Syphilis - Treatment and Monitoring - UpToDate

4/7/2020 Syphilis: Treatment and monitoring - UpToDate
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Sífilis: tratamiento y monitoreo

Autores: Charles B Hicks, MD, Meredith Clement, MD
Editor de sección: Jeanne Marrazzo, MD, MPH, FACP, FIDSA
Subdirector: Jennifer Mitty, MD, MPH
Todos los temas se actualizan a medida que hay nuevas pruebas disponibles y nuestro proceso de revisión por pares
está completo.
Revisión de literatura actualizada hasta: junio de 2020. | Última actualización de este tema: 30 de junio de
2020.
INTRODUCCIÓN
La sífilis es una infección causada por la bacteria Treponema pallidum . Durante la fase inicial de
la infección, el organismo se disemina ampliamente, preparando el escenario para
manifestaciones posteriores. Si no se trata, la sífilis puede tener una serie de resultados adversos
tardíos significativos, que incluyen complicaciones cardiovasculares, gomosas y neurológicas. El
manejo de la sífilis se basa en su clasificación en etapas de la enfermedad: sífilis temprana
(incluye sífilis primaria, secundaria y latente temprana); tardía (incluye sífilis latente tardía,
cardiovascular y gomatosa); y neurosífilis (incluye enfermedad del sistema nervioso central y
sífilis ocular en cualquier momento).
Aquí se revisará el tratamiento de la sífilis en adultos no embarazadas y la monitorización del

paciente después del tratamiento. Otros temas relacionados con el tratamiento de la sífilis se
analizan en otra parte:
● (Consulte "Sífilis: detección y pruebas de diagnóstico" ).

● (Ver "Sífilis: Epidemiología, fisiopatología y manifestaciones clínicas en pacientes sin VIH" .)
● (Ver "Neurosífilis" ).
● (Ver "Sífilis en el paciente infectado con VIH" .)
● (Ver "Sífilis en el embarazo" ).
● (Ver "Sífilis congénita: características clínicas y diagnóstico" .)
● (Ver "Sífilis congénita: evaluación, manejo y prevención" ).
ENFOQUE GENERAL DE LA TERAPIA ANTIMICROBIANA

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Nuestro enfoque para el tratamiento de adultos no embarazadas con sífilis es consistente con las
pautas de 2015 de los Centros para el Control y la Prevención de Enfermedades de los Estados
Unidos (CDC) [ 1 ]. Los debates sobre el tratamiento de la sífilis en el contexto de la infección por
VIH y el embarazo, así como la sífilis congénita, se encuentran en otros lugares. (Consulte "Sífilis
en la paciente infectada por el VIH" y "Sífilis congénita: evaluación, tratamiento y prevención" y
"Sífilis en el embarazo", sección "Tratamiento materno" ).
Evaluación previa al tratamiento : los pacientes con signos y síntomas compatibles con sífilis
deben someterse a pruebas serológicas para confirmar el diagnóstico. Sin embargo, ciertos
grupos de pacientes pueden ser tratados empíricamente para la sífilis temprana según los
hallazgos clínicos (p. Ej., Pacientes con sospecha de chancro) o una exposición reciente
conocida, especialmente si es poco probable que hagan un seguimiento. (Ver "Sífilis:
Epidemiología, fisiopatología y manifestaciones clínicas en pacientes sin VIH", sección "Sífilis
primaria (chancro)" y "Tratamiento de la sífilis temprana" a continuación).
Se debe obtener una prueba serológica no treponémica justo antes de iniciar la terapia
(idealmente, el primer día de tratamiento) para establecer el título previo al tratamiento. Dado que
los títulos no treponémicos pueden aumentar significativamente entre la fecha de diagnóstico y la
fecha de tratamiento, esta prueba es crítica para establecer la adecuación de la respuesta
serológica posterior al tratamiento. (Consulte "Sífilis: detección y pruebas de diagnóstico", sección
sobre 'Pruebas serológicas' y 'Monitoreo de pacientes' a continuación).
La penicilina como tratamiento de elección : la penicilina G administrada por vía parenteral

