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This document is being maintained for historical purposes, but is now out of date. To view current guidelines please visit:

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1993 Sexually Transmitted Diseases Treatment Guidelines

09/24/1993

SUGGESTED CITATION
Centers for Disease Control and Prevention. 1993 Sexually
transmitted diseases treatment guidelines. MMWR 1993;42(No. RR-14):
{inclusive page numbers}.

CIO Responsible for this publication:
National Center for Prevention Services,
Division of Sexually Transmitted Diseases and HIV Prevention

Syphilis

General Principles

Background -
     
     Syphilis is a systemic disease caused by T. pallidum. Patients
with syphilis may seek treatment for signs or symptoms of primary
infection (ulcer or chancre at site of infection), secondary
infection (manifestations that include rash, mucocutaneous lesions,
and adenopathy), or tertiary infection (cardiac, neurologic,
ophthalmic, auditory, or gummatous lesions). Infections also may be
detected during the latent stage by serologic testing. Patients
with latent syphilis who are known to have been infected within the
preceding year are considered to have early latent syphilis; others
have late latent syphilis or syphilis of unknown duration.
Theoretically, treatment for late latent syphilis (as well as
tertiary syphilis) requires therapy of longer duration because
organisms are dividing more slowly; however, the validity of this
division and its timing are unproven.

Diagnostic Considerations and Use of Serologic Tests -
     
     Darkfield examinations and direct fluorescent antibody tests
of lesion exudate or tissue are the definitive methods for
diagnosing early syphilis. Presumptive diagnosis is possible with
the use of two types of serologic tests for syphilis: a)
nontreponemal (e.g., Venereal Disease Research Laboratory {VDRL}
and RPR, and b) treponemal (e.g., fluorescent treponemal antibody
absorbed {FTA-ABS} and microhemagglutination assay for antibody to
T. pallidum {MHA-TP}). The use of one type of test alone is not
sufficient for diagnosis. Nontreponemal test antibody titers
usually correlate with disease activity, and results should be
reported quantitatively. A fourfold change in titer, equivalent to
a change of two dilutions (e.g., from 1:16 to 1:4, or from 1:8 to
1:32), is necessary to demonstrate a substantial difference between
two nontreponemal test results that were obtained using the same
serologic test. A patient who has a reactive treponemal test
usually will have a reactive test for a lifetime, regardless of
treatment or disease activity (15%-25% of patients treated during
the primary stage may revert to being serologically nonreactive
after 2-3 years). Treponemal test antibody titers correlate poorly
with disease activity and should not be used to assess response to
treatment.

     Sequential serologic tests should be performed using the same
testing method (e.g., VDRL or RPR) by the same laboratory. The VDRL
and RPR are equally valid, but quantitative results from the two
tests cannot be directly compared because RPR titers are often
slightly higher than VDRL titers.

     Abnormal results of serologic testing (unusually high,
unusually low, and fluctuating titers) have been observed among
HIV-infected patients. For such patients, use of other tests (e.g.,
biopsy and direct microscopy) should be considered. However,
serologic tests appear to be accurate and reliable for the
diagnosis of syphilis and for evaluation of treatment response for
the vast majority of HIV-infected patients.

     No single test can be used to diagnose neurosyphilis among all
patients. The diagnosis of neurosyphilis can be made based on
various combinations of reactive serologic test results,
abnormalities of cerebrospinal fluid (CSF) cell count or protein,
or a reactive VDRL-CSF (RPR is not performed on CSF) with or
without clinical manifestations. The CSF leukocyte count is usually
elevated ( greater than 5 WBC/mm3) when active neurosyphilis is
present, and it is also a sensitive measure of the effectiveness of
therapy. The VDRL-CSF is the standard serologic test for CSF; when
reactive in the absence of substantial contamination of the CSF
with blood, it is considered diagnostic of neurosyphilis. However,
the VDRL-CSF may be nonreactive when neurosyphilis is present. Some
experts recommend performing an FTA-ABS test on CSF. The CSF
FTA-ABS is less specific (i.e., yields more false positives) for
neurosyphilis than the VDRL-CSF; however, the test is believed to
be highly sensitive.

Treatment -
     
     Parenteral penicillin G is the preferred drug for treatment of
all stages of syphilis. The preparation(s) used (i.e., benzathine,
aqueous procaine, or aqueous crystalline), the dosage, and the
length of treatment depend on the stage and clinical manifestations
of disease.

     The efficacy of penicillin for the treatment of syphilis was
well established through clinical experience before the value of
randomized controlled clinical trials was recognized. Therefore,
nearly all the recommendations for the treatment of syphilis are
based on expert opinion reinforced by case series, open clinical
trials, and 50 years of clinical experience.

     Parenteral penicillin G is the only therapy with documented
efficacy for neurosyphilis or for syphilis during pregnancy.
Patients with neurosyphilis and pregnant women with syphilis in any
stage who report penicillin allergy should almost always be treated
with penicillin, after desensitization, if necessary. Skin testing
for penicillin allergy may be useful for some patients and in some
settings (see Management of the Patient With a History of
Penicillin Allergy). However, minor determinants needed for
penicillin skin testing are not available commercially.

