Stage I is characterized by a small genital papule or vesicle that appears between
3 and 30 days after exposure. The patient usually is asymptomatic; the ulcer heals
rapidly and leaves no scar. This primary lesion is consistent with that reported by
S.F. Many patients with LGV recall no primary lesion. Stage II is characterized by
acute, painful lymphadenitis with bubo formation (the inguinal syndrome); it is often
accompanied by pain and fever, as illustrated by S.F. Without treatment, the buboes
may rupture, forming numerous sinus tracts that drain chronically. Adenopathy above
and below the inguinal ligament results in the “groove sign.” Healing occurs slowly,
and most patients suffer no serious sequelae. Patients in this stage may also present
with an anogenitorectal syndrome, which is accompanied by proctocolitis and
hyperplasia of intestinal and perirectal lymphatic tissue. Stage III is characterized by
perirectal abscesses, rectovaginal fistulae (in women), rectal strictures, and genital
68 Appropriate treatment of stage II LGV usually prevents these late
An acute anorectal syndrome of LGV occurs in homosexual men who acquire the
infection through rectal receptive intercourse. In these cases, a primary anal ulcer
may be noted with associated inguinal adenopathy (anal lymphatics drain to inguinal
nodes). Subsequently, acute hemorrhagic proctocolitis occurs with tenesmus, rectal
pain, constipation, and a mucopurulent, bloody rectal discharge. Rectal biopsy may
show granulomatous colitis, mimicking Crohn’s disease. Perirectal pelvic
CASE 72-6, QUESTION 2: How should S.F. be treated?
Current CDC recommendations for LGV include doxycycline 100 mg PO twice
daily or erythromycin base 500 mg PO 4 times a day for 21 days.
intervention may be needed for later forms of the disease. Azithromycin 1 g weekly
for 3 weeks may be effective, as well as fluoroquinolones, but clinical data on its use
Syphilis is caused by the spirochete, Treponema pallidum. The rates of primary and
secondary syphilis in the United States increased in the late 1980s secondary to crack
cocaine use (and associated unsafe sex practices), but from 1990 to 2000 the rates
have decreased to those reported in 1941 when reporting began, representing a
70 However, the number of cases of primary and
secondary syphilis have steadily risen since 2000, reaching a high of 17,375 cases in
4 Another concern is that syphilis facilitates the transmission of HIV, and a high
proportion of syphilis is reported in HIV-positive MSM.
congenital syphilis have not increased until 2013, when 348 cases were reported to
the CDC representing 8.7 cases per 100,000 individuals, a 0.3% increase from 2012
3 This increase was attributable to the increase in the rate of primary and
secondary syphilis cases in the West among females during 2010 to 2013. The
Healthy People 2020 (HP) goals for primary and secondary syphilis among women is
1.4 cases per 100,000 individuals and among men it is 6.8 cases per 100,000
The clinical manifestations of syphilis have not changed appreciably since their
first description. However, early diagnosis, treatment, and greater physician/patient
awareness of the disease have reduced the incidence of its severe forms. Penicillin
continues to be the mainstay of therapy.
syphilis. Are D.M.’s symptoms consistent with this infection?
The average incubation period for syphilis is 3 weeks and ranges from 10 to 90
72 During this incubation period, T. pallidum can be demonstrated in the lymph
and blood. The primary chancre develops at the site of inoculation as a painless
papule that becomes ulcerated and indurated. The ulcer is nontender and filled with
spirochetes. The chancre usually involves the penis in the heterosexual male; the
penis or anus in the homosexual male; and the vulva, perineum, or cervix in the
female. Occasionally, the lip or tongue is involved. Regional lymph nodes are
enlarged, firm, and nontender. Unfortunately, the typical chancre described earlier
often is missed, particularly in women or homosexual men.
primary chancre resolves spontaneously, usually in 2 to 6 weeks. The differential
diagnosis of genital ulcers also includes chancroid and genital herpes. Like
chancroid, genital herpes produces painful, superficial, nonindurated ulcers with
tender inguinal adenopathy. However, unlike chancroid, lesions of genital herpes
characteristically proceed through a vesicular state and often are associated with
urethritis, cervicitis, and constitutional symptoms, such as fever and chills. Syphilis
can be differentiated from herpes by a nonpainful versus painful lesion, a papular
versus vesicular appearance, and single versus multiple lesions. Chancroid is more
Surveillance 2013. Atlanta, GA: US Dept of Health and Human Services; 2014.
