(Last Revision: May 17 2005)
Discuss all cases of suspected or proven syphilis with the attending physician
prior to treatment, regardless of the stage or duration of infection.
A serologic test for syphilis (STS) should be performed on all patients who have
not been tested within the preceding 3 months and on any patient with
undiagnosed genital lesions, regardless of time since the previous serology.
Obtain a stat RPR for all patients with genital or perianal ulcerations that are not
typical of genital herpes, warts that are not typical for condylomata acuminata,
any undiagnosed general skin rash, or a patient who is a sexual contact of a
partner with syphilis. It may be necessary in some cases to dilute the serum 1:8
to detect a positive RPR (prozone phenomenon). Perform a darkfield (DF)
examination of any genital, anal, or perianal ulcerative lesion not typical of genital
Staging is as follows:
1. Primary: Dark Field positive material from a chancre-like lesion, with
positive serology (RPR+/FTA+ or RPR-/FTA+) and no past history of
syphilis. In principal, primary syphilis should not be diagnosed without a
positive darkfield microscopy.
2. Secondary: signs of systemic infection (bilaterally symmetric macular/
papular/papulosquamous/pustular skin lesions, alopecia, loss of
eyelashes and lateral eyebrows, condylomata lata, mucous patches,
generalized lymphadenopathy, fever and malaise) with positive serology
3. Early latent: patient without symptoms/signs of syphilis with positive
serology (RPR+/FTA+) known to have had in the past year: a) negative
STS, b) symptoms of primary or secondary syphilis, c) exposure to known
case of early (primary, secondary, or early latent) syphilis, or d) > 4-fold
increase in titer on serial RPR.
4. Late latent: patient without symptoms/signs of syphilis with positive
serology (RPR+/FTA+) and no prior treatment for syphilis who does not
meet definition of early latent disease.
5. Establishing a diagnosis of syphilis in a patient with a prior history of
treated syphilis requires a positive DF exam or > 4-fold rise in RPR titer.
6. Persistent infection is suggested by persistent/recurrent signs or
symptoms of syphilis, a > 4-fold increase in RPR titer, or the failure of a
high-titer RPR (> 1:32) to decrease > 4-fold within 12 months.
7. In ALL stages of syphilis, patients should be interviewed about possible
neurologic symptoms (headache, photophobia, dizziness, memory loss,
weakness or numbness of arms or legs, seizures, difficulty concentrating,
problems with vision or hearing). Those with any suggestion of
neurologic problems should have a neurologic exam by the attending
physician. A CSF exam should be considered, in consultation with the
clinic physician, if any of the following are present:
a) Neurologic or ophthalmologic signs or symptoms
b) Documented treatment failure (recurrent symptoms or 4-fold-rise
in absence of likely re-infection)
c) Other evidence of active syphilis (aortitis, gumma, iritis)
d) HIV infection
8. All patients with active syphilis should be advised to have an HIV test and
a follow-up HIV test in 3 months.
For all stages of syphilis, IM penicillin G is the treatment of choice, and is the only
therapy with documented efficacy for neurosyphilis or syphilis in pregnancy. If
doxycycline or erythromycin are given, it is extremely important to counsel the
patient firmly about adherence to the regimen, since missing only a few doses
will significantly increase the failure rate.
1. Early syphilis (primary, secondary, and early latent syphilis)
a) Long-acting benzathine penicillin G (LAB) 2.4 million units IM
b) Doxycycline 100 mg BID PO for 14 days; use only if patient is
allergic to penicillin.
Note 1: All penicillin injections should be given in a divided dose, half of
the recommended dose to the upper outer quadrant of each hip. The
patient should be asked to wait 20-30 minutes, before leaving the clinic, in
case of allergic response to the medication.
Note 2: The Jarisch-Herxheimer reaction is an acute febrile reaction
frequently accompanied by headache and myalgia, and other symptoms
that usually occurs within the first 24 hours following treatment for early
syphilis. Patients should be informed about this possible adverse
Note 3: The use of alternative treatments, including azithromycin and
ceftriaxone may be considered in certain cases, but should be discussed
with the attending physician.
2. Late latent syphilis
a) LAB 2.4 million units IM weekly for 3 doses (total 7.2 million units)
b) Doxycycline 100 mg PO BID x 28 days; use only if patient is
allergic to penicillin.
Note: If a patient misses a dose of penicillin in the course of weekly
therapy for late syphilis, the sequence of injections must be restarted.