     The Jarisch-Herxheimer reaction is an acute febrile reaction -- 
accompanied by headache, myalgia, and other symptoms -- that may occur 
within the first 24 hours after any therapy for syphilis; patients should 
be advised of this possible adverse reaction. The Jarisch-Herxheimer 
reaction is common among patients with early syphilis. Antipyretics may 
be recommended, but there are no proven methods for preventing this 
reaction. The Jarisch-Herxheimer reaction may induce early labor or 
cause fetal distress among pregnant women. This concern should not 
prevent or delay therapy (see Syphilis During Pregnancy).

Management of Sex Partners -
     
     Sexual transmission of T. pallidum occurs only when
mucocutaneous syphilitic lesions are present; such manifestations
are uncommon after the first year of infection. However, persons
sexually exposed to a patient with syphilis in any stage should be
evaluated clinically and serologically according to the following
recommendations:

--   Persons who were exposed to a patient with primary, secondary,
     or latent (duration less than 1 year) syphilis within the preceding
     90 days might be infected even if seronegative, and therefore
     should be treated presumptively.

--   Persons who were sexually exposed to a patient with primary,
     secondary, or latent (duration less than 1 year) syphilis greater
     than 90 days before examination should be treated presumptively if
     serologic test results are not available immediately, and the
     opportunity for follow-up is uncertain.

--   For purposes of partner notification and presumptive treatment
     of exposed sex partners, patients who have syphilis of unknown
     duration and who have high nontreponemal serologic test titers (
     greater than or equal to 1:32) may be considered to be infected
     with early syphilis.

--   Long-term sex partners of patients with late syphilis should
     be evaluated clinically and serologically for syphilis.


     The time periods before treatment used for identifying at-risk
sex partners are 3 months plus duration of symptoms for primary
syphilis, 6 months plus duration of symptoms for secondary
syphilis, and 1 year for early latent syphilis.

Primary and Secondary Syphilis

Treatment
     Four decades of experience indicate that parenteral penicillin
G is effective in achieving local cure (healing of lesions and
prevention of sexual transmission) and in preventing late sequelae.
However, no adequately conducted comparative trials have been
performed to guide the selection of an optimal penicillin regimen
(i.e., dose, duration, and preparation). Substantially fewer data
on nonpenicillin regimens are available.

Recommended Regimen for Adults -
     Nonallergic patients with primary or secondary syphilis should
be treated with the following regimen:

     Benzathine penicillin G, 2.4 million units IM in a single
     dose.

NOTE: Recommendations for treating pregnant women and
HIV-infected persons for syphilis are discussed in separate
sections.

Recommended Regimen for Children -
     After the newborn period, children diagnosed with syphilis
should have a CSF examination to exclude a diagnosis of
neurosyphilis, and birth and maternal medical records should be
reviewed to assess whether the child has congenital or acquired
syphilis (see Congenital Syphilis). Children with acquired primary
or secondary syphilis should be evaluated (including consultation
with child-protection services) and treated using the following
pediatric regimen (see Sexual Assault or Abuse of Children).

     Benzathine penicillin G, 50,000 units/kg IM, up to the adult
     dose of 2.4 million units in a single dose.

Other Management Considerations
     All patients with syphilis should be tested for HIV. In areas
with high HIV prevalence, patients with primary syphilis should be
retested for HIV after 3 months.

     Patients who have syphilis and who also have symptoms or signs
suggesting neurologic disease (e.g., meningitis) or ophthalmic
disease (e.g., uveitis) should be fully evaluated for neurosyphilis
and syphilitic eye disease (including CSF analysis and ocular
slit-lamp examination). Such patients should be treated
appropriately according to the results of this evaluation.

     Invasion of CSF by T. pallidum with accompanying CSF
abnormalities is common among adults who have primary or secondary
syphilis. However, few patients develop neurosyphilis after
treatment with the regimens described in this report. Therefore,
unless clinical signs or symptoms of neurologic involvement are
present (e.g., auditory, cranial nerve, meningeal, or ophthalmic
manifestations), lumbar puncture is not recommended for routine
evaluation of patients with primary or secondary syphilis.

Follow-Up
     Treatment failures can occur with any regimen. However,
assessing response to treatment is often difficult, and no
definitive criteria for cure or failure exist. Serologic test
titers may decline more slowly among patients with a prior syphilis
infection. Patients should be re-examined clinically and
serologically at 3 months and again at 6 months.

     Patients with signs or symptoms that persist or recur or who
have a sustained fourfold increase in nontreponemal test titer
compared with either the baseline titer or to a subsequent result,
can be considered to have failed treatment or to be reinfected.
These patients should be re-treated after evaluation for HIV
infection. Unless reinfection is likely, lumbar puncture also
should be performed.

     Failure of nontreponemal test titers to decline fourfold by 3
months after therapy for primary or secondary syphilis identifies
persons at risk for treatment failure. Those persons should be
evaluated for HIV infection. Optimal management of such patients is
unclear if they are HIV negative. At a minimum, these patients
should have additional clinical and serologic follow-up. If further
follow-up cannot be assured, re-treatment is recommended. Some
experts recommend CSF examination in such situations.