Approximately 6 weeks after a chancre first appears, the untreated patient manifests
signs and symptoms of the secondary stage of syphilis. This stage is currently
evidenced by D.M. Skin lesions of secondary syphilis may erupt in a variety of
patterns and are usually widespread in distribution. A macular lesion is often the
earliest manifestation in this stage. The lesion is round or oval, occurs primarily on
the trunk, and is rose or pink in color. As lesions mature, they become papular or
nodular with scaling (the so-called papulosquamous rash). The differential diagnosis
of diffuse papulosquamous rashes includes psoriasis, pityriasis rosea, and lichen
planus. In syphilis, the palms and soles are characteristically involved, and oral
lesions (mucous patches) may occur. Generalized lymphadenopathy usually is
present, and patchy alopecia may be seen. The most infectious lesion of secondary
syphilis is condyloma latum. Condylomata lata are characteristically wet, indurated
lesions occurring primarily in the perineum or around the anus as a result of direct
spread from the primary lesion. Laboratory studies sometimes reveal anemia,
leukocytosis, or an increased erythrocyte sedimentation rate. Other manifestations of
secondary syphilis include mild hepatitis, aseptic meningitis, uveitis, neuropathies,
By definition, untreated, asymptomatic persons with serologic evidence for syphilis
have latent syphilis. The latent stage is divided into two phases: the early latent (<1
year’s duration) and late latent (>1 year’s duration). In the Oslo study of patients with
untreated syphilis, 25% experienced secondary relapses, usually within the first
75 Patients who relapse to the secondary stage are infectious; those in the late
latent stage are not infectious and are immune to reinfection with T. pallidum.
Serious morbidity and mortality are caused by pathologic progresses involving the
skin, bones, central nervous system, and cardiovascular system. Infectious
granulomas (gummas), the characteristic lesions of tertiary syphilis, are observed
infrequently. Most gummas respond quickly to specific therapy, although if critical
organs are involved (heart, brain, liver), they can be fatal.
manifestations of syphilitic cardiovascular disease are aortic insufficiency and
aortitis, with aneurysm of the ascending aorta.
Neurosyphilis may be classified as asymptomatic early or late, meningeal,
parenchymatous, or gummatous. Although neurosyphilis has been a rare complication
for more than 40 years because of the widespread of use of penicillin, syphilitic
meningitis, an early form of neurosyphilis, may be more common in HIV-positive
77 Late neurosyphilis may be asymptomatic or accompanied by a variety of
manifestations; the most common syndromes are meningovascular syphilis, general
paresis, tabes dorsalis (locomotor ataxia), and optic atrophy. In patients with
asymptomatic neurosyphilis, examination of the cerebrospinal fluid (CSF) typically
reveals mononuclear pleocytosis, an elevated protein concentration, and a positive
Patients with asymptomatic neurosyphilis are at increased risk for experiencing
neurologic disease. Meningovascular syphilis, accounting for almost 38% of all
cases of neurosyphilis, typically begins abruptly with hemiparesis or hemiplegia,
78 General paresis is characterized by extensive parenchymal
damage and includes abnormalities associated with the mnemonic PARESIS
(personality, affect, reflexes [hyperactive], eye [Argyll Robertson pupil], sensorium
[hallucination, delusions, illusions], intellect [decreased recent memory,
calculations, judgment], and speech). Tabes dorsalis occurs after demyelinization of
the spinal cord. Symptoms observed include an ataxic, wide-based gait and foot slap;
paresthesias; bladder irregularities; impotence; areflexia; and loss of position, deep
pain, and temperature sensation. The Argyll Robertson pupil, seen in both paresis
and tabes dorsalis, is a small, irregular pupil that reacts to accommodation but not to
CASE 72-7, QUESTION 2: Evaluate D.M.’s laboratory findings.
Exudate expressed from the chancre or from condyloma latum is examined with a
dark-field microscope. The diagnosis of syphilis is made if spirochetes with
characteristic corkscrew morphology and mobility are present. Dark-field
examination is the most specific and sensitive method but only with an experienced
80 Three dark-field examinations on consecutive days should be
performed before considering the test negative in suspected primary syphilis. This
technique and other methods, such as DFA and PCR, which detect T. pallidum
directly from exudate or tissue are definitive diagnostic methods for syphilis.
Serologic tests become reactive during the primary stage, but they may be negative at
the time of presentation with primary syphilis. When the history or examination
suggests primary syphilis, a VDRL should be sent to the laboratory, or an RPR test
should be performed in the clinic (see discussion on nontreponemal tests, next). If
initial serology and dark-field examinations are negative, the serology should be
repeated in 1 to 4 weeks to exclude primary syphilis. If the dark-field examination is
positive, an RPR may still be ordered to establish a baseline for follow-up after
Serologic tests are uniformly positive in secondary syphilis.
are used for the serodiagnosis of syphilis: nontreponemal tests, which measure serum
concentrations of reagin (antibody to cardiolipin), and treponemal tests, which detect
the presence of antibodies specific for T. pallidum.
