Seminar
Syphilis
Lancet 2023; 402: 336–46
London School of Hygiene &
Tropical Medicine, London, UK
(Prof R W Peeling PhD,
D Mabey MD); University of
Manitoba, Winnipeg, MB,
Canada (Prof R W Peeling);
Institute of Dermatology,
Chinese Academy of Medical
Sciences and Peking Union
Medical College, Nanjing, China
(Prof X S Chen MD); National
Center for STD Control,
Nanjing, China (Prof X S Chen);
Center for Global Health,
Southern Medical University,
Guangzhou, China
(Prof X S Chen); School of Public
Health, Universidad Peruana
Cayetano Heredia, Lima, Peru
(P J Garcia, MD); University of
Washington, Seattle, WA, USA
(P J Garcia)
Correspondence to:
Prof Rosanna W Peeling, Clinical
Research Department, London
School of Hygiene & Tropical
Medicine, London WC1E 7HT, UK
rosanna.peeling@lshtm.ac.uk
336 www.thelancet.com Vol 402 July 22, 2023
Rosanna W Peeling, David Mabey, Xiang-Sheng Chen, Patricia J Garcia
Syphilis is a sexually and vertically transmitted bacterial infection caused by the bacterium Treponema pallidum. Its
prevalence is high in low-income and middle-income countries, and its incidence has increased in high-income
countries in the last few decades among men who have sex with men. Syphilis is a major cause of adverse pregnancy
outcomes in low-income and middle-income countries. Clinical features include a primary chancre at the point of
inoculation, followed weeks later by the rash of secondary syphilis, a latent period, and in some cases, involvement of
the eyes, CNS, and cardiovascular systems. It is diagnosed serologically. A single intramuscular dose of long-acting
benzathine penicillin is recommended for people who have had syphilis for less than 1 year and longer courses for
people with late latent syphilis. Control strategies include screening and treatment of all pregnant women, and
targeted interventions for groups at high risk. Vaccine development, research on antibiotic prophylaxis, and digital
messaging as prevention strategies are ongoing.
Introduction vaccine development and the WHO and UNAIDS goal of
Syphilis is a sexually and vertically transmitted bacterial global elimination of mother-to-child transmission of
infection caused by Treponema pallidum. It was HIV.
first described in Europe in the early 16th century,
leading to the suggestion that it was brought back from Epidemiology
North America by Columbus and his crew, but According to the most recent estimate by WHO, there
contemporary evidence suggests that it is more likely to were approximately 17·7 million adults aged between
have been imported from Africa through contact with 15 years and 49 years with syphilis globally in 2012, and
cases of yaws, as originally suggested by an estimated 6·3 million new cases in 2016.5,6 The
Thomas Sydenham in 1679.1 T pallidum is also the cause estimated prevalence and incidence varied substantially
of the non-venereal treponematoses yaws, pinta and by region and country, with the highest prevalence in
bejel (endemic syphilis), which are spread by skin-to- Africa, and more than 60% of new patient diagnoses
skin contact, mainly between children living in warm occurring in LMICs. High-income countries have a low
climates. Although these infections are caused by syphilis prevalence among heterosexual men and women,
different sub-species, these four sub-species are but they are witnessing a resurgence among men who
morphologically and antigenically indistinguishable, have sex with men (MSM). This resurgence is closely
they share more than 99·8% DNA sequence homology,2 associated with HIV infection and high-risk sexual
and the diseases they cause are clinically similar. This behaviours.7 Some studies have observed some degree of
supports the unitarian hypothesis, which states that the risk compensation for syphilis after the implementation
only difference between syphilis and the non-venereal of pre-exposure prophylaxis (PrEP) for HIV among
treponematoses is the route of transmission.3 populations at high risk, particularly in MSM.8,9 This risk
Syphilis can be diagnosed at the point of care (POC) by compensation signals the potential for future increases in
rapid lateral flow antibody test and effectively treated syphilis cases along with expansion of the PrEP, if no
with a single dose of long-acting penicillin; yet it remains interventions occur.10
a major cause of adverse pregnancy outcomes in many In the USA the incidence of primary and secondary
low-income and middle-income countries (LMICs), and syphilis among MSM (229 cases per 100 000 people) was
its incidence has increased in high-income countries in 243 times the rate for women (0·94 cases
the last few decades. Syphilis has been described as the per 100 000 people) in 2013, and 214 times the rate for
great imitator because of its many and varied clinical heterosexual men (1·07 cases per 100 000 people);11 but
manifestations.4 In this Seminar we describe the the reported rate of primary and secondary syphilis
epidemiology, clinical features, diagnosis, and among women doubled between 2014 and 2018, an
management of syphilis, and we assess progress towards increase strongly associated with injecting drug use.12
The number of patients diagnosed with congenital
syphilis increased four times between 2013 and 2018.13 In
Search strategy and selection criteria Canada, most provinces and territories reported increases
We searched PubMed to identify peer-reviewed articles in their infectious syphilis rates between 2014 and 2018
published in English between Jan 1, 2010, and Feb 28, 2021, with the highest being 261 cases per 100 000 people.14
using the terms “syphilis”, “syphilis epidemiology”, and In 2012, syphilis rates in men were 18 times higher than
“syphilis treatment”. We also referred to older literature on in women, with the highest rates observed in the age