     When patients are re-treated, most experts recommend
re-treatment with three weekly injections of benzathine penicillin
G 2.4 million units IM, unless CSF examination indicates that
neurosyphilis is present.

Management of Sex Partners
     Refer to General Principles, Management of Sex Partners.

Special Considerations

Penicillin Allergy -
     Nonpregnant penicillin-allergic patients who have primary or
secondary syphilis should be treated with the following regimen.

     Doxycycline 100 mg orally 2 times a day for 2 weeks
                           or
     Tetracycline 500 mg orally 4 times a day for 2 weeks.

     There is less clinical experience with doxycycline than with
tetracycline, but compliance is likely to be better with
doxycycline. Therapy for a patient who cannot tolerate either
doxycycline or tetracycline should be based upon whether the
patient's compliance with the therapy regimen and with follow-up
examinations can be assured.

     For nonpregnant patients whose compliance with therapy and
follow-up can be assured, an alternative regimen is erythromycin
500 mg orally 4 times a day for 2 weeks. Various ceftriaxone
regimens also may be considered.

     Patients whose compliance with therapy or follow-up cannot be
assured should be desensitized, if necessary, and treated with
penicillin. Skin testing for penicillin allergy may be useful in
some situations (see Management of the Patient With a History of
Penicillin Allergy).

     Erythromycin is less effective than other recommended
regimens. Data on ceftriaxone are limited, and experience has been
too brief to permit identification of late failures. Optimal dose
and duration have not been established for ceftriaxone, but
regimens that provide 8-10 days of treponemicidal levels in the
blood should be used. Single dose ceftriaxone therapy is not
effective for treating syphilis.

Pregnancy -
     Pregnant patients who are allergic to penicillin should be
treated with penicillin, after desensitization, if necessary (see
Management of the Patient With a History of Penicillin Allergy and
Syphilis During Pregnancy).

HIV Infection -
     Refer to Syphilis Among HIV-Infected Patients.

Latent Syphilis
     
     Latent syphilis is defined as those periods after infection
with T. pallidum when patients are seroreactive, but show no other
evidence of disease. Patients who have latent syphilis and who have
acquired syphilis within the preceding year are classified as
having early latent syphilis. Patients can be demonstrated to have
acquired syphilis within the preceding year on the basis of
documented seroconversion, a fourfold or greater increase in titer
of a nontreponemal serologic test, history of symptoms of primary
or secondary syphilis, or if they had a sex partner with primary,
secondary, or latent syphilis (documented independently as duration
less than 1 year). Nearly all others have latent syphilis of
unknown duration and should be managed as if they had late latent
syphilis.

Treatment
     Treatment of latent syphilis is intended to prevent occurrence
or progression of late complications. Although clinical experience
supports belief in the effectiveness of penicillin in achieving
those goals, limited evidence is available for guidance in choosing
specific regimens. There is very little evidence to support the use
of nonpenicillin regimens.

Recommended Regimens for Adults -
     These regimens are for nonallergic patients with normal CSF
examination (if performed).

     Early Latent Syphilis -
        Benzathine penicillin G, 2.4 million units IM in a single
        dose.

     Late Latent Syphilis or Latent Syphilis of Unknown Duration -
        Benzathine penicillin G, 7.2 million units total, administered
        as 3 doses of 2.4 million units IM each, at 1-week intervals.

Recommended Regimens for Children -
     After the newborn period, children diagnosed with syphilis
should have a CSF examination to exclude neurosyphilis, and birth
and maternal medical records should be reviewed to assess whether
the child has congenital or acquired syphilis (see Congenital
Syphilis). Older children with acquired latent syphilis should be
evaluated as described for adults and treated using the following
pediatric regimens (see Sexual Assault or Abuse of Children). These
regimens are for nonallergic children who have acquired syphilis
and who have had a normal CSF examination.

     Early Latent Syphilis -
        Benzathine penicillin G, 50,000 units/kg IM, up to the adult
        dose of 2.4 million units in a single dose.

     Late Latent Syphilis or Latent Syphilis of Unknown Duration
        Benzathine penicillin G, 50,000 units/kg IM, up to the adult
        dose of 2.4 million units, for three total doses (total 150,000
        units/kg up to adult total dose of 7.2 million units).


Other Management Considerations
     All patients with latent syphilis should be evaluated
clinically for evidence of tertiary disease (e.g., aortitis,
neurosyphilis, gumma, and iritis). Recommended therapy for patients
with latent syphilis may not be optimal therapy for the persons
with asymptomatic neurosyphilis. However, the yield from CSF
examination, in terms of newly diagnosed cases of neurosyphilis, is
low.

     Patients with any one of the criteria listed below should have
a CSF examination before treatment:

--   Neurologic or ophthalmic signs or symptoms;

--   Other evidence of active syphilis (e.g., aortitis, gumma,
     iritis);

--   Treatment failure;

--   HIV infection;

--   Serum nontreponemal titer greater than or equal to 1:32,
     unless duration of infection is known to be less than 1 year; or

--   Nonpenicillin therapy planned, unless duration of infection is
     known to be less than 1 year.

