Authors: Charles B Hicks, MD, Meredith Clement, MD

Section Editor: Jeanne Marrazzo, MD, MPH, FACP, FIDSA

Deputy Editor: Jennifer Mitty, MD, MPH

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Feb 2019. | This topic last updated: May 21, 2018.

INTRODUCTION

Syphilis is an infection caused by the bacterium Treponema pallidum. During the initial
phase of infection, the organism disseminates widely, setting the stage for subsequent
manifestations. If untreated, syphilis can have a number of significant late adverse
outcomes, including cardiovascular, gummatous, and neurologic complications. The
management of syphilis is based upon its classification into stages of disease: early
syphilis (includes primary, secondary, and early latent syphilis); late (includes late latent,
cardiovascular, and gummatous syphilis); and neurosyphilis (includes central nervous
system disease and ocular syphilis at any time).

The treatment of syphilis in nonpregnant adults and patient monitoring after treatment
will be reviewed here. Other topics related to the treatment of syphilis are discussed
elsewhere:

● (See "Syphilis: Screening and diagnostic testing".)

● (See "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in HIV-
uninfected patients".)
● (See "Neurosyphilis".)
● (See "Syphilis in the HIV-infected patient".)
● (See "Syphilis in pregnancy".)
● (See "Congenital syphilis: Clinical features and diagnosis".)

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 ● (See "Congenital syphilis: Evaluation, management, and prevention".)

GENERAL APPROACH TO ANTIMICROBIAL THERAPY

Our approach to the treatment of nonpregnant adults with syphilis are consistent with
the 2015 guidelines from the United States Centers for Disease Control and Prevention
(CDC) [1]. Discussions of the treatment of syphilis in the setting of HIV infection and
pregnancy, as well as congenital syphilis, are found elsewhere. (See "Syphilis in the
HIV-infected patient" and "Congenital syphilis: Evaluation, management, and
prevention" and "Syphilis in pregnancy", section on 'Maternal treatment'.)

Pre-treatment evaluation — Patients with signs and symptoms consistent with syphilis
should undergo serologic testing to confirm the diagnosis. However, certain groups of
patients can be treated empirically for early syphilis based upon clinical findings (eg,
patients with a suspected chancre) or a known recent exposure, especially if they are
unlikely to follow up. (See "Syphilis: Epidemiology, pathophysiology, and clinical
manifestations in HIV-uninfected patients", section on 'Primary syphilis (chancre)' and
'Treatment of early syphilis' below.)

A nontreponemal serologic test should be obtained just before initiating therapy (ideally,
on the first day of treatment) to establish the pre-treatment titer. Since nontreponemal
titers can increase significantly between the date of diagnosis and the date of treatment,
this test is critical to establishing the adequacy of the post-treatment serologic
response. (See "Syphilis: Screening and diagnostic testing", section on 'Serologic tests'
and 'Patient monitoring' below.)

Penicillin as the treatment of choice — Parenterally-delivered penicillin G is the

treatment of choice for all stages of syphilis (table 1) [2]. Treatment recommendations
are based upon the pharmacokinetics of the available drugs, the microbe's slow growth
rate (penicillin is active against dividing organisms and requires prolonged antimicrobial
exposure for effective killing), the in vitro activity of antimicrobial agents against T.
pallidum, and more than 50 years of clinical experience [1,3].

In all types of syphilis, prolonged continuous levels of penicillin are necessary for the
elimination of treponemes [4]. However, the dosage, formulation, and duration of

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 treatment depend upon the stage of disease and whether or not infection involves
"protected sites" that sequester T. pallidum (eg, ocular structures, the central nervous
system) (table 1). As an example, long-acting benzathine penicillin given
intramuscularly (standard treatment of early syphilis) provides continuous levels of
penicillin in all tissues except these protected sites. Thus, patients with syphilis
involving these areas should be treated with intravenous (IV) penicillin G. (See
'Treatment of neurosyphilis' below.)

For patients without neurosyphilis, the appropriate formulation of parenteral penicillin is

penicillin G benzathine, which is marketed under the trade name Bicillin L-A. This agent
should only be given via the intramuscular (IM) route since IV administration has been
associated with cardiopulmonary arrest and death [4]. IM administration of benzathine
penicillin produces detectable serum concentrations for up to 30 days.

Bicillin L-A must be distinguished from Bicillin C-R (which contains equal concentrations
of procaine and benzathine penicillin), which should not be used to treat patients with
syphilis. Bicillin C-R results in detectable serum drug levels for only seven days.
Inadvertent use of this shorter-acting preparation in a Los Angeles sexually transmitted
disease clinic led to a large-scale public health investigation and retesting and
retreatment of a significant number of patients [5]. The Bicillin C-R product is now
labeled with a warning: "not for the treatment of syphilis." This agent is typically used for
the treatment of susceptible streptococci. (See "Treatment and prevention of
streptococcal pharyngitis", section on 'Antibiotic treatment'.)