the management and clinical presentations of the disease groups 25–29 years and 30–39 years. However, over the
written in the pre-penicillin era. past 5 years, infection rates have substantially increased
in women of reproductive age.15 Preliminary data indicate
 Seminar

a reduction in the male-to-female ratio of new syphilis

infections from eight males to one female in 2017, to
four males to one female in 2018, with the rate of
congenital syphilis in Canada in 2018, at its highest in the
last 25 years.14 In Europe an increase in syphilis incidence
has been reported since 2010 and this trend appears to be
accelerating, especially among MSM. Outbreaks in
heterosexual populations have also been reported, with
an increase in congenital syphilis cases.16
In LMICs, spread of syphilis among heterosexual
relationships has declined in the general population in
recent years,17 but prevalence remains high in sub-
populations at high risk such as female sex workers
(FSWs) and their male clients. A 2016 study of female sex
Figure 1: Primary chancre with desquamating palmar rash of secondary
workers in Johannesburg, South Africa, found that syphilis
21% of participating women had serological evidence of
past or current syphilis, and 3% had an active infection.18
In China, syphilis incidence and prevalence remains low
in the general population, but there is up to 5% prevalence
of syphilis among FSWs and 3% in their male clients.19–21
In 2016 the prevalence of syphilis in pregnant women
was estimated to be 0·69% globally with marked regional
differences, from 0·10% in the European region to 1·52%
in the African region.22 Worldwide syphilis in pregnancy
was estimated to have caused 397 000 adverse birth
outcomes in 2012 and 355  000 in 2016, including
143 000 early fetal deaths or stillbirths, and 61 000 neonatal
deaths.23 The decrease in adverse birth outcomes due to
syphilis between 2012 and 2016 is believed to reflect Figure 2: Papular palmar rash of secondary syphilis
increased access to syphilis screening and treatment at
antenatal clinics. However, 57% of the adverse birth syphilis present between 3 weeks and 8 weeks after the
outcomes in 2016 were estimated to have been in women initial appearance of the primary chancre.
who had attended an antenatal clinic for HIV screening The rash of secondary syphilis can be macular or
but were not screened for syphilis, representing a missed papular, is often desquamating, typically affects the palms
opportunity.23 and soles, and does not itch (figure 2). Other common
signs include oral ulceration or mucous patches,
Clinical presentation, signs, and symptoms generalised lymphadenopathy, and in moist areas such as
After an incubation period of 10–70 days (median 21 days) the axillae and perineum, soft, raised wart-like lesions
a primary chancre develops at the site of inoculation known as condylomata lata (figure 3). Fever, hepatitis, and
(figure 1).7,24 The chancre is typically a painless, single, nephritis might also be seen in secondary syphilis.
non-tender, indurated ulcer, with a raised edge and a Lumbar puncture is not routinely recommended in
clean base. The primary presentation of syphilis has also patients who are HIV negative, but can reveal
been described with two or more painful ulcers,25,26 but it cerebrospinal fluid (CSF) abnormalities. On serum
might be accompanied by regional lymphadenopathy, testing, raised protein and cell counts are commonly seen
which is also typically painless and non-tender. None of in the blood of patients with secondary syphilis and these
the known characteristics of the chancre are sufficiently can be accompanied by meningeal symptoms. The
specific and, in fact, the differential diagnosis of syphilis significance of these findings and the need for treatment
has to be included in the face of any mucosal ulceration in patients with no clinical evidence of neurological
or erosion. Since the chancre is usually painless and, in involvement remains unclear and continues to be an area
women, is often on the cervix, the patient might be of controversy. The significance of positive syphilis
unaware of it. serology on CSF samples is difficult to assess due to the
The differential diagnosis of primary syphilis includes passive transfer of antibodies from blood through the
genital herpes simplex, lymphogranuloma venereum, blood–brain barrier. Ocular involvement can also be seen
Behçet’s disease, and less common sexually transmitted in secondary syphilis, most commonly posterior uveitis or
diseases (STDs) such as chancroid and granuloma panuveitis, which can lead to blindness unless promptly
inguinale. The primary chancre usually resolves treated.27 It has been suggested that ocular and CNS
spontaneously over several weeks. The signs of secondary involvement is more common in patients with HIV.28

www.thelancet.com Vol 402 July 22, 2023 337

 Seminar
Figure 3: Condylomata lata of secondary syphilis
Figure 4: Bullous rash in a neonate with congenital syphilis
Figure 5: Macular, desquamating rash in a baby with congenital syphilis
The lesions of secondary syphilis generally resolve
within a few weeks in the absence of treatment, although
studies from the pre-antibiotic era suggest that syphilis
relapses in about 25% of patients, usually within the
first year.29 The disease then enters the latent stage, with
no symptoms or signs, but the patient is at risk of
developing tertiary syphilis in the future. Studies from
the pre-antibiotic era suggest that, in the absence of
treatment, approximately a third of patients will develop
tertiary syphilis. The lesions of tertiary syphilis fall into
three categories: gummatous, cardiovascular, or
neurosyphilis. A gumma is a painless, punched-out ulcer
with little or no inflammatory reaction, usually affecting
the skin, but occasionally involving bones or viscera.