     If dictated by circumstances and patient preferences, CSF
examination may be performed for persons who do not meet the
criteria listed above. If a CSF examination is performed and the
results show abnormalities consistent with CNS syphilis, the
patient should be treated for neurosyphilis (see Neurosyphilis).

--   All syphilis patients should be tested for HIV.

Follow-Up
     Quantitative nontreponemal serologic tests should be repeated
at 6 months and again at 12 months. Limited data are available to
guide evaluation of the response to therapy for a patient with
latent syphilis. If titers increase fourfold, or if an initially
high titer ( greater than or equal to 1:32) fails to decline at
least fourfold (two dilutions) within 12-24 months, or if the
patient develops signs or symptoms attributable to syphilis, the
patient should be evaluated for neurosyphilis and re-treated
appropriately.

Management of Sex Partners
     Refer to General Principles, Management of Sex Partners.

Special Considerations

Penicillin Allergy -
     For patients who have latent syphilis and who are allergic to
penicillin, nonpenicillin therapy should be used only after CSF
examination has excluded neurosyphilis. Nonpregnant,
penicillin-allergic patients should be treated with the following
regimens.
     Doxycycline 100 mg orally 2 times a day
                    or
     Tetracycline 500 mg orally 4 times a day.

     Both drugs are administered for 2 weeks if duration of
infection is known to have been less than 1 year; otherwise, for 4
weeks.

Pregnancy -
     Pregnant patients who are allergic to penicillin should be
treated with penicillin, after desensitization, if necessary (see
Management of the Patient With a History of Penicillin Allergy and
Syphilis During Pregnancy).

HIV Infection -
     Refer to Syphilis Among HIV-Infected Patients.

Late Syphilis
     
     Late (tertiary) syphilis refers to patients with gumma and
patients with cardiovascular syphilis, but not to neurosyphilis.
Nonallergic patients without evidence of neurosyphilis should be
treated with the following regimen.

Recommended Regimen -
     Benzathine penicillin G, 7.2 million units total, administered
     as 3 doses of 2.4 million units IM, at 1-week intervals.

Other Management Considerations
     Patients with symptomatic late syphilis should undergo CSF
examination before therapy. Some experts treat all patients who
have cardiovascular syphilis with a neurosyphilis regimen. The
complete management of patients with cardiovascular or gummatous
syphilis is beyond the scope of these guidelines. These patients
should be managed in consultation with experts.

Follow-Up
     There is minimal evidence regarding follow-up of patients
infected with late syphilis. Clinical response depends partly on
the nature of the lesions.

Management of Sex Partners
     Refer to General Principles, Management of Sex Partners.

Special Considerations

Penicillin Allergy -
     Patients allergic to penicillin should be treated according to
treatment regimens recommended for late latent syphilis.

Pregnancy -
     Pregnant patients who are allergic to penicillin should be
treated with penicillin, after desensitization, if necessary (see
Management of the Patient With a History of Penicillin Allergy and
Syphilis During Pregnancy).

HIV Infection -
     Refer to Syphilis Among HIV-Infected Patients.

Neurosyphilis

Treatment
     Central nervous system disease can occur during any stage of
syphilis. A patient with clinical evidence of neurologic
involvement (e.g., ophthalmic or auditory symptoms, cranial nerve
palsies) with syphilis warrants a CSF examination. Although four
decades of experience have confirmed the effectiveness of
penicillin, the evidence to guide the choice of the best regimen is
limited.

     Syphilitic eye disease is frequently associated with
neurosyphilis, and patients with this disease should be treated
according to neurosyphilis treatment recommendations. CSF
examination should be performed on all such patients to identify
those patients with CSF abnormalities who should have follow-up CSF
examinations to assess response to treatment.

     Patients who have neurosyphilis or syphilitic eye disease
(e.g., uveitis, neuroretinitis, or optic neuritis) and who are not
allergic to penicillin should be treated with the following
regimen.


Recommended Regimen -
     12-24 million units aqueous crystalline penicillin G daily,
     administered as 2-4 million units IV every 4 hours, for 10-14 days.

     If compliance with therapy can be assured, patients may be
treated with the following alternative regimen.

Alternative Regimen -
     2.4 million units procaine penicillin IM daily, plus
     probenecid 500 mg orally 4 times a day, both for 10-14 days.

     The durations of these regimens are shorter than that of the
regimen used for late syphilis in the absence of neurosyphilis.
Therefore, some experts administer benzathine penicillin, 2.4
million units IM after completion of these neurosyphilis treatment
regimens to provide a comparable total duration of therapy.

Other Management Considerations
     Other considerations in the management of the patient with
neurosyphilis are the following:

--   All patients with syphilis should be tested for HIV.

--   Many experts recommend treating patients with evidence of
     auditory disease caused by syphilis in the same manner as for
     neurosyphilis, regardless of the findings on CSF examination.