Given periodic shortages of penicillin G benzathine, it is important to follow

recommended dosing regimens (eg, a single dose of benzathine penicillin for early
syphilis) (table 1) [6]. In addition, use of benzathine penicillin for syphilis treatment
should be prioritized for pregnant women, and alternative regimens, such as
doxycycline, may need to be utilized for nonpregnant adults if supplies are limited. (See
'Alternative regimens for early syphilis' below and 'Alternative regimens for late syphilis'
below and "Syphilis in pregnancy", section on 'Maternal treatment'.)

Patients who are allergic to penicillin — If a patient is allergic to penicillin, the choice
of agent is less clear. Options include:

● Testing for penicillin allergy and/or rechallenging with penicillin

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 ● Desensitizing to penicillin if allergy testing is positive

● Using an alternative agent with close post-treatment monitoring

For patients with a documented history of a penicillin allergy, we typically initiate an

alternative regimen if the patient has early disease or late latent syphilis and can be
closely monitored after treatment. Alternative antimicrobial agents include tetracyclines
and cephalosporins (table 1). Some patients who are allergic to penicillin may also be
allergic to ceftriaxone (see "Allergy evaluation for immediate penicillin allergy: Skin test-
based diagnostic strategies and cross-reactivity with other beta-lactam antibiotics").
However, if ceftriaxone is used, we typically prefer IV administration rather than IM
injections, which are often painful. Azithromycin should be used only if other agents are
not available due to reports of treatment failures associated with macrolide resistance.
A more detailed discussion of how to choose an alternative agent is found below. (See
'Alternative regimens for early syphilis' below.)

Patients should generally be tested for allergy and desensitized to or rechallenged with
penicillin if they are pregnant, or present with neurosyphilis, cardiovascular
manifestations of late syphilis, and/or treatment failure. Patients with a history of an
immediate-type hypersensitivity reaction require desensitization. For patients with a
history of a delayed-type reaction, some can be rechallenged with penicillin, while
others should have skin testing prior to being re-exposed. Detailed discussions of the
management of patients with a penicillin allergy are found elsewhere. (See "Penicillin
allergy: Immediate reactions" and "Penicillin allergy: Delayed hypersensitivity
reactions".)

TREATMENT OF EARLY SYPHILIS

The goals of treatment for early syphilis are to prevent long-term adverse outcomes of
infection and reduce transmission to others. Early syphilis refers to primary, secondary,
and early latent syphilis. A diagnosis of early syphilis implies that T. pallidum infection
occurred within the previous year.

● Primary – Following acquisition of T. pallidum, the initial clinical manifestations are

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 termed primary syphilis and usually consist of a painless chancre at the site of
inoculation, accompanied by regional adenopathy. (See "Syphilis: Epidemiology,
pathophysiology, and clinical manifestations in HIV-uninfected patients", section on
'Primary syphilis (chancre)'.)

● Secondary – Approximately 25 percent of individuals with untreated primary

infection will develop a systemic illness that represents secondary syphilis. Clinical
manifestations are protean, but often include a disseminated rash, condylomata
lata, lymphadenopathy, alopecia, and/or hepatitis. (See "Syphilis: Epidemiology,
pathophysiology, and clinical manifestations in HIV-uninfected patients", section on
'Secondary syphilis'.)

● Early latent – Latent syphilis refers to the period when a patient is infected with T.
pallidum, as demonstrated by serologic testing, but has no symptoms. Early latent
syphilis by definition occurs within the first year of initial infection. Patients
diagnosed with early latent syphilis should be considered to be potentially
infectious. (See "Syphilis: Epidemiology, pathophysiology, and clinical
manifestations in HIV-uninfected patients", section on 'Latent syphilis
(asymptomatic)' and "Syphilis: Screening and diagnostic testing", section on 'Latent
syphilis'.)

Preferred regimens for early syphilis — A single dose of penicillin G benzathine (2.4
million units intramuscularly [IM]) is standard therapy for most patients with primary,
secondary, and early latent syphilis (table 1) [1,7]. Long-acting benzathine penicillin
should only be given via the IM route [4]. (See 'Penicillin as the treatment of choice'
above.)

Patients with neurologic manifestations should be evaluated for neurosyphilis. The

clinical manifestations, diagnosis, and treatment of neurosyphilis are discussed
elsewhere. (See "Neurosyphilis", section on 'Early neurosyphilis' and 'Treatment of
neurosyphilis' below.)