338 www.thelancet.com Vol 402 July 22, 2023
Cardiovascular lesions include aortitis, aortic aneurysm,
aortic valve disease, and coronary ostial occlusion.
Involvement of the CNS can occur at any time in the
course of syphilis. Mild meningeal symptoms are not
uncommon in secondary syphilis, and can resolve
without treatment.30 Meningovascular syphilis, due to
inflammation of small arteries in the brain or spinal
cord, presents typically as a stroke 5–10 years after
infection. Later neurological manifestations include
tabes dorsalis, due to involvement of the posterior
columns of the spinal cord, and general paresis, a form
of progressive dementia sometimes with psychotic
features. These late manifestations were commonly seen
in the pre-antibiotic era but are now rare.
Children born to women with untreated syphilis are at
risk of congenital syphilis, acquired in utero. The risk is
highest in babies born to women with primary, secondary,
or early latent syphilis. In the absence of treatment, a
study in Tanzania showed that 25% of women with latent
syphilis (and rapid plasma reagin [RPR] titres of 1:8 or
higher), will deliver a stillborn baby, and 33% of women
with untreated syphilis will deliver a low-birthweight
baby.31 Signs of syphilis in the neonate include a
generalised, bullous rash (figure 4), anaemia, jaundice,
and hepatosplenomegaly. Infants with congenital
syphilis can appear healthy at birth and present in the
first few months of life with failure to thrive, a
desquamating rash that usually affects the palms and
soles (figure 5), persistent nasal discharge, anaemia, and
hepatosplenomegaly. Bone involvement (osteitis or
periostitis) is common and can cause pseudoparalysis of
a limb due to pain, but it is not always clinically apparent.
Older children can present with late complications,
including deafness, interstitial keratitis, and
abnormalities of the bones and teeth (figure 6).
Pathophysiology
Syphilis is caused by the spirochaete Treponema pallidum
(order Spirochaetales), a long, thin, slowly growing spiral
shaped bacterium that, until recently, could not be
cultured in vitro, but can now be cultured in rabbit tissue
cells.32 Transmission occurs during sexual contact with
an actively infected partner. Spirochaetes directly
penetrate mucous membranes or they enter through
abrasions in skin. To establish infection, T pallidum must
adhere to epithelial cells and extracellular matrix
components. Once below the epithelium, organisms
multiply locally at the site of the primary chancre and
later disseminate through lymphatics and bloodstream
giving rise to the lesions of secondary syphilis.33
Although a local inflammatory response to T pallidum
causes the clinical manifestations of syphilis, the
mechanisms that cause tissue damage and the host
defenses that eventually gain a measure of control over
the bacterium are poorly defined. Perivascular infiltrates
composed of lymphocytes, histiocytes, and plasma cells,
accompanied by endothelial cell swelling and proliferation

are histological hallmarks of syphilis, regardless of site or
disease stage. Endothelial swelling and proliferation can
progress to frank endarteritis obliterans, leading to
occlusion of arteries and severe clinical manifestations,
such as the stroke syndromes of meningovascular
syphilis.
T pallidum has an abundance of lipoproteins that are
predominantly located below its cytoplasmic surface. This
feature enables the spirochaete to avoid triggering host
innate immune mechanisms, facilitating local replication
and early dissemination. The low surface antigenicity of
T pallidum promotes evasion of adaptive immune
responses, facilitating persistence, and earning T pallidum
its recognition as the “stealth pathogen”.33,34
Diagnosis
T pallidum can be detected in the lesions of primary and
secondary syphilis. Traditionally this diagnosis was done
by dark field microscopy, which requires a dark field
microscope condenser and a skilled microscopist, and is
no longer widely used. Nucleic acid amplification tests
have been used to detect the DNA of the spirochaete in
skin, mucosal, oral or rectal lesions.35,36 These tests for
early syphilis could play an important role in controlling
the syphilis epidemic. A study in 2019 has shown that the
combination of antibody and nucleic acid amplification
testing in a population that is at high risk from the
disease (ie, MSM) can increase the sensitivity of syphilis
screening.37 There is also the potential to use nucleic
amplification tests in neonates with congenital syphilis.