Follow-Up
     If CSF pleocytosis was present initially, CSF examination
should be repeated every 6 months until the cell count is normal.
Follow-up CSF examinations also may be used to evaluate changes in
the VDRL-CSF or CSF protein in response to therapy, though changes
in these two parameters are slower and persistent abnormalities are
of less certain importance. If the cell count has not decreased at
6 months, or if the CSF is not entirely normal by 2 years,
re-treatment should be considered.

Management of Sex Partners
     Refer to General Principles, Management of Sex Partners.

Special Considerations

Penicillin Allergy -
     No data have been collected systematically for evaluation of
therapeutic alternatives to penicillin for treatment of
neurosyphilis. Therefore, patients who report being allergic to
penicillin should be treated with penicillin, after desensitization
if necessary, or should be managed in consultation with an expert.
In some situations, skin testing to confirm penicillin allergy may
be useful (see Management of the Patient With a History of
Penicillin Allergy).

Pregnancy -
     Pregnant patients who are allergic to penicillin should be
treated with penicillin, after desensitization if necessary (see
Syphilis During Pregnancy).

HIV Infection -
     Refer to Syphilis Among HIV-Infected Patients.

Syphilis Among HIV-Infected Patients

Diagnostic Considerations
     Unusual serologic responses have been observed among
HIV-infected persons who also have syphilis. Most reports involved
serologic titers that were higher than expected, but false-negative
serologic test results or delayed appearance of seroreactivity have
also been reported. Nevertheless, both treponemal and nontreponemal
serologic tests for syphilis are accurate for the majority of
patients with syphilis and HIV coinfection.

     When clinical findings suggest that syphilis is present, but
serologic tests are nonreactive or confusing, it may be helpful to
perform such alternative tests as biopsy of a lesion, darkfield
examination, or direct fluorescent antibody staining of lesion
material.

     Neurosyphilis should be considered in the differential
diagnosis of neurologic disease among HIV-infected persons.

Treatment
     Although adequate research-based evidence is not available,
published case reports and expert opinion suggest that HIV-infected
patients with early syphilis are at increased risk for neurologic
complications and have higher rates of treatment failure with
currently recommended regimens. The magnitude of these risks,
although not precisely defined, is probably small. No treatment
regimens have been demonstrated to be more effective in preventing
development of neurosyphilis than those recommended for patients
without HIV infection. Careful follow-up after therapy is
essential.

Primary and Secondary Syphilis Among HIV-Infected Patients

Treatment
     Treatment with benzathine penicillin G 2.4 million units IM,
as for patients without HIV infection, is recommended. Some experts
recommend additional treatments, such as multiple doses of
benzathine penicillin G as suggested for late syphilis, or other
supplemental antibiotics in addition to benzathine penicillin G 2.4
million units IM.

Other Management Considerations
     CSF abnormalities are common among HIV-infected patients who
have primary or secondary syphilis, but these abnormalities are of
unknown prognostic significance. Most HIV-infected patients respond
appropriately to currently recommended penicillin therapy; however,
some experts recommend CSF examination before therapy and
modification of treatment accordingly.

Follow-Up
     Patients should be evaluated clinically and serologically for
treatment failure at 1 month and at 2, 3, 6, 9, and 12 months after
therapy. Although of unproven benefit, some experts recommend
performing CSF examination after therapy (i.e., at 6 months).

     HIV-infected patients who meet the criteria for treatment
failure should undergo CSF examination and be retreated just as for
patients without HIV infection. CSF examination and re-treatment
also should be strongly considered for patients in whom the
suggested fourfold decrease in nontreponemal test titer does not
occur within 3 months for primary or secondary syphilis. Most
experts would re-treat patients with benzathine penicillin G 7.2
million units (as 3 weekly doses of 2.4 million units each) if the
CSF examination is normal.


Special Considerations

Penicillin Allergy -
     Penicillin regimens should be used to treat HIV-infected
patients in all stages of syphilis. Skin testing to confirm
penicillin allergy may be used (see Management of the Patient With
a History of Penicillin Allergy), but data on the utility of that
approach among immunocompromised patients are inadequate. Patients
may be desensitized, then treated with penicillin.

Latent Syphilis Among HIV-Infected Patients

Diagnostic Considerations
     Patients who have both latent syphilis (regardless of apparent
duration) and HIV infection should undergo CSF examination before
treatment.

Treatment
     A patient with latent syphilis, HIV infection, and a normal
CSF examination can be treated with benzathine penicillin G 7.2
million units (as 3 weekly doses of 2.4 million units each).

Special Considerations

Penicillin Allergy

     Penicillin regimens should be used to treat all stages of
syphilis among HIV- infected patients. Skin testing to confirm
penicillin allergy may be used (see Management of the Patient With
a History of Penicillin Allergy), but data on the utility of that
approach in immunocompromised patients are inadequate. Patients may
be desensitized, then treated with penicillin.