A persistent level >0.018 mcg/mL of penicillin for 7 to 10 days without interruption of

>24 to 30 hours is needed in the blood to ensure killing of T. pallidum in early infection
[8]. A single 2.4 million unit dose of benzathine penicillin maintains this serum
concentration for about three weeks [9]. Increasing the dose does not clear treponemes

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 more quickly [10]. In addition, no resistance has been reported despite several decades
of penicillin G use. However, sensitivity testing is not typically performed because the
organism cannot be readily grown in the laboratory.

The use of single-dose treatment of early syphilis was supported in a systematic review,
which included data from two large randomized clinical trials evaluating the efficacy of a
single dose of 2.4 million units of IM benzathine penicillin for the treatment of primary
and secondary syphilis [2,11,12]. Clinical cure rates were 90 to 100 percent for both
HIV-uninfected and HIV-infected persons. In addition, data from the 1950s suggested
that long-acting depot penicillin therapy for early syphilis prevented subsequent
development of late syphilis, including neurosyphilis [13,14]. Several studies have
evaluated "enhanced" therapy with additional doses of benzathine penicillin and found
no additional benefit [15-17].

Alternative regimens for early syphilis — Alternative regimens are typically

administered to patients who are unable to take penicillin. However, they may also be
needed when penicillin G benzathine is unavailable (table 1) [6].

We prefer doxycycline as our first-line alternative agent in nonpregnant adults, even

though it requires multiple doses. Such patients with early syphilis may be treated with
14 days of doxycycline (100 mg PO twice daily). Tetracycline (500 mg PO four times
daily) can also be used, but few patients are able to adhere to this challenging regimen.
Data from small, retrospective studies indicate serologic response rates of 83 to 100
percent when patients were treated with these agents [18-24].

For patients requiring an alternative regimen (such as when benzathine penicillin is not
available) who are not allergic to penicillin, oral amoxicillin with probenecid can be used
(amoxicillin 3 g plus probenecid 500 mg orally, both given twice daily for 14 days).
However, this regimen requires prolonged oral dosing in addition to probenecid. This
regimen was evaluated in Japan (where benzathine penicillin is not available) in a
retrospective observational study of 286 HIV-infected persons presenting with all stages
of syphilis [25]. The treatment duration was 14 to 30 days, and successful treatment
was defined as at least a fourfold decline in nontreponemal titer. Approximately 95
percent of patients with early syphilis were successfully treated with this regimen.

Ceftriaxone can also be used to treat early syphilis [26,27]; however, some patients who

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 are allergic to penicillin may also be allergic to ceftriaxone. Given the limited clinical
data with this regimen [28], the optimal dose and duration of treatment have not been
defined. Guidelines recommend 1 to 2 grams (IM or intravenously [IV]) daily for 10 to 14
days [1]. An additional discussion of the use of ceftriaxone is found above. (See
'Patients who are allergic to penicillin' above.)

A single 2-gram dose of azithromycin is another alternative, although it is generally not

recommended unless no other alternative options are available. Azithromycin was
found to be equivalent to benzathine penicillin for the treatment of early syphilis in two
randomized trials [11,29,30]; however, its use is greatly limited due to the rapid
emergence of macrolide resistance in T. pallidum associated with treatment failure
[29,31-33].

TREATMENT OF LATE SYPHILIS

Late syphilis includes tertiary syphilis and late latent syphilis, and such patients require
a longer duration of treatment compared with those who have early syphilis. Patients
with neurologic manifestations should be treated for neurosyphilis. (See 'Treatment of
neurosyphilis' below.)

● Tertiary – Tertiary syphilis refers to patients with late syphilis who have
symptomatic manifestations involving the cardiovascular system or gummatous
diseases (usually of the skin and subcutaneous tissues). (See "Syphilis:
Epidemiology, pathophysiology, and clinical manifestations in HIV-uninfected
patients", section on 'Late syphilis'.)

● Late latent – Latent syphilis refers to the period when a patient is infected with T.
pallidum, as demonstrated by serologic testing, but has no symptoms. Late latent
syphilis by definition occurs more than one year after initial infection. If the timing of
an infection is not known, late latent syphilis is presumed [34]. Transmission is
unlikely to occur in this stage of disease. (See "Syphilis: Screening and diagnostic
testing", section on 'Latent syphilis' and "Syphilis: Epidemiology, pathophysiology,
and clinical manifestations in HIV-uninfected patients", section on 'Latent syphilis
(asymptomatic)'.)

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 Preferred regimen for late syphilis — Penicillin G benzathine (2.4 million units
intramuscularly [IM] once weekly for three weeks) is standard therapy for tertiary and
late latent syphilis as it provides adequate and persistent serum levels of penicillin
(table 1) [1,7,13,14]. While it has the advantage of not requiring daily patient adherence,
it does require that the patient follow up consistently over the entire span of treatment to
receive the full course of therapy. If a patient misses a dose, and if more than 14 days
have elapsed since the prior dose, the course should be reinitiated [35].