However, they are not recommended for use with blood
or CSF as few organisms are present. These nucleic acid
amplification tests require technical expertise and
laboratory equipment, have not been thoroughly
clinically validated, and are not widely available.
Antibodies to T pallidum are detectable 10–15 days after
the appearance of the primary chancre, and syphilis is
usually diagnosed serologically.38 There are two categories
of serological tests for syphilis, one that detects non-
treponemal antibodies and the other that detects
treponemal antibodies.
Non-treponemal tests (NTTs) include rapid plasma
reagin (RPR), the Venereal Disease Research Laboratory
(VDRL), and the toluidine red unheated serum test
(TRUST). They use antigens synthesised from lecithin,
cholesterol, and cardiolipin to detect
IgG and IgM antibodies produced in response to
T pallidum infection by agglutination of antigen-coated
particles. NTTs can be performed as qualitative assays for
screening or as quantitative assays, using doubling
dilutions to determine titre, to help stage infection and
assess the response to treatment. Low titre (1:2 or 1:4)
biological false positive NTT results, with a negative
treponemal test, occur in about 2−5% of the population.
As the antigen is not specific for T pallidum, false positive
results can be due to acute febrile illnesses, pregnancy, or
chronic conditions such as autoimmune diseases,
www.thelancet.com Vol 402 July 22, 2023 339
Seminar
Figure 6: Notched incisors of Hutchinson’s teeth in a child with congenital
syphilis
hepatitis C, or leprosy. False negative results can occur
when there is an excess of antibody, a phenomenon
known as the prozone effect. This can be resolved if
serum samples are tested in 2 or 3 dilutions. Titres
generally decline after treatment and become non-reactive
within 12 months. However, about 10% of individuals
with syphilis have a persistently reactive NTT even after
effective treatment (the so-called serofast state).39
Treponemal tests detect antibodies to T pallidum
proteins and are highly specific, although they do not
distinguish between syphilis and the non-venereal
treponematoses. As treponemal antibodies usually
persist for life, they cannot be used to distinguish
between active, past, or previously treated infection, or as
a test of cure. Treponemal tests include the fluorescent
treponemal antibody absorbed (FTA-ABS) test, the
T pallidum particle agglutination (TPPA) and T pallidum
haemagglutination (TPHA) assays, and a number of
commercially available enzyme immunoassays.
Treponemal tests have traditionally been used as
confirmatory assays following a positive NTT result but,
since treponemal enzyme immunoassays and rapid tests
became available, a reverse testing algorithm has been
adopted in some countries. In this algorithm, patients
are first screened using a treponemal test, and those who
test positive then have an NTT to distinguish between
active and previously treated syphilis.40
Rapid, serological tests that can be performed at the
point-of-care (POC) and meet the ASSURED criteria (they
are affordable, sensitive, specific, user friendly, rapid and
robust, equipment-free, and deliverable) are now available
for syphilis.41 These are lateral flow assays, which only
require one drop of blood obtained from a finger prick
and can give a result in 15 min, enabling immediate
treatment of those who test positive. Systematic reviews of
commercially available rapid treponemal tests showed
that these tests have sensitivities of 76–86% and
specificities of 96–99% compared with laboratory
reference assays such as TPPA.42,43 Studies to implement
 Seminar
HIV–syphilis dual rapid diagnostic tests
Syphilis
Positive Negative Negative
Treat
Figure 7: Syphilis testing and treatment algorithm for prenatal screening50
Pregnant women who have tested positive and received treatment during a
previous pregnancy should be considered for re-treatment on receiving a
positive syphilis test result in subsequent pregnancies.