Syphilis During Pregnancy
     
     All women should be screened serologically for syphilis during
the early stages of pregnancy. In populations in which utilization
of prenatal care is not optimal, RPR-card test screening and
treatment, if that test is reactive, should be performed at the
time a pregnancy is diagnosed. In communities and populations with
high syphilis prevalence or for patients at high risk, serologic
testing should be repeated during the third trimester and again at
delivery. (Some states mandate screening at delivery for all
women.) Any woman who delivers a stillborn infant after 20 weeks
gestation should be tested for syphilis. No infant should leave the
hospital without the serologic status of the infant's mother having
been determined at least once during pregnancy.

Diagnostic Considerations
     Seropositive pregnant women should be considered infected
unless treatment history is clearly documented in a medical or
health department record and sequential serologic antibody titers
have appropriately declined.

Treatment
     Penicillin is effective for preventing transmission to fetuses
and for treating established infection among fetuses. Evidence is
insufficient, however, to determine whether the specific,
recommended penicillin regimens are optimal.

Recommended Regimens -
     Treatment during pregnancy should be the penicillin regimen
     appropriate for the woman's stage of syphilis. Some experts
     recommend additional therapy (e.g., a second dose of benzathine
     penicillin 2.4 million units IM) 1 week after the initial dose,
     particularly for those women in the third trimester of pregnancy
     and for women who have secondary syphilis during pregnancy.

Other Management Considerations
     Women who are treated for syphilis during the second half of
pregnancy are at risk for premature labor or fetal distress, or
both, if their treatment precipitates the Jarisch-Herxheimer
reaction. These women should be advised to seek medical attention
following treatment if they notice any change in fetal movements or
if they have contractions. Stillbirth is a rare complication of
treatment; however, since therapy is necessary to prevent further
fetal damage, that concern should not delay treatment. All patients
with syphilis should be tested for HIV.

Follow-Up
     Serologic titers should be checked monthly until adequacy of
treatment has been assured. The antibody response should be
appropriate for the stage of disease.

Management of Sex Partners
     Refer to General Principles, Management of Sex Partners.

Special Considerations

Penicillin Allergy -
     There are no proven alternatives to penicillin. A pregnant
woman with a history of penicillin allergy should be treated with
penicillin, after desensitization, if necessary. Skin testing may
be helpful for some patients and in some settings (see Management
of the Patient With a History of Penicillin Allergy).
Tetracycline and doxycycline are contraindicated during pregnancy.
Erythromycin should not be used because it cannot be relied upon to
cure an infected fetus.

Congenital Syphilis

Diagnostic Considerations

Who Should Be Evaluated -
     Infants should be evaluated for congenital syphilis if they
were born to seropositive (nontreponemal test confirmed by
treponemal test) women who meet the following criteria:

--   Have untreated syphilis;* or

--   Were treated for syphilis during pregnancy with erythromycin; or

--   Were treated for syphilis less than 1 month before delivery; or

--   Were treated for syphilis during pregnancy with the
     appropriate penicillin regimen, but nontreponemal antibody titers
     did not decrease sufficiently after therapy to indicate an adequate
     response ( greater than or equal to fourfold decrease); or

--   Do not have a well-documented history of treatment for
     syphilis; or

--   Were treated appropriately before pregnancy but had
     insufficient serologic follow-up to assure that they had responded
     appropriately to treatment and are not currently infected ( greater
     than or equal to fourfold decrease for patients treated for early
     syphilis; stable or declining titers less than or equal to 1:4 for
     other patients).

     No infant should leave the hospital without the serologic
status of the infant's mother having been documented at least once
during pregnancy. Serologic testing also should be performed at
delivery in communities and populations at risk for congenital
syphilis. Serologic tests can be nonreactive among infants infected
late during their mother's pregnancy.

* A woman treated with a regimen other than those recommended for
treatment of syphilis (for pregnant women or otherwise) in these
guidelines should be considered untreated.

Evaluation of the Infant -
     The clinical and laboratory evaluation of infants born to
women described above should include the following:

--   A thorough physical examination for evidence of congenital
     syphilis;

--   A quantitative nontreponemal serologic test for syphilis
     performed on the infant's sera (not on cord blood);

--   CSF analysis for cells, protein, and VDRL;

--   Long bone x-rays;

--   Other tests as clinically indicated (e.g., chest x-ray,
     complete blood count, differential and platelet count, liver
     function tests);

--   For infants who have no evidence of congenital syphilis on the
     above evaluation, determination of presence of specific
     antitreponemal IgM antibody by a testing method recognized by CDC
     as having either provisional or standard status;

--   Pathologic examination of the placenta or amniotic cord using
     specific fluorescent antitreponemal antibody staining.

Treatment

Therapy Decisions -
     Infants should be treated for presumed congenital syphilis if
they were born to mothers who, at delivery, had untreated syphilis
or who had evidence of relapse or reinfection after treatment (see
Congenital Syphilis, Diagnostic Considerations). Additional
criteria for presumptively treating infants with congenital
syphilis are as follows:

--   Physical evidence of active disease;

--   X-ray evidence of active disease;

--   A reactive VDRL-CSF or, for infants born to seroreactive
     mothers, an abnormal ** CSF white blood cell count or protein,
     regardless of CSF serology;

--   A serum quantitative nontreponemal serologic titer that is at
     least fourfold greater than the mother's titer ***;

--   Specific antitreponemal IgM antibody detected by a testing
     method that has been given provisional or standard status by CDC;

--   If they meet the previously cited criteria for "Who Should Be
     Evaluated," but have not been fully evaluated (see Congenital
     Syphilis, Diagnostic Considerations).