Nontreponemal tests are not specific for T. pallidum but can be quantified. They are
inexpensive and useful for screening large numbers of people. The most widely used
nontreponemal tests are the VDRL test and the RPR Card Test. The RPR test is the
most widely used because it is simpler to perform than the VDRL. Although they are
equally valid assays, results of the VDRL and RPR are not interchangeable; thus, the
same test should be used throughout the posttreatment monitoring period.
The result reported in the quantitative VDRL test is the most dilute serum
concentration with a positive reaction. This test may be used to follow the decline in
VDRL titer after effective therapy (see Case 72-7, Question 5). In some individuals,
a serofast reaction occurs in which nontreponemal antibodies may remain at a low
titer for up to their entire lives. When false-positive tests occur, the titer usually is
low (e.g., VDRL or RPR titer of 1:8).
In secondary syphilis, sensitivity of the RPR
and VDRL approach 100% owing to the high antibody concentrations.
Specific treponemal tests, such as FTA-ABS, T. pallidum particle agglutination
relatively difficult and expensive to perform, they are not traditionally used for
CASE 72-7, QUESTION 3: How should D.M. be treated?
The CDC recommends penicillin G for the treatment of all stages of syphilis
2 Every effort should be made to rule out penicillin allergy before
choosing alternative agents. Considering that penicillin-resistant T. pallidum has
never been observed, treatment regimens for syphilis have changed relatively little
As shown in Table 72-4, recommended therapy for primary, secondary, or latent
syphilis (with negative findings in the CSF) of less than 1 year’s duration is a single,
IM 2.4 million-unit dose of benzathine penicillin G. If penicillin is contraindicated,
tetracycline 500 mg PO 4 times a day or doxycycline 100 mg PO twice a day for 14
days are the main alternatives. If the patient is allergic to penicillin, is not pregnant,
and cannot receive tetracycline or doxycycline, a 10- to 14-day regimen of
ceftriaxone 1 g IM or IV every day or a single 2 g dose of azithromycin are options.
The use of erythromycin as an alternative is no longer recommended by the CDC
because of its poor efficacy. The optimal dose, duration, and efficacy of these
alternative regimens are not well-defined, necessitating close follow-up of patients.
However, recent studies have shown that azithromycin 2 g PO as a 1-time dose is at
least equivalent to benzathine penicillin G.
85 Skin testing should be performed for
individuals who claim allergy to penicillin. If the patient is truly allergic, he or she
2 Late latent syphilis (>1 year’s duration) and tertiary syphilis
(gummas or cardiovascular syphilis) are treated with IM benzathine penicillin G
(50,000 units/kg, up to 2.4 million-units) weekly for a total of 3 weeks.
CASE 72-7, QUESTION 4: Would D.M.’s treatment differ if his CSF had tested positive for syphilis?
Neurosyphilis can present at any stage of syphilis. When conventional IM doses of
benzathine penicillin G are administered, measurable levels of penicillin are not
obtainable in the CSF. However, this does not mean that penicillin does not
concentrate in meningeal tissue.
86 Treatment failures, as well as late clinical
progression to neurosyphilis, can occur after treatment with the recommended IM
regimen. After one dose, benzathine penicillin reaches peak plasma concentrations
slower (13–24 hours) but with more prolonged treponemicidal plasma
concentrations (7–10 days) when compared with procaine penicillin (1–4 hours to
peak; 12–24 hour treponemicidal plasma concentrations).
penicillin failures in the 1970s has resulted in the CDC recommending treatment with
aqueous crystalline penicillin G, 3 to 4 million-units IV every 4 hours, or 18 to 24
million-units per day continuous infusion for 10 to 14 days. Alternatively,
neurosyphilis can be treated with concurrent procaine penicillin (2.4 million-units
IM daily) and probenecid (500 mg PO 4 times a day) for 10 to 14 days. Some experts
add benzathine penicillin G (2.4 million-units IM once a week for up to 3 weeks)
after the completion of aqueous penicillin G or procaine penicillin.
should be desensitized and treated with an appropriate penicillin regimen. Some data
suggest that ceftriaxone 2 g IM or IV daily for 10 to 14 days can be used as an
alternative in patients whose concern for cross-sensitivity between ceftriaxone and
2 Alternatively, the World Health Organization recommends
penicillin-allergic nonpregnant patients receive either doxycycline 200 mg PO twice
a day or tetracycline 500 mg PO 4 times a day for 30 days.