HIV–syphilis dual rapid diagnostic tests
Syphilis
Treat if no previous treatment Positive Negative Negative
Non-treponemal tests
Positive Negative
Treat
Figure 8: Syphilis testing and treatment algorithm for populations at high risk50
these tests show that they can be catalysts for health-
system strengthening as well as saving newborn lives.44,45
A rapid POC test that detects both treponemal and non-
treponemal antibodies, and can therefore distinguish
between active, previous, and treated infection, has been
evaluated in several settings and found to be both
sensitive and specific.46–48 Although the sensitivity of the
non-treponemal component is lower in samples with a
low (<1:8) RPR titre.46,47,48
Dual HIV–syphilis (treponemal) rapid tests are also
available and can be used to expand screening in prenatal
and high-risk populations.49 WHO has published
algorithms on how to use them in high-prevalence and
low-prevalence settings (figure 7 and 8).50 A systematic
review showed that they have satisfactory performance
and three tests have been pre-qualified by WHO.51–53 The
use of a single specimen to screen for both HIV and
syphilis in prenatal and populations at high risk is more
efficient and cost saving compared with separate
340 www.thelancet.com Vol 402 July 22, 2023
screening programmes.54,55 These rapid POC tests not
only make testing accessible for syphilis diagnosis in
general, but also play an important role in reducing
adverse pregnancy outcomes and moving towards the
HIV global elimination of congenital syphilis by ensuring that
all pregnant women are screened and treated at their first
visit to the antenatal clinic.23
Patients with neurological symptoms or signs should
Positive
have a lumbar puncture. Since there is no standard test for
the diagnosis of neurosyphilis, a combination of laboratory
Refer for confirmatory tests and clinical signs and symptoms is used.56–58 A reactive
testing
CSF VDRL test is highly predictive of neurosyphilis, but
less than 80% sensitive. More than five white cells
per mm³ of CSF (or >20 cells per mm³ in patients with
HIV who are not receiving antiretroviral therapy) is a
sensitive but not a specific marker for neurosyphilis.
CSF protein concentrations can be elevated in patients
with neurosyphilis, but this finding has low sensitivity and
specificity. In low-resource settings where syphilis and
HIV are prevalent, rapid and simple tests should be
integrated with less invasive and more acceptable
approaches of specimen collection. Studies in people with
HIV and without HIV have shown that patients with a serum
RPR titre greater than or equal to ≥1/32 or a peripheral
blood CD4 count less than 350 cells per mL, or both, were
Positive significantly more likely to have neurosyphilis, indicating
use of criteria based on these tests could improve the
ability and efficiency to identify asymptomatic
Refer for confirmatory
testing neurosyphilis.59
The diagnosis of congenital syphilis can be difficult
since maternal IgG antibodies cross the placenta,
complicating the interpretation of reactive serological
tests in neonates. Treatment decisions must be made on
the basis of the identification of syphilis in the mother,
adequacy of maternal treatment, presence of clinical,
laboratory, or radiographic evidence of syphilis in the
neonate, and comparison of maternal (at delivery) and
neonatal NTT titres.40
Management
Penicillin remains the treatment of choice for syphilis,
and resistance to penicillin has never been reported in
T pallidum. There was a worldwide shortage of benzathine
penicillin which has been resolved.60–62 For treatment of
early syphilis WHO, the US Centers for Disease Control
and Prevention (CDC), and European guidelines
recommend a single dose of intramuscular benzathine
penicillin, or intramuscular procaine penicillin daily for
10 days. Since T pallidum divides more slowly than most
bacteria, it is necessary to maintain penicillin
concentrations in the blood above the minimum
inhibitory concentration for at least 10 days. The
CDC treatment guidelines are shown in the table.40
Although a single dose of benzathine penicillin G is
effective in most cases of early syphilis, some experts
recommend that primary, secondary, and early latent
cases be treated with two doses of benzathine penicillin G
 Seminar

2·4 million units 1 week apart, particularly in pregnant
women. This recommendation is due to difficulty in
accurately staging cases of syphilis and physiological
changes in pregnancy that can alter the pharmacokinetics
of penicillin and reduce plasma penicillin levels.63 Soon
after the onset of treatment, around 30% of patients will
experience a Jarisch-Herxheimer reaction, with fever,
rigors, myalgia, and arthralgia. This is more common in
patients with secondary syphilis, and usually resolves
within 24 h. Patients with a Jarisch-Herxheimer reaction
can be treated with antipyretics.
Patients who are allergic to penicillin should be treated
with doxycycline or ceftriaxone (unless penicillin allergy
was severe or a type 1 IgE-mediated hypersensitivity
reaction, given the small risk of cross-reactivity with
cephalosporins) or treated with penicillin following
desensitisation. A single oral dose of azithromycin 2 g
was shown to be equivalent to benzathine penicillin in
the treatment of early syphilis in two trials in Africa,64,65
but strains of T pallidum with mutations conferring
resistance to azithromycin and other macrolides are now
common worldwide and macrolides are no longer
recommended, except in situations in which alternative
treatments cannot be given and close follow-up can be
guaranteed.66–69
Patients with late latent syphilis (>1 year post-infection)
should receive longer courses of treatment with
benzathine penicillin or procaine penicillin than the
courses given for early syphilis. Similarly, for those with
late syphilis who cannot be treated with penicillin, longer
schedules of doxycycline are recommended, followed up
with repeat NTT serology (table).