● Tertiary syphilis – Patients with gummatous or cardiovascular infection should

have a cerebrospinal fluid examination prior to initiation of therapy to assess for
neurosyphilis. The management of neurosyphilis is described below. (See
'Treatment of neurosyphilis' below.)

If neurosyphilis is not present, we administer penicillin G benzathine (2.4 million

units IM) once a week for three weeks [1]. Cutaneous gummas usually heal rapidly
after penicillin therapy with little scarring. For those with cardiovascular disease,
antibiotic therapy does not reverse the clinical manifestations of syphilis, but it may
halt progression of disease.

Although we do not advocate for intravenous (IV) penicillin in the absence of

neurosyphilis, some experts recommend using the same treatment regimen for
cardiovascular syphilis as for neurosyphilis [1]. In addition, some experts
recommend the administration of 40 to 60 mg of prednisolone daily for three days
beginning 24 hours before treatment for any form of cardiovascular syphilis [36].
However, there are no data supporting the use of IV penicillin or glucocorticoids for
patients with cardiovascular manifestations.

● Late latent syphilis – Patients with late latent syphilis should be treated with three
doses of penicillin G benzathine (2.4 million units IM) once a week for three weeks
(table 1) [1].

Alternative regimens for late syphilis — For patients without neurosyphilis who are
allergic to penicillin, we test for penicillin allergy and then desensitize if testing is
positive. If desensitization is not possible, we generally use doxycycline or ceftriaxone
(if the patient can be safely treated with other beta-lactam drugs). (See "Allergy
evaluation for immediate penicillin allergy: Skin test-based diagnostic strategies and

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 cross-reactivity with other beta-lactam antibiotics".)

● For patients with gummatous or cardiovascular infection, we generally prefer

doxycycline (100 mg PO twice daily for 28 days) if adherence to treatment seems
likely. There have been no studies evaluating the use of extended released
doxycycline 200 mg once daily for the treatment of syphilis. For patients whose
adherence seems questionable, we administer ceftriaxone (2 g IV or IM daily for 10
to 14 days). (See 'Patients who are allergic to penicillin' above.)

● For those with late latent syphilis, doxycycline 100 mg PO twice daily for 28 days
should be administered [1].

● We avoid azithromycin given concerns for resistance and subsequent treatment

failure.

There are very limited data on the efficacy of these regimens in late syphilis, and
therefore, we closely monitor the response to therapy [37,38]. (See 'Patient monitoring'
below.)

TREATMENT OF NEUROSYPHILIS

Neurosyphilis can occur at any time during the course of infection. Patients with early
neurosyphilis typically present with ocular disease, cranial nerve dysfunction (especially
auditory or facial nerve involvement), or meningitis. Later in disease, the most common
forms involve the brain and spinal cord parenchyma (general paresis and tabes
dorsalis) (table 1). (See "Neurosyphilis", section on 'Clinical manifestations'.)

Patients with neurosyphilis should generally be treated with intravenous (IV) therapy.
The rationale for using IV rather than intramuscular (IM) therapy includes:

● The dose of IM benzathine penicillin that is administered for other stages of syphilis
does not produce measurable cerebrospinal fluid (CSF) levels of the drug [39].

● Several case reports of HIV-infected patients treated with benzathine penicillin who
subsequently developed symptomatic neurosyphilis have been published; in some
instances, viable T. pallidum were demonstrated in CSF after therapy

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 [13,14,40,41].

We also administer IV therapy to patients strongly suspected of having CNS syphilis

(eg, compatible clinical syndrome, reactive blood serology, and CSF pleocytosis) even if
they have a nonreactive CSF-Venereal Disease Research Laboratory (VDRL) since the
CSF-VDRL test may be falsely negative in as many as 70 percent of patients with
neurosyphilis. A more detailed discussion of how to diagnose neurosyphilis is found
elsewhere. (See "Neurosyphilis".)

Preferred regimens for neurosyphilis — Patients with neurosyphilis should be

treated with IV penicillin G (3 to 4 million units IV every four hours, or 18 to 24 million
units per day by continuous infusion) for 10 to 14 days (table 1) [1].

For patients with late disease, we generally administer a single dose of penicillin G
benzathine (2.4 million units IM) after completion of IV penicillin since the duration of
treatment for neurosyphilis is shorter than the regimens used for late syphilis. This
approach is based upon the pathophysiology of the organism, the required drug levels
needed to eradicate the organism in later stages of disease, and the overall safety of
the drug. However, there are no clinical trial data to support any firm recommendations.
Some specialists administer three weekly doses of benzathine penicillin 2.4 million units
IM after completion of the neurosyphilis regimen [1]. Although this approach is also
reasonable, patient follow-up for the full course of therapy may be challenging.
Shortages of the drug may also compromise this approach.