es el tratamiento de elección para todas las etapas de la sífilis ( tabla 1 ) [ 2 ]. Las
recomendaciones de tratamiento se basan en la farmacocinética de los medicamentos
disponibles, la tasa de crecimiento lento del microbio (la penicilina es activa contra los organismos
en división y requiere una exposición prolongada a los antimicrobianos para una destrucción
efectiva), la actividad in vitro de los agentes antimicrobianos contra T. pallidum y más de 50 años
de experiencia clínica [ 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 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
● 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 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 patients without HIV", 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
patients without HIV", 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 patients without HIV", 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 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 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 patients without HIV", 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 patients without HIV", section on
'Latent syphilis (asymptomatic)'.)
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 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 [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 "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, 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 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].
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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 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 [37,49,54].
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
• 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.
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 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 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.)
● 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.)
● 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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sus penicillin G benzathine for early syphilis. Cochrane Database of Systematic Reviews 20
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Treponema pallidum specimens from Madagascar. Sex Transm Dis 2009; 36:775.
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dc.gov/std/stats/CaseDefinitions-2014.pdf (Accessed on March 21, 2014).
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38. Augenbraun MH. Treatment of syphilis 2001: nonpregnant adults. Clin Infect Dis 2002;
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fluid after different treatment regimens for syphilis. Br J Vener Dis 1980; 56:363.
40. Gordon SM, Eaton ME, George R, et al. The response of symptomatic neurosyphilis to high-
dose intravenous penicillin G in patients with human immunodeficiency virus infection. N
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41. Walter T, Lebouche B, Miailhes P, et al. Symptomatic relapse of neurologic syphilis after
benzathine penicillin G therapy for primary or secondary syphilis in HIV-infected patients.
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43. Yim CW, Flynn NM, Fitzgerald FT. Penetration of oral doxycycline into the cerebrospinal fluid
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50. Augenbraun M, Rolfs R, Johnson R, et al. Treponemal specific tests for the serodiagnosis of
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52. Li J, Wang LN, Zheng HY. Predictors of serological cure and serofast state after treatment in
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Associated Factors Among Syphilis Patients With and Without HIV in a Sexually Transmitted
Infections Center, Thailand. Sex Transm Dis 2020; 47:283.
Topic 7597 Version 22.0
GRAPHICS
Clinical manifestations and treatment of syphilis in nonpregnant adults
Clinical Monitoring after

Treatment ¶
manifestations* treatment Δ
Early syphilis Primary syphilis: Preferred: Clinical exam and serologic

Typically consists of a single Penicillin G benzathine 2.4 testing with a nontreponemal
painless chancre at the site of million units IM once test (eg, RPR) at 6 and 12
inoculation, accompanied by Alternatives (choose months.
regional adenopathy. one) ◊: Titers should be checked more
Secondary syphilis: Doxycycline 100 mg orally frequently if the patient is HIV
A systemic illness that often twice daily for 14 days infected, follow-up is
includes a rash (disseminated Ceftriaxone 1 to 2 g daily uncertain, or reinfection is a
and/or involving the palms and IM or IV for 10 to 14 days concern.
soles), fever, malaise, and Tetracycline 500 mg orally
other symptoms such as four times daily for 14 days
pharyngitis, hepatitis, mucous
Amoxicillin 3 g plus
patches, condyloma lata,
probenecid 500 mg, both
alopecia.
given orally twice daily for
Early latent: 14 days
Refers to the period when a
patient is infected with
Treponema pallidum as
demonstrated by serologic
testing, but has no symptoms.
Early latent syphilis occurs
within the first year of initial
infection.
Late syphilis Tertiary syphilis: Preferred: Clinical exam and serologic

Patients with late syphilis who Penicillin G benzathine 2.4 testing with a nontreponemal
have symptomatic million units IM once weekly test (eg, RPR) at 6, 12, and 24
manifestations involving the for three weeks months.
cardiovascular system or Alternatives (choose one):
gummatous disease
(granulomatous disease of the Doxycycline 100 mg orally
skin and subcutaneous tissues, twice daily for four weeks
bones, or viscera). Ceftriaxone 2 g daily IM or
IV for 10 to 14 days
Late latent syphilis:
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.
Neurosyphilis Neurosyphilis: Preferred: Clinical and serologic

Can occur at any time during Aqueous penicillin G 3 to 4 monitoring with
the course of infection. million units IV every four nontreponemal tests (eg,
Early neurosyphilis: hours (or 18 to 24 million RPR). The frequency depends
Patients with early units continuous IV upon the stage of disease (eg,
neurosyphilis may have infusion) for 10 to 14 days § early or late).
asymptomatic meningitis; Penicillin G procaine 2.4 CSF monitoring may be
symptomatic meningitis; or million units IM daily plus warranted. ‡
less commonly probenecid 500 mg
meningovascular disease (ie, orally four times daily, both
meningitis and stroke). Vision for 10 to 14 days
or hearing loss with or without If possible, patients allergic