CNS involvement can occur at any stage of syphilis but,
in the absence of clinical evidence of ocular or
neurological symptoms or signs, there is no need for
more intensive treatment. Patients with neurosyphilis, or
with ophthalmic or auditory abnormalities should be
treated with high-dose aqueous crystalline, or daily
intramuscular procaine penicillin plus probenecid for
10–14 days (table).
Patients who are HIV positive with early syphilis are
more likely to have CSF abnormalities than those who
are HIV negative.39,70 Since the single dose of benzathine
penicillin recommended for treatment of early syphilis
does not reliably lead to a treponemacidal level in
the CSF, it has been suggested that patients with HIV
and early syphilis should receive more intensive
treatment. A randomised controlled trial compared the
outcomes of treatment for early syphilis between patients
who received a single injection of benzathine penicillin
and patients who received enhanced therapy comprising
benzathine penicillin, amoxicillin, and probenecid. 101 of
the 541 patients enrolled were HIV positive. There was
no significant difference in clinical outcome between
patients receiving standard or enhanced treatment.39
However, people with HIV responded less well

Treatment option 1 Treatment option 2 Treatment option 3

Primary and secondary syphilis in non-
pregnant adults, including adults with
HIV
Early latent syphilis in non-pregnant
adults, including adults with HIV
Late latent syphilis in non-pregnant
adults, including adults with HIV
Late syphilis (gummas and
cardiovascular manifestations) but not
neurosyphilis
Neurosyphilis and ocular syphilis
Primary and secondary syphilis in
pregnancy
Early latent syphilis in pregnancy
Late latent syphilis in pregnancy
Congenital syphilis
Penicillin G benzathine, 2·4 million units in a single Doxycycline, 100 mg orally twice a day for Ceftriaxone, 1 g daily, intramuscular or
intramuscular dose 14 days intravenous, for 10–14 days
Penicillin G benzathine, 2·4 million units in a single Doxycycline, 100 mg orally twice a day for ··
intramuscular dose 28 days
Penicillin G benzathine, 7·2 million units total, Doxycycline, 100 mg orally twice a day for ··
administered in 3 intramuscular doses of 28 days
2·4 million units each at 1-week intervals
Penicillin G benzathine, 7·2 million units total, ·· ··
administered in 3 intramuscular doses of
2·4 million units each at 1-week intervals
Aqueous crystalline penicillin G, Penicillin G procaine, 2·4 million units in a single ..
18–24 million units per day, administered in intramuscular dose daily, plus probenecid,
INTRAVENOUS doses of 3–4 million units every 4 h 500 mg administered orally four times per day,
or as a continuous infusion, for 10–14 days both for 10–14 days
Penicillin G benzathine, 2·4 million units in a single ·· ··
intramuscular dose
Penicillin G benzathine, 2·4 million units in a single ·· ··
intramuscular dose
Penicillin G benzathine, 7·2 million units total, ·· ··
administered in 3 intramuscular doses of
2·4 million units each at 1-week intervals
Aqueous crystalline penicillin G Procaine penicillin G 50 000 units/kg per dose ..
100 000–150 000 units/kg per day, administered as intramuscular in a single daily dose for 10 days
50 000 units/kg per dose intravenous every 12 h
during the first 7 days of life and every 8 h
thereafter for a total of 10 days

Table: Centers for Disease Control and Prevention Syphilis Treatment Guidelines40

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serologically and, due to loss of patients during follow-
up, the study was underpowered to detect a clinical
difference. Given the inconclusive results of this and
other studies, many clinicians continue to offer enhanced
therapy to patients with both HIV and early syphilis.
Since it is not possible to confirm or exclude the
presence of viable T pallidum after treatment the efficacy
of treatment for syphilis is measured indirectly, using
serology. Cure is usually defined as reversion to negative,
or a four-fold drop in titre of an NTT such as the RPR or
VDRL.7 However, few patients remain seropositive, or do
not attain this reduction threshold, despite almost
certainly having been cured and with no evidence of
progressive disease—the so-called serofast state.39 The
management of these patients depends on taking a
detailed sexual history to exclude the possibility of
reinfection, which can be challenging. The serofast state is
more commonly seen in patients with late syphilis and
low RPR titres, and in HIV-positive patients who are not
on antiretroviral treatment.39 Since few data are available
on long-term clinical outcomes for patients in a serofast
state, CDC guidelines recommend continuing clinical
follow-up, and retreatment if follow-up cannot be
ensured.40
A study in Tanzania showed that adverse pregnancy
outcomes due to syphilis can be prevented with a single
dose of benzathine penicillin given before 28 weeks’
gestation.71 In that setting, in which 5–6% of pregnant
women had syphilis, this was one of the most cost-effective
interventions available in terms of cost per disability-
adjusted life-year saved.72 Pregnant women who test
positive using a rapid syphilis (treponemal) test should be
given a dose of benzathine penicillin without waiting for a
confirmatory test for active infection, as the confirmatory
test often has to be sent to a laboratory and women might
fail to return for their follow-up appointments. Long-acting
penicillin is the only antibiotic known to be effective in
preventing adverse pregnancy outcomes due to syphilis.60
Since doxycycline is contraindicated in pregnancy, and
macrolides such as azithromycin and erythromycin do not
cross the placenta, there are few alternatives to penicillin
for the treatment of pregnant women with syphilis who
are allergic to penicillin. WHO and CDC recommend
desensitisation and treatment with penicillin for those
who are allergic to penicillin or, alternatively, treatment
with ceftriaxone.40
Infants with confirmed congenital syphilis, and infants
born to mothers with syphilis who are asymptomatic but
whose mothers were not treated with a recommended
penicillin-containing regimen more than 30 days before
delivery, should be treated with aqueous benzyl penicillin
intravenously or intramuscular procaine penicillin daily
for 10 days (see table).