On rare occasion, we treat HIV-uninfected patients with mild neurologic symptoms and
a questionable diagnosis of neurosyphilis the same way we treat those with other forms
of late syphilis (ie, three weekly doses of benzathine penicillin 2.4 million units IM).
Such patients are typically elderly patients with mild cognitive deficits consistent with
early dementia, where the risk and inconvenience of sampling CSF and/or
administering IV therapy may exceed the risk of undertreated neurosyphilis. If
symptoms are more specific for neurosyphilis, IV penicillin can be given even when
CSF sampling cannot be done.

Alternative regimens for neurosyphilis — Patients should generally be desensitized

to or rechallenged with penicillin if they present with neurosyphilis so they can receive
the standard IV regimen rather than using an alternative regimen (table 1). (See

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 "Penicillin allergy: Immediate reactions" and "Penicillin allergy: Delayed hypersensitivity
reactions" and 'Preferred regimens for neurosyphilis' above.)

Alternatives to IV penicillin include:

● Procaine penicillin (2.4 million units IM once daily) plus probenecid (500 mg orally
four times a day) both for 10 to 14 days [1]. Although this combination provides
higher serum levels than benzathine penicillin, CSF levels of penicillin are often are
not detectable, and this regimen has not been well studied for the treatment of
neurosyphilis [42]. In addition, IM procaine penicillin can be painful, therefore,
patient willingness to complete the full course of therapy is variable.

● Ceftriaxone (2 g IV daily for 10 to 14 days) if the patient can be safely treated with
other beta-lactam drugs. (See "Allergy evaluation for immediate penicillin allergy:
Skin test-based diagnostic strategies and cross-reactivity with other beta-lactam
antibiotics".)

Doxycycline (200 mg orally twice daily) for 21 days is also an alternative approach, but
should be reserved for exceptional circumstances. This regimen has very limited
supporting data [43] and is not recommended by the United States Centers for Disease
Control and Prevention [34].

PATIENT MONITORING

Patients should be monitored clinically and with laboratory testing to ensure they are
responding appropriately to therapy.

Jarisch-Herxheimer reaction — The Jarisch-Herxheimer reaction (JHR) is an acute,

self-limited, febrile reaction that usually occurs within the first 24 hours after the patient
receives therapy for any spirochetal infection, including syphilis. This reaction occurs in
approximately 10 to 35 percent of cases [44]. It is seen most commonly after treatment
of early syphilis.

The fever may be accompanied by systemic symptoms, including headache, myalgias,

rigors, diaphoresis, hypotension, and worsening of rash if initially present. Uncommon
manifestations include meningitis, respiratory distress, renal and/or hepatic dysfunction,

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 mental status changes, stroke, seizures, and uterine contractions in pregnancy [45]. An
additional discussion of the JHR in pregnancy is found elsewhere. (See "Syphilis in
pregnancy", section on 'Potential complications of treatment: Jarisch-Herxheimer
reaction'.)

The mechanism by which this reaction develops is not completely understood.

However, it is thought to result from accelerated phagocytosis by polymorphonuclear
leukocytes, followed by the release of lipoproteins, cytokines, and immune complexes
from killed organisms [44,46,47].

There is no way to prevent this reaction. Patients should be informed of the possible
signs and symptoms and advised to contact their clinicians if a severe reaction occurs.
Although these symptoms often resolve without intervention within 12 to 24 hours, non-
steroidal anti-inflammatory drugs (NSAIDS) or other antipyretics can be used if
symptoms arise and they may reduce the severity of symptoms and the duration of the
reaction.

Clinical assessment — Patients with early syphilis should be assessed clinically for
resolution of symptoms (eg, rash, ulcer). However, for patients with late stage
cardiovascular or noncutaneous gummatous disease, a significant change in symptoms
is unlikely. For individuals with symptomatic neurosyphilis, serial neurological
examinations should be performed every six months.

Serologic testing — Nontreponemal (rapid plasma reagin [RPR] or Venereal Disease

Research Laboratory) titers should be monitored after treatment. The frequency of
serologic monitoring is described below. (See 'How often to monitor' below.)

Since T. pallidum cannot be cultured in the laboratory, the success of treatment must be
inferred through this indirect measure. Although definitive criteria for cure or failure have
not been established, the United States Centers for Disease Control and Prevention
has suggested definitions to assess the patient's response to treatment [1]. A
description of the types of serologic tests used to diagnose and monitor syphilis is found
elsewhere. (See "Syphilis: Screening and diagnostic testing", section on 'Serologic
tests'.)

Adequate response — A fourfold decline in the nontreponemal titer, equivalent to a

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 change of two dilutions (eg, from 1:16 to 1:4 or from 1:32 to 1:8), is considered to be an
acceptable response to syphilis therapy. Over time, most patients successfully treated
for syphilis experience seroreversion; however, some remain serofast. In a systematic
review that included data from 20 studies, a fourfold or greater decline in
nontreponemal titers was associated with younger age, higher baseline nontreponemal
titers, and earlier syphilis stage [48].