NOTE: Infants with clinically evident congenital syphilis
should have an ophthalmologic examination.

** In the immediate newborn period, interpretation of CSF test
results may be difficult; normal values vary with gestational age
and are higher in preterm infants.  Other causes of elevated values
also should be considered when an infant is being evaluated for
congenital syphilis.  Though values as high as 25 white blood
cells(WBC)/mm3 and 150 mg protein/dL occur among normal neonates,
some experts recommend that lower values (5 WBC/mm3 and 40 mg/dL)
be considered the upper limits of normal.  The infant should be
treated if test results cannot exclude infection.

*** The absence of a fourfold greater titer for an infant cannot be
used as evidence against congenital syphilis.


Recommended Regimens -
     Aqueous crystalline penicillin G, 100,000-150,000 units/kg/day
     (administered as 50,000 units/kg IV every 12 hours during the first
     7 days of life and every 8 hours thereafter) for 10-14 days,
                                or
     Procaine penicillin G, 50,000 units/kg IM daily in a single
     dose for 10-14 days.

     If more than 1 day of therapy is missed, the entire course
should be restarted. An infant whose complete evaluation was normal
and whose mother was a) treated for syphilis during pregnancy with
erythromycin, or b) treated for syphilis less than 1 month before
delivery, or c) treated with an appropriate regimen before or
during pregnancy but did not yet have an adequate serologic
response should be treated with benzathine penicillin G, 50,000
units/kg IM in a single dose. In some cases, infants with a normal
complete evaluation for whom follow-up can be assured can be
followed closely without treatment.

Treatment of Older Infants and Children with Congenital Syphilis
     After the newborn period, children diagnosed with syphilis
should have a CSF examination to exclude neurosyphilis and records
should be reviewed to assess whether the child has congenital or
acquired syphilis (see Primary and Secondary Syphilis and Latent
Syphilis). Any child who is thought to have congenital syphilis (or
who has neurologic involvement) should be treated with aqueous
crystalline penicillin G, 200,000-300,000 units/kg/day IV or IM
(administered as 50,000 units/kg every 4-6 hours) for 10-14 days.

Follow-Up
     A seroreactive infant (or an infant whose mother was
seroreactive at delivery) who is not treated for congenital
syphilis during the perinatal period should receive careful
follow-up examinations at 1 month and at 2, 3, 6, and 12 months
after therapy. Nontreponemal antibody titers should decline by 3
months of age and should be nonreactive by 6 months of age if the
infant was not infected and the titers were the result of passive
transfer of antibody from the mother. If these titers are found to
be stable or increasing, the child should be re-evaluated,
including CSF examination, and fully treated. Passively transferred
treponemal antibodies may be present for as long as 1 year. If they
are present greater than 1 year, the infant should be re-evaluated
and treated for congenital syphilis.

     Treated infants also should be followed every 2-3 months to
assure that nontreponemal antibody titers decline; these infants
should have become nonreactive by 6 months of age (response may be
slower for infants treated after the neonatal period). Treponemal
tests should not be used to evaluate response to treatment because
test results can remain positive despite effective therapy if the
child was infected. Infants with CSF pleocytosis should undergo CSF
examination every 6 months, or until the cell count is normal. If
the cell count is still abnormal after 2 years, or if a downward
trend is not present at each examination, the child should be
re-treated. The VDRL-CSF also should be checked at 6 months; if
still reactive, the infant should be re-treated.

     Follow-up of children treated for congenital syphilis after
the newborn period should be the same as that prescribed for
congenital syphilis among neonates.

Special Considerations

Penicillin Allergy -
     Children who require treatment for syphilis after the newborn
period, but who have a history of penicillin allergy, should be
treated with penicillin after desensitization, if necessary. Skin
testing may be helpful in some patients and settings (see
Management of the Patient With a History of Penicillin Allergy).

HIV Infection -
     Mothers of infants with congenital syphilis should be tested
for HIV. Infants born to mothers who have HIV infection should be
referred for evaluation and appropriate follow-up.

     No data exist to suggest that infants with congenital syphilis
whose mothers are coinfected with HIV require different evaluation,
therapy, or follow-up for syphilis than is recommended for all
infants.

Management of the Patient With a History of Penicillin Allergy
     
     No proven alternatives to penicillin are available for
treating neurosyphilis, congenital syphilis, or syphilis among
pregnant women. Penicillin also is recommended for use, whenever
possible, with HIV-infected patients. Unfortunately, 3%-10% of the
adult population in the United States have experienced urticaria,
angioedema, or anaphylaxis (upper airway obstruction, bronchospasm,
or hypotension) with penicillin therapy. Re-administration of
penicillin can cause severe immediate reactions among these
patients. Because anaphylactic reactions to penicillin can be
fatal, every effort should be made to avoid administering
penicillin to penicillin-allergic patients, unless the anaphylactic
sensitivity has been removed by acute desensitization.