Treatment Guidelines for Syphilis
Stage Recommended Regimen Alternative Regimen
Early (primary, secondary, or early
Benzathine penicillin G 2.4 millionunits single dose IM
Tetracycline 500 mg PO QID for
Ceftriaxone 1 g IM/IV every day
Late latent or latent syphilis of
Lumbar puncture Lumbar puncture
If CSF normal: benzathine penicillin
G 2.4 million-units/week × 3 weeks
If CSF normal: doxycycline 100 mg
Tetracycline 500 mg PO QID for
If CSF abnormal: Treat as If CSF abnormal: treat as
Aqueous crystalline penicillin G 18–
24 million-units IV every day × 10–
Procaine penicillin 2.4 million-units
IM daily plus probenecid 500 mg
Congenital Aqueous crystalline penicillin G
units/kg/dose IV q12h during the
first 7 days of life, and every 8
hours thereafter for a total of 10
If CSF normal: benzathine penicillin
G 50,000 units/kg/dose IM in a
units/kg/dose IM a day in a single
Syphilis in pregnancy According to stage According to stage
aSome experts recommend repeating this regimen after 7 days for HIV-infected patients.
regimens to provide a comparable total duration of therapy.
cAdministered as 3–4 million-units IV every 4 hours or continuous infusion.
Adapted from Workowski KA, Bolan GA; Centers for Disease Control and Prevention (CDC). Sexually
transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep. 2015;64(RR-03):1–137.
Physical examination and a quantitative VDRL or RPR test for primary and
secondary syphilis should be repeated at least 6 and 12 months after therapy.
Retreatment should be considered when the RPR or VDRL titer does not decline
fourfold in 6 months. Patients with HIV coinfection should receive periodic serologic
72 Patients with latent syphilis should be retested 6, 12, and 24 months after
treatment. Close serologic monitoring is necessary if antibiotics other than penicillin
months; CSF examinations should be repeated at 6-month intervals until normal. If
still abnormal at 2 years, retreatment should be considered. Return of lesions, a
fourfold increase in titer, or a titer of 1:8 that does not fall at least fourfold within 12
months necessitates retreatment. Suspected treatment failures, especially with
Within 2 years, most patients with early syphilis become seronegative. However,
if the disease is treated during the late stages, complete seroreversion may not occur.
Patients treated with oral doxycycline or erythromycin are less likely to become
88 Therapy is considered adequate in patients who never become
seronegative as long as the titer decreases fourfold. Although the disease process
may be halted in patients with tertiary syphilis, existing damage to the cardiovascular
or nervous systems cannot be reversed.
Although pregnancy may be associated with false-positive nontreponemal tests,
the presence of both a positive treponemal test (e.g., FTA-ABS) and a nontreponemal
test (e.g., RPR) virtually excludes a false-positive reaction.
determine whether N.W. already has been treated adequately. If she has previously
received adequate treatment and follow-up and shows no evidence of persistence or
recurrence of syphilis, then she requires no further therapy. Pregnancy has no known
effect on the clinical course of syphilis.
89 However, her infant should be observed
carefully. If N.W. has not been treated previously for syphilis, then she should be
treated with penicillin in the same doses recommended for nonpregnant women; some
experts recommend a second dose 1 week later of 2.4 million-units of benzathine
The goal of therapy should be to treat the mother with syphilis as soon as possible.
Syphilis transmission can occur transplacentally as early as 9 to 10 weeks’ gestation
via direct contact with lesions in the birth canal.
If the mother is left untreated,
70% to 100% of fetuses born to mothers with primary or 40% with secondary
syphilis may be aborted, stillborn, or born with congenital syphilis (see Case 72-8,
There is no completely satisfactory alternative for the pregnant woman with an
accelerated allergic reaction to penicillin. Tetracycline, as well as doxycycline,
should be avoided during pregnancy, especially during the second or third trimester,
because of tetracycline’s known effects on the fetus (tooth staining and inhibition of
93 Erythromycin has been used to treat pregnant patients with syphilis;
however, the transplacental transfer rate of erythromycin is inadequate,
explaining the increased rate of aborted or stillborn infants in erythromycin-treated
patients. Erythromycin and azithromycin are not recommended as alternative therapy
for syphilis during pregnancy.
2 A woman with a history of allergy to penicillin should
be skin tested; if allergy is confirmed, she should be desensitized and treated with
It is possible that the newer cephalosporins may ultimately prove to be
acceptable alternatives to penicillin G in the pregnant woman with syphilis, who is
allergic to penicillin, but there is sufficient evidence for the CDC to recommend their
use. Adequate treatment with penicillin can prevent up to 98% of fetal infections.
Serologic titers, at a minimum should be followed up at 28 to 32 weeks’ gestation
and at delivery. Monthly serologic titers may be considered in women at high risk for
reinfection or those in geographical areas of high syphilis rates; thereafter, she should
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