Seroreversion — The loss of antibodies over time (seroreversion) in a patient

who has been successfully treated for syphilis is considered to be consistent with
clinical cure. The majority of patients who are treated for early syphilis will experience
seroreversion over time. Although seroreversion is typically seen with nontreponemal
antibodies, seroreversion of treponemal tests has also been reported, with rates as high
as 24 percent (particularly in patients treated early during primary syphilis) [49,50]. In
the rare instance in which treatment is initiated prior to any detectable serologic
response (eg, primary syphilis diagnosed clinically or by direct spirochete detection),
serologic testing may remain nonreactive.

Serofast state — Patients who have had an adequate (≥fourfold) decline in titers,
but whose nontreponemal titers do not serorevert or continue to fall after 24 months of
monitoring, are considered serofast. The serofast state is seen in approximately 15 to
20 percent of patients with early syphilis and has been reported to be as high as 35
percent in patients with late latent syphilis [51-53]. Generally the nontreponemal titer
stabilizes at a low level (eg, a titer of <1:8), but higher serofast titers are occasionally
seen, particularly in HIV-infected patients. Individuals who are serofast should be tested
for HIV infection, since the serofast state can be the result of immunodysregulation of
antibody production [1].

Treatment failure — Persons with syphilis are considered to have treatment failure
if nontreponemal titers do not decline fourfold or greater or if there is a documented
fourfold increase after initial decline. Treatment failure should be distinguished from
reinfection. (See 'Management of treatment failure' below.)

How often to monitor — A nontreponemal titer should be obtained just before initiating
therapy (ideally, on the first day of treatment) since titers can increase significantly over
a few days between diagnosis of syphilis and treatment initiation. The subsequent

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 frequency of monitoring depends upon the stage of disease and presence of HIV
coinfection.

● In patients with early syphilis, serologic testing should be performed 6 and 12

months following treatment and at any time if clinical symptoms recur. In general,
such patients should experience an adequate response by 12 months. (See
'Adequate response' above.)

● Patients with late syphilis (including late latent syphilis) should undergo follow-up
serologic testing at 6, 12, and 24 months, as some patients with late syphilis may
not have an adequate response for up to two years following treatment.

● Patients with HIV are typically monitored more frequently. The management of HIV-
infected patients with syphilis is discussed elsewhere. (See "Syphilis in the HIV-
infected patient".)

Once the nontreponemal titer has become nonreactive (seroreversion), additional

testing is not needed unless it is being done based on concerns for a new infection.
(See 'Seroreversion' above.)

Patients who have had an adequate response to therapy may still have a detectable
nontreponemal titer following treatment. For such patients, we continue to monitor the
nontreponemal titer every six months until seroreversion of the nontreponemal test has
occurred, or the patient is considered to be serofast (see 'Serofast state' above). After
identifying a patient as serofast, we generally repeat nontreponemal tests every six
months for one to two years to assess for stability, and then at increasing intervals (eg,
annually) to assess for possible late failure or reinfection.

Antibody titers decline at varying rates following treatment, depending upon the stage of
infection and the magnitude of the pre-treatment titer. Patients with early syphilis may
experience more rapid relative declines in RPR titers than patients with late syphilis. As
an example, in a systematic review, serologic response to treatment was typically seen
by six months in patients with early syphilis, but generally demonstrated a slower
decline (12 to 24 months) in patients with late latent disease [2]. Other factors that may
slow the rate at which titers decline following therapy include prior episodes of syphilis,
the duration of infection prior to therapy, and the presence of HIV coinfection [37,49].

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 Patients with neurosyphilis — Patients with neurosyphilis should undergo clinical and
serologic monitoring at the same frequency as patients without neurosyphilis. In
addition, monitoring of cerebrospinal fluid abnormalities may also be warranted. A
discussion of monitoring after treatment for neurosyphilis is found elsewhere. (See
"Neurosyphilis", section on 'Monitoring'.)

MANAGEMENT OF TREATMENT FAILURE

Persons with syphilis are suspected of treatment failure if nontreponemal titers do not
decline fourfold or greater, or if there is a documented fourfold increase after an initial
decline. Additional discussions of treatment failure in patients with neurosyphilis and
HIV are found elsewhere. (See 'Serologic testing' above and 'How often to monitor'
above and "Neurosyphilis", section on 'Monitoring' and "Syphilis in the HIV-infected
patient", section on 'Approach to treatment failure'.)