Control and prevention
As for other sexually transmitted infections, primary
prevention through health education and condom
342 www.thelancet.com Vol 402 July 22, 2023
promotion should be encouraged. Control programmes
worldwide have known since the 1930s that testing is a
critical component of syphilis control. Premarital syphilis
testing used to be mandatory, as was prenatal screening,
and on entry into military service, certain businesses,
and educational institutions. With the decline in syphilis,
all these testing requirements ceased except for screening
and treatment of pregnant women, which remains
recommended in almost every country.
With most pregnant women accessing antenatal care
and the availability of reliable rapid POC tests, prenatal
syphilis screening should be feasible, even for populations
in LMICs that do not have access to laboratory testing.
In 2015, Cuba became the first country to be validated for
the elimination of mother-to-child transmission of HIV
and syphilis (eMTCT).73 Since then, 15 other countries,
Anguilla, Antigua, Armenia (HIV only), Barbuda, Belarus,
Bermuda, Cayman Islands, Malaysia, Maldives, Moldova
(syphilis only), Montserrat, Oman, Saint Kitts and Nevis,
Sri Lanka, and Thailand have achieved eMTCT.73 The
important lesson here is that countries do not need to have
high incomes to achieve dual eMTCT. What it takes is
political will, a well-functioning health-care system in
which no one is left behind in provision of prenatal testing
and timely treatment, and follow-up of sexual partners for
testing and treatment. In the Western Pacific Region of
WHO, member states endorsed the Asia Pacific Regional
Framework for Triple Elimination of Mother-to-Child
Transmission of HIV, Hepatitis B and Syphilis 2018–2030.74
However, the opportunities for prevention of congenital
syphilis with timely syphilis diagnosis and treatment of
pregnant women and their partners with syphilis, are still
missed by many settings in either LMICs or high-income
countries.
Screening programmes for groups at high risk, and
notification and treatment of sexual partners of patients
with syphilis are also recommended. Most cases of syphilis
in high-income countries are in MSM, among whom HIV
co-infection is common. Adopting the dual HIV–syphilis
rapid screening test for MSM would be useful. Regular
screening of patients with HIV, and those using pre-
exposure prophylaxis against HIV, is a high priority. China
has implemented effective national syphilis control
programmes targeting both groups at high risk and
pregnant women through cross-cutting strategies focusing
on Three Screenings Linked to One Standardized Care
(3 × 1 Screening Linked to Standardised Care), in addition
to continuously promoting sustained behaviour change
and condom promotion which is integrated into HIV
prevention.75,76
Increasingly, more tools and options have been developed
to improve syphilis messaging and testing in populations
at high risk. The success of self-testing and using dried
blood spots to increase access to HIV testing might
translate into similar programmes for syphilis or into
integrated HIV and syphilis programmes.77–80 Different
models of provision or distribution of self-testing have been

reported.81,82 The use of a social entrepreneurship model or
monetary incentives to promote self-testing in China was
successful at increasing uptake of testing and access to care
for people with HIV and syphilis.83,84 In addition, a study in
South Africa indicated that allocation of a gift (a US$5 food
voucher for families) to a family could significantly increase
the probability of family members consenting to home-
based HIV testing in the same year by 25 percentage
points.85
Innovative approaches for populations at high risk are
being piloted, with social network strategies and
technologies used to promote the uptake of testing. A
randomised controlled trial aimed at promoting the uptake
of syphilis testing by recruiting participants from an
MSM-oriented mobile social app is ongoing.86 Participants
are randomised to one of three groups: (1) the control
group in which participants are provided information
about local STD services and encouraged to take up free
syphilis testing at their local testing or counselling clinic;
(2) a standard self-test group in which participants can
request syphilis self-tests online and packages are sent by
mail, along with text message reminders for testing;
(3) a lottery incentivised self-testing group in which
participants are provided with the interventions in both the
control group and the standard syphilis self-testing group.