concomitant meningitis may to penicillin should be
also be present, and desensitized and treated
ocular/otologic syphilis is with IV penicillin
treated as neurosyphilis. Alternatives ¥:
Late neurosyphilis: Ceftriaxone 2 g IV daily for
The most common forms 10 to 14 days
involve the brain and spinal
cord (dementia [general
paresis] and tabes dorsalis).
CSF: cerebrospinal fluid; IM: intramuscular; IV: intravenous; RPR: rapid plasma reagin.
* Refer to the topics that discuss the clinical manifestations of syphilis and neurosyphilis for more detailed information.
¶ For the treatment of pregnant women and children, refer to the topics that discuss syphilis and pregnancy and
congenital syphilis.
Δ HIV-infected patients are typically monitored more frequently. Refer to the topic that discusses the treatment of syphilis
in patients with HIV infection.
◊ A single 2 g dose of azithromycin administered orally is an alternative only if other options are not possible since
azithromycin resistance is a concern.
§ For patients with late neurosyphilis, some UpToDate authors administer a single dose of benzathine penicillin G upon
completion of IV penicillin since the total duration of penicillin treatment for neurosyphilis is shorter than the regimens
used for late syphilis.
¥ Limited clinical experience suggests that doxycycline (200 mg orally twice daily) for 21 to 28 days may be effective as
an alternative regimen. However, this regimen should be reserved for exceptional circumstances.
‡ Refer to the topic on neurosyphilis for a more detailed discussion of monitoring after treatment.
Graphic 50435 Version 8.0
Contributor Disclosures
Charles B Hicks, MD Nothing to disclose Meredith Clement, MD Grant/Research/Clinical Trial Support:
Janssen [COVID-19]; Gilead [HIV]. Jeanne Marrazzo, MD, MPH, FACP, FIDSA Grant/Research/Clinical
Trial Support: BD Diagnostics [Vaginal infections, STI (diagnostic tests)]. Consultant/Advisory Boards: BD
Diagnostics [Vaginitis (diagnostic testing strategies)]; Gilead [HIV (pre-exposure prophylaxis)]. Other
Financial Interest: Gilead [HIV (Data and Safety Monitoring Board member)]. Jennifer Mitty, MD,
MPH Nothing to disclose
Las divulgaciones de los colaboradores son revisadas por conflictos de intereses por el grupo editorial.
Cuando se encuentran, se abordan examinando a través de un proceso de revisión multinivel y a través de
los requisitos de referencias que se proporcionarán para respaldar el contenido. Se requiere el contenido de
referencia apropiado de todos los autores y debe cumplir con los estándares de evidencia de UpToDate.
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4/7/2020 Syphilis: Treatment and monitoring - UpToDate

Reimpresión oficial de UpToDate ®

Sífilis: tratamiento y monitoreo

Aquí se revisará el tratamiento de la sífilis en adultos no embarazadas y la monitorización del

● (Consulte "Sífilis: detección y pruebas de diagnóstico" ).

ENFOQUE GENERAL DE LA TERAPIA ANTIMICROBIANA

La penicilina como tratamiento de elección : la penicilina G administrada por vía parenteral

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

● Testing for penicillin allergy and/or rechallenging with penicillin

● Desensitizing to penicillin if allergy testing is positive

● Using an alternative agent with close post-treatment monitoring

TREATMENT OF EARLY SYPHILIS

● Secondary – Approximately 25 percent of individuals with untreated primary infection will

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

TREATMENT OF LATE SYPHILIS

● Tertiary syphilis – Patients with gummatous or cardiovascular infection should have a

Alternative regimens for neurosyphilis — Patients should generally be desensitized to or

Alternatives to IV penicillin include:

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

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

MANAGEMENT OF TREATMENT FAILURE

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

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

• Signs or symptoms of syphilis that persist or recur

TREATMENT AFTER AN EXPOSURE

SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

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

SUMMARY AND RECOMMENDATIONS

including cardiovascular, gummatous, and neurologic complications. (See 'Introduction'

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

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

3. MAGNUSON HJ, THOMAS EW, OLANSKY S, et al. Inoculation syphilis in human

4. The pink sheet. F-D-C Reports. Chevy Chase, MD 2004, p.17.

9. Rein MF. Biopharmacology of syphilotherapy. J Am Vener Dis Assoc 1976; 3:109.

11. Riedner G, Rusizoka M, Todd J, et al. Single-dose azithromycin versus penicillin G

18. Li J, Zheng HY. Early syphilis: serological treatment response to doxycycline/tetracycline

20. Wong T, Singh AE, De P. Primary syphilis: serological treatment response to

27. Spornraft-Ragaller P, Abraham S, Lueck C, Meurer M. Response of HIV-infected patients

12, Issue 6. Art No.: CD007270.

32. Van Damme K, Behets F, Ravelomanana N, et al. Evaluation of azithromycin resistance in

36. Kingston M, French P, Higgins S, et al. UK national guidelines on the management of

39. Polnikorn N, Witoonpanich R, Vorachit M, et al. Penicillin concentrations in cerebrospinal

45. Butler T. The Jarisch-Herxheimer Reaction After Antibiotic Treatment of Spirochetal

46. Butler T, Aikawa M, Habte-Michael A, Wallace C. Phagocytosis of Borrelia recurrentis by

54. Atsawawaranunt K, Kittiyaowamarn R, Phonrat B, et al. Time to Serological Cure and

Topic 7597 Version 22.0

Clinical manifestations and treatment of syphilis in nonpregnant adults

Clinical Monitoring after

Early syphilis Primary syphilis: Preferred: Clinical exam and serologic

Late syphilis Tertiary syphilis: Preferred: Clinical exam and serologic

Neurosyphilis Neurosyphilis: Preferred: Clinical and serologic

or hearing loss with or without If possible, patients allergic

Graphic 50435 Version 8.0

Política de conflicto de intereses

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