If a patient has not had an adequate response to treatment, it is important to determine

if the individual has been reinfected, is experiencing a slow response to treatment, or
has failed treatment. Since drug resistance to penicillin has not been described,
treatment failure is likely due to poor adherence with the treatment regimen, treatment
with an alternative agent, immunocompromised status, or undiagnosed central nervous
system disease.

Our approach to patients with possible treatment failure is as follows:

● We first assess the patient to see if there is a history of possible new exposure or
clinical evidence of a new infection (eg, chancre, rash). In addition, we repeat
testing for HIV.

● If there is no evidence of new infection, we then assess for evidence of potential

neurosyphilis. We perform a lumbar puncture (LP) in HIV-uninfected patients with
the following:

• Neurologic symptoms

• Signs or symptoms of syphilis that persist or recur

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 • A fourfold or greater increase in nontreponemal test titers persisting for >2
weeks

• Persons treated for late latent syphilis with an initially high titer (≥1:32) that
fails to decline at least fourfold within 12 to 24 months of treatment

If the cerebrospinal fluid (CSF) is abnormal, then the patient needs a treatment
course for neurosyphilis. (See 'Treatment of neurosyphilis' above.)

If the CSF is unremarkable, but there continues to be concern for treatment failure,
we retreat the patient with another course of therapy. This should be accomplished
with a regimen recommended for late syphilis, even if the initial presentation was
early syphilis. Such patients who failed an alternative regimen should be
reassessed to see if penicillin can be administered. In the case of reported
penicillin allergy, testing for true allergy should be pursued, and if present, the
patient should undergo desensitization.

After the patient has been retreated, we continue close clinical and serologic
follow-up (eg, every six months) and determine the need for additional evaluation
and management based upon subsequent changes in nontreponemal titers.

When an alternative regimen has been used because of a reported penicillin allergy
and treatment response is inadequate (ie, nontreponemal titers fail to decline fourfold
within 12 months of treatment), it is reasonable to test for penicillin allergy and consider
treatment with penicillin G benzathine in those whose allergy testing is negative. If
treatment with penicillin is not possible, the management plan should be formulated on
a case-by-case basis; the primary options are to continue monitoring nontreponemal
titers closely (and retreat if the titer increases) or to perform an LP to evaluate for
neurosyphilis. An additional discussion of the treatment of patients who are allergic to
penicillin is found above. (See 'Patients who are allergic to penicillin' above.)

For patients with neurosyphilis and evidence of treatment failure, retreatment usually
requires 14 days of intravenous penicillin G. There is no evidence that longer courses of
treatment or use of different antibiotics changes the outcome.

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 TREATMENT AFTER AN EXPOSURE

There is no vaccine for syphilis. Thus, persons exposed sexually to a partner who has
syphilis in any stage should be evaluated clinically and serologically for evidence of
infection.

● If the patient has clinical evidence of syphilis, treatment is tailored to the specific
manifestation as summarized in the table (table 1) and described in more detail
above. (See 'Treatment of early syphilis' above and 'Treatment of neurosyphilis'
above.)

● For those who are asymptomatic, we treat empirically for early syphilis if the patient
had condomless oral, anal, or vaginal sex with:

• A sex partner who was diagnosed with primary, secondary, or early latent
syphilis within the preceding 90 days.

• A sex partner who was diagnosed with late latent syphilis within the preceding
90 days if the partner had a high nontreponemal titer (eg, >1:32). A high
serologic titer is often associated with early infection, and the patient may have
been misdiagnosed with late disease when in fact infection occurred more
recently.

For such patients, baseline serologic testing is performed at the time of

presentation, although we do not withhold treatment pending serology results.
Serologic testing may be negative in those with incubating or early disease.
However, if nontreponemal testing is positive, it should be used to monitor the
response to therapy. (See 'Serologic testing' above.)

● For asymptomatic patients who were exposed to a sex partner with syphilis more
than 90 days preceding their partner’s diagnosis, we generally determine the need
for treatment based upon the results of baseline serologic testing. However, if
serologic testing is not readily available, or if follow up is uncertain, we treat
empirically. The specific treatment regimen depends upon when the patient was
exposed (ie, early versus late latent syphilis). In general, we prefer to treat persons

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 in this setting whose exposure is uncertain since the risk of undertreatment
typically exceeds that of overtreatment. (See 'Treatment of early syphilis' above
and 'Treatment of late syphilis' above.)

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and

regions around the world are provided separately. (See "Society guideline links:
Sexually transmitted infections".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond
the Basics." The Basics patient education pieces are written in plain language, at the 5th
to 6th grade reading level, and they answer the four or five key questions a patient might
have about a given condition. These articles are best for patients who want a general
overview and who prefer short, easy-to-read materials. Beyond the Basics patient
education pieces are longer, more sophisticated, and more detailed. These articles are
written at the 10th to 12th grade reading level and are best for patients who want in-
depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you
to print or e-mail these topics to your patients. (You can also locate patient education
articles on a variety of subjects by searching on "patient info" and the keyword(s) of
interest.)

