundice; GI adverse effects are
Precautions
common (give doses pc); discontinue use if nausea,
vomiting, malaise, abdominal colic, or fever occur

FOLLOW-UP Section 8 of 10
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Further Outpatient Care:

 Patients treated for primary and secondary syphilis should have follow-up
VDRL at 3, 6, and 12 months after treatment.

o Most patients with primary syphilis who are treated adequately

have a nonreactive VDRL within 1 year, and almost all patients
treated for secondary syphilis have a negative VDRL result within 2
years.

o A small minority of patients remain seropositive in spite of

successful treatment.

o Therapy is considered a failure if the signs and symptoms of

syphilis return.
 o This occurs when the titer of the nontreponemal test increases 4-
fold or a 4-fold decrease from the initial VDRL titer does not occur
within 1 year.

 Patients with neurosyphilis should have follow-up at 6-month intervals for

at least 3 years with physical examinations and CSF and serologic testing.

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

Deterrence/Prevention:

 Safe sex practices

 Use of condoms

Complications:

 Cardiovascular disease

 CNS disease

 Membranous glomerulonephritis

 Paroxysmal cold hemoglobinemia

 Irreversible end-organ damage

 Jarisch-Herxheimer reaction

Prognosis:

 The prognosis in primary and secondary syphilis is excellent. T pallidum

remains highly responsive to the penicillins and cure is likely.

 The prognosis in tertiary syphilis is less sanguine, although a significant

number of patients demonstrate cure with antibiotic therapy.

 The course of untreated syphilis was investigated in the Oslo study in

which 2000 patients were enrolled and over 1000 were monitored during
the period from 1891-1951.

o The mortality rate as a direct result of syphilis was about 20% in

this group, with most of those deaths resulting from cardiovascular
syphilis.
 o Over 60% of the subjects went through their lives with no apparent
ill effects of advanced disease.

 The Tuskegee study, which began in the 1930s, monitored a number of

African American males with syphilis over several decades and showed
similar results. (This study is notorious for the moral and ethical lapses
that occurred when these subjects were not treated after the development
of antibiotic therapy in the early 1940s.)

Patient Education:

 As with all STDs, patient education must stress the importance of safer
sexual practices and the need for prompt medical evaluation of chancres
and other symptoms of STDs.

 For excellent patient education resources, visit eMedicine's Sexually

Transmitted Diseases Center and Pregnancy and Reproduction Center.
Also, see eMedicine's patient education articles Sexually Transmitted
Diseases, Syphilis, Birth Control Overview, and Birth Control FAQs.

MISCELLANEOUS Section 9 of 10
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Medical/Legal Pitfalls:

 Failure to conduct testing for syphilis because the lesion or rash is

suggestive of another entity is the major potential pitfall in patients with
syphilis.

o Given the ability of syphilis to masquerade as a number of

illnesses, routine serologic testing for syphilis is prudent when
rendering a diagnosis of pityriasis rosea or another generalized
rash. Similar logic applies to genital lesions.

o If the alternative diagnosis is an STD, such as chancroid, good

medical care includes testing for syphilis.

o Regardless of the symptoms, testing for coexisting syphilis is

recommended when diagnosing other STDs, such as urethritis or
cervicitis. An increase in attention to this issue in women with
suspected STDs is needed.

Special Concerns:

 Pregnancy
 o The penicillin regimen appropriate to the stage of disease is the
only treatment recommended.

o Do not administer tetracycline or doxycycline during pregnancy.

BIBLIOGRAPHY Section 10 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

 Brillman JC, Quenzer RW: Infectious Disease in Emergency Medicine.

2nd ed. Lippincott-Raven; 1998:686-92.
 Clinical Effectiveness Group: National guidelines for the management of
early syphilis. Sex Transm Dis 1999; 75: 29-33.
 Csonka GW, Oates JK: Sexually Transmitted Diseases. WB Saunders;
1990:227-76.
 Garfinkel M, Blumstein H: Gender differences in testing for syphilis in
emergency department patients diagnosed with sexually transmitted
diseases. J Emerg Med 1999 Nov-Dec; 17(6): 937-40[Medline].
 Hoeprich PD, Jordan MC: Infectious Diseases. 4th ed. Lippincott-Raven;
1989:666-83.
 Isselbacher KJ, Braunwald E, Wilson JD: Harrison's Principles of Internal
Medicine. 13th ed. McGraw-Hill; 1994:726-37.