3. Neurosyphilis, both symptomatic and asymptomatic
Patient with neurosyphilis need to be managed in combination with the
AIDS/ID clinic or inpatient medicine service. There are no satisfactory
alternatives to penicillin for treatment of neurosyphilis and those with a
history of penicillin allergy should be skin-tested and, if necessary,
a) The treatment of choice is hospitalization for penicillin G, 18-24
million units IV daily for 14 days, followed by weekly injections of
LAB 2.4 million units for 3 weeks.
b) Procaine penicillin G 2.4 million units IM daily plus probenecid 500
mg PO qid, both for 10-14 days, followed by weekly injections of
LAB 2.4 million units for 21 days.
4. Syphilis in pregnancy: Penicillin is the only treatment known to be
effective in preventing or treating syphilis in the fetus. In case of penicillin
allergy, refer for penicillin desensitization and treatment. Treatment of
early syphilis in women in the second half of pregnancy should be
undertaken with obstetrical consultation as the Jarisch-Herxheimer
reaction may lead to premature labor and fetal distress.
Treatment failure is common in all stages of syphilis, even with recommended
treatment regimens. In addition to resolution of signs and symptoms, the
serological response is used to define cure. Most patients should be seen on the
following schedules (although visits may be individualized by the clinic
1. Early syphilis (primary, secondary, early latent):
a. Clinic examination after 1 week.
b. Repeat serology (quantitative RPR) 6 and 12 months after
2. Late syphilis:
a. Repeat serology (quantitative RPR) 6, 12 and 24 months after
b. Evaluate for neurosyphilis if the RPR titer increases 4-fold, an
initially high titer ( 1:32) fails to fall 4-fold in 12-24 months, or if
signs or symptoms of syphilis develop.
a. Repeat serology (quantitative RPR) at 6, 12 and 24 months after
b. Follow-up CSF examination at 6-month intervals until cell count is
D. Management of contacts
Refer all patients with syphilis to CDPHE DIS staff for partner notification
1. To determine risk of partners, the time periods before treatment are a) 3
months plus duration of symptoms for primary syphilis; b) 6 months plus
duration of symptoms for secondary syphilis; and c) 1 year for early
2. Contacts of patients with primary, secondary, or early latent syphilis:
Routine history, examination, and syphilis serology, including stat RPR;
administer epidemiologic treatment for all contacts within the preceding 3
months, regardless of syphilis serology (LAB 2.4 million units IM x 1).
Treponomal test (FTA) should be performed for all contacts to syphilis,
since they may be positive when non-treponomal tests (RPR, VDRL) are
still negative in early syphilis.
3. Contacts of patients with late syphilis: serology (RPR, FTA) in all long-
term contacts, and for the children of infected women; treat only if
4. Contacts of patient with latent syphilis of unknown duration (no prior
serologic test) should be managed as are contacts of early latent syphilis
even though the source contact patient is typically treated for possible
late latent infection.
5. For purposes of partner notification and presumptive treatment of
exposed sex partners, patients with syphilis of unknown duration who
have high treponemal serologic tests (i.e., >1:32) can be assumed to
have early syphilis. However, serologic tests should not be used to
differentiate early from latent syphilis for the purpose of treatment.
6. Advise sexual abstinence for 1 week after one-time penicillin for early
syphilis therapy or until completion of treatment with other regimens.
E. Syphilis in HIV-Infected Patients
1. Clinic physician should see all HIV-positive syphilis patients to assess the
presence of neurologic problems.
2. Patients with primary, secondary, and confirmed early latent syphilis
should be treated with LAB 2.4 million units once, as for HIV-negative
patients. Those with late latent syphilis, or syphilis of unknown duration,
should have a CSF exam prior to treatment, especially if neurologic
symptoms or signs, treatment failure, or low CD4 count (<200) are
present. If the patient has a normal CSF exam then he/she should be
treated with LAB 2.4 mu weekly x 3; if the patient has CSF consistent with
neurosyphilis then he/she should be managed the same as patients with
neurosyphilis. Depending on the patient’s circumstances, the attending
physician has the discretion to authorize starting treatment prior to CSF
3. Penicillin regimens should be used whenever possible for all stages of
syphilis in HIV-infected patients. Penicillin-allergic patients should be
skin-tested and, if positive, considered for desensitization. The efficacy of
alternative non-penicillin regimens in HIV-infected persons has not been
4. In order to detect early treatment failure, it is important that HIV-infected
patients with early syphilis have follow-up serology performed at 3, 6, 9,
12, and 24 months, while those with late latent syphilis should have
follow-up serology performed at 6, 12, 18, and 24 months after therapy.
Patients with late latent syphilis who develop symptoms consistent with
syphilis, a 4-fold increase in RPR titer, or whose RPR fails to decline
4-fold should have a repeat CSF examination and re-treatment for late
latent syphilis. Patients with early syphilis whose titers increase or fail to
decrease 4-fold within 6 months should undergo a CSF exam and be
retreated as for late latent syphilis.