● Basics topic (see "Patient education: Syphilis (The Basics)")

SUMMARY AND RECOMMENDATIONS

● Syphilis is an infection caused by the bacterium Treponema pallidum. During the

initial phase of infection, the organism disseminates widely, setting the stage for
subsequent manifestations. If untreated, syphilis can have a number of significant

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 late manifestations, including cardiovascular, gummatous, and neurologic
complications. (See 'Introduction' above.)

● A nontreponemal titer should be obtained just before initiating therapy (ideally, on

the first day of treatment) since titers can increase significantly over a few days
between diagnosis of syphilis and treatment initiation. (See 'Pre-treatment
evaluation' above.)

● Penicillin is the treatment of choice for all stages of syphilis (table 1). For patients
who are allergic to penicillin, alternative agents include tetracyclines, ceftriaxone,
and azithromycin. However, we only use azithromycin if no other options are
available due to concerns of treatment failure associated with macrolide resistance.
(See 'General approach to antimicrobial therapy' above.)

● For nonpregnant adults with early syphilis (primary, secondary, and early latent
syphilis) without evidence of neurosyphilis, we recommend a single dose of
penicillin G benzathine (2.4 million units intramuscularly [IM]) rather than an
extended course of penicillin therapy (Grade 2B). For patients who are allergic to
penicillin, we suggest doxycycline for 14 days rather than another agent (Grade
2C). (See 'Treatment of early syphilis' above.)

● For patients with tertiary syphilis (gummatous or cardiovascular disease) or late

latent syphilis without evidence of neurosyphilis, we suggest IM penicillin G
benzathine rather than intravenous (IV) therapy (Grade 2C). An IM injection of 2.4
million units benzathine penicillin should be given once weekly for three weeks. If a
patient misses a dose, and if more than 14 days have elapsed since the prior dose,
the course should be reinitiated. (See 'Treatment of late syphilis' above.)

● For patients with neurosyphilis, we recommend IV penicillin G rather than IM

therapy (Grade 1B). Penicillin G should be administered as 3 to 4 million units IV
every four hours (or 18 to 24 million units per day by continuous infusion) for 10 to
14 days. For patients with late disease, we generally administer a single dose of IM
benzathine penicillin after the IV course has been completed, since the duration of
treatment for neurosyphilis is shorter than the regimens used for late syphilis. (See
'Treatment of neurosyphilis' above.)

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 ● Patients should be monitored clinically and with serologic testing after treatment to
ensure they are responding appropriately to therapy. A fourfold decline in the
nontreponemal titer, equivalent to a change of two dilutions (eg, from 1:16 to 1:4 or
from 1:32 to 1:8), is considered to be an acceptable response. Over time, most
patients successfully treated for syphilis experience seroreversion; however, some
remain serofast. (See 'Clinical assessment' above and 'Serologic testing' above.)

● The frequency of serologic monitoring depends upon the stage of disease and
presence of HIV coinfection (see 'How often to monitor' above):

• In HIV-uninfected patients with early syphilis, serologic testing should be

performed 6 and 12 months following treatment and at any time if clinical
symptoms recur. In general, such patients should experience an adequate
response by 12 months.

• HIV-uninfected patients with late syphilis should undergo follow-up serologic

testing at 6, 12, and 24 months, as some patients with late syphilis may not
have an adequate response for up to two years following treatment.

• Patients with HIV are typically monitored more frequently. This is discussed in
a separate topic review. (See "Syphilis in the HIV-infected patient".)

● Patients with neurosyphilis should undergo clinical and serologic monitoring at the
same frequency as patients without neurosyphilis. Monitoring of cerebrospinal fluid
abnormalities may also be warranted. (See "Neurosyphilis", section on
'Monitoring'.)

● Persons with syphilis are suspected of treatment failure if nontreponemal titers do

not decline fourfold or greater, or if there is a documented fourfold increase after an
initial decline. If a patient has not had an adequate response to treatment, it is
important to determine if the individual has been reinfected, is experiencing a slow
response to treatment, or has failed treatment. Since drug resistance to penicillin
has not been described, treatment failure is likely due to poor adherence with the
treatment regimen, treatment with an alternative agent, immunocompromised
status, or undiagnosed central nervous system disease. (See 'Management of
treatment failure' above.)

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 ● Persons exposed sexually to a partner who has syphilis should be evaluated
clinically and serologically for evidence of infection. The need for empiric treatment
depends primarily upon when the exposure occurred and the stage of their
partner’s infection. (See 'Treatment after an exposure' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge P

Frederick Sparling, MD, who contributed to an earlier version of this topic review.

Use of UpToDate is subject to the Subscription and License Agreement.

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