     However, only approximately 10% of persons who report a
history of severe allergic reactions to penicillin are still
allergic. With the passage of time after an allergic reaction to
penicillin, most persons who have experienced a severe reaction
stop expressing penicillin-specific IgE. These persons can be
treated safely with penicillin. Many studies have found that skin
testing with the major and minor determinants can reliably identify
persons at high risk for penicillin reactions. Although these
reagents are easily generated and have been available in academic
centers for greater than 30 years, currently only
penicilloyl-poly-L-lysine (Pre-Pen, the major determinant) and
penicillin G are available commercially. Experts estimate that
testing with only the major determinant and penicillin G detects
90%-97% of the currently allergic patients. However, because skin
testing without the minor determinants would still miss 3%-10% of
allergic patients, and serious or fatal reactions can occur among
these minor determinant positive patients, experts suggest caution
when the full battery of skin test reagents listed in the table is
not available.

Recommendations
     If the full battery of skin-test reagents is available,
including the major and minor determinants (see Penicillin Allergy
Skin Testing), patients who report a history of penicillin reaction
and are skin-test negative can receive conventional penicillin
therapy. Skin-test positive patients should be desensitized.

     If the full battery of skin-test reagents, including the minor
determinants, is not available, the patient should be skin tested
using penicilloyl (the major determinant, Pre-Pen) and penicillin
G. Those with positive tests should be desensitized. Some experts
believe that persons with negative tests, in that situation, should
be regarded as probably allergic and should be desensitized. Others
suggest that those with negative skin tests can be test-dosed
gradually with oral penicillin in a monitored setting in which
treatment for anaphylactic reaction is possible.

Penicillin Allergy Skin Testing
     Patients at high risk for anaphylaxis (i.e., a history of
penicillin-related anaphylaxis, asthma or other diseases that would
make anaphylaxis more dangerous, or therapy with beta-adrenergic
blocking agents) should be tested with 100-fold dilutions of the
full-strength skin-test reagents before testing with full-strength
reagents. In these situations, patients should be tested in a
monitored setting in which treatment for an anaphylactic reaction
is possible. If possible, the patient should not have taken
antihistamines (e.g., chlorpheniramine maleate or terfenadine
during the past 24 hours, diphenhydramine HCl or hydroxyzine during
the past 4 days, or astemizole during the past 3 weeks).

Reagents (Adapted from Beall {14})*

     Major Determinant -

     --   Benzylpenicilloyl poly-L-lysine (Pre-Pen {Taylor Pharmacal
          Company, Decatur, Illinois}) (6 x 10-5M).

     Minor Determinant Precursors **

     --   Benzylpenicillin G (10-2M, 3.3 mg/mL, 6000 U/mL),

     --   Benzylpenicilloate (10-2M, 3.3 mg/mL),

     --   Benzylpenilloate (or penicilloyl propylamine)(10-2M, 3.3
          mg/mL).

Positive Control -

--   Commercial histamine for epicutaneous skin testing (1 mg/mL).

Negative Control -

--   Diluent used to dissolve other reagents, usually phenol
     saline.

Procedures -
     Dilute the antigens 100-fold for preliminary testing if the
patient has had a life-threatening reaction, or 10-fold if the
patient has had another type of immediate, generalized reaction
within the past year.

     Epicutaneous (prick) tests. Duplicate drops of skin-test
reagent are placed on the volar surface of the forearm. The
underlying epidermis is pierced with a 26-gauge needle without
drawing blood.

     An epicutaneous test is positive if the average wheal diameter
after 15 minutes is 4 mm larger than that of negative controls;
otherwise, the test is negative. The histamine controls should be
positive to assure that results are not falsely negative because of
the effect of antihistaminic drugs.

     Intradermal test. If epicutaneous tests are negative,
duplicate 0.02 mL intradermal injections of negative control and
antigen solutions are made into the volar surface of the forearm
using a 26- or 27-gauge needle on a syringe. The crossed diameters
of the wheals induced by the injections should be recorded.

     An intradermal test is positive if the average wheal diameter
15 minutes after injection is 2 mm or larger than the initial wheal
size and also is at least 2 mm larger than the negative controls.
Otherwise, the tests are negative.

Desensitization
     Patients who have a positive skin test to one of the
penicillin determinants can be desensitized. This is a
straightforward, relatively safe procedure that can be done orally
or IV. Although the two approaches have not been compared, oral
desensitization is thought to be safer, simpler, and easier.
Patients should be desensitized in a hospital setting because
serious IgE-mediated allergic reactions, although unlikely, can
occur. Desensitization can usually be completed in about 4 hours,
after which the first dose of penicillin is given Table_1. STD
programs should have a referral center where patients with positive
skin tests can be desensitized. After desensitization, patients
must be maintained on penicillin continuously for the duration of
the course of therapy.

* Reprinted with permission from G.N. Beall in Annals of Internal
Medicine.

** Aged penicillin is not an adequate source of minor determinants.
Penicillin G should be freshly prepared or should come from a
fresh-frozen source.

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