In addition, participants who confirm that they have tested
for syphilis during the trial period either through self-
testing or facility-testing will be entered into a lottery draw.
The primary outcome is the proportion of participants who
tested for syphilis in the past 3 months. The use of the
internet and text messaging to remind those at high risk of
testing and to notify partners of syphilis cases has been
shown to be effective in increasing the detection of early
syphilis in asymptomatic individuals before progression to
secondary syphilis.87–90
For clinic-based settings, a systematic review comparing
the cost and effectiveness of different interventions to
improve STD screening or rescreening in clinic-based
settings published between 2000 and 2014 showed that
low-cost interventions such as strategic placement or
automated collection of specimens and electronic health
records were effective and low cost.91 Patient reminders for
screening or rescreening using text, telephone, or
postcards were highly or moderately effective at low or
moderate cost. Having dedicated clinic staff to promote
and carry out testing was effective but came at a high cost.
In this digital age, electronic readers for rapid tests can
prevent subjective reading of the rapid test results, and the
digitised data can be transmitted automatically to a central
database for real-time surveillance.92
Outlook and future research
A vaccine against syphilis is a high priority and there is
evidence that previous infection and vaccination can give
rise to protective immunity against T pallidum. Studies in
the rabbit model showed (likely in the 1950s) that
untreated animals infected with T pallidum for 3 or more
www.thelancet.com Vol 402 July 22, 2023 343
Seminar
months are completely protected from symptomatic
reinfection with the same isolate, and can be protected
from symptomatic infection with a different
(heterologous) isolate.93 Vaccination of rabbits with
gamma-irradiated T pallidum provides complete
protection against homologous infection,94 and a subunit
vaccine has been shown to reduce the bacterial organ-
load following T pallidum challenge.95 That protective
immunity is conferred by previous infection with
T pallidum in humans was first noted almost 200 years
ago by Abraham Colles, who reported that chancres of the
nipple were commonly seen in women who breastfed
infants with congenital syphilis who were not their own,
but they were not seen in breastfeeding mothers of such
infants.96 Protective immunity has been confirmed in a
recent study that showed that previous syphilis attenuates
the clinical and laboratory manifestations of T pallidum
infection.97
The incidence of congenital syphilis decreased worldwide
between 2012 and 2016 although maternal prevalence was
stable,22 suggesting that the reduction was due to increased
access to antenatal screening and treatment. Achieving
global elimination, however, will require further
improvements in access to screening and treatment of
early antenatal syphilis, improving partner management,
and reducing syphilis prevalence in the general population
by expanding testing, treatment, and partner referral,
which could be difficult to achieve due to the impact of the
COVID-19 pandemic on health-care seeking and provision.
Only through effective control of the infection among
populations at high risk such as MSM, female sex workers,
and their clients can the elimination of mother-to-child
transmission of syphilis be made sustainable. The
diagnosis of congenital syphilis has been difficult as
IgM tests are not sufficiently sensitive, especially in infants
who are asymptomatic. Recent studies on an IgA antibody
test to diagnose active syphilis also have potential as a
diagnostic test for congenital syphilis since IgA does not
cross the placenta.98 Facing the increase of congenital
syphilis cases in high-income countries, further studies on
innovative strategies including the use of POC testing in
these countries are needed.
Research into the prevention of syphilis transmission
in populations at high risk are ongoing, with particular
concern over the syndemics of HIV, hepatitis C, and
syphilis.99,100 Preliminary results from an open-label trial
in France showed that antibiotic prophylaxis with a single
dose of doxycycline 200 mg was effective in reducing the
incidence of both chlamydia and syphilis in people
taking PrEP.101 Although these early results are
promising, concerns about its sustainability, potential
impact on antibiotic resistance, and possible rebound in
infections following the conclusion of the study need to
be addressed.102
Looking into the future, a better understanding of
syphilis transmission, including estimates of trans­
missibility for primary and secondary syphilis, and the
 Seminar
extent and duration of infectiousness in latent syphilis is
needed. Accurate tests to aid in the diagnosis of congenital
syphilis, reinfection, and a test of cure would be useful.
Research to elucidate host immune responses to infection,
especially the serofast state, and how treatment at varying
stages of infection modifies the risk of re-infection could
translate into better patient management. Ultimately,
research on disease-prevention methods including
antibiotic prophylaxis, and how best to incentivise healthy
sexual behaviours in people at risk from syphilis, offer the
best hope in control and elimination of this silent
epidemic.
Contributors
RWP and DM conceived the paper and all authors contributed to the
writing and finalisation of the manuscript.
Declaration of interests
We declare no competing interests.
Acknowledgments
For photo credits, we gratefully acknowledge: 1) photos for the first
4 figures provided by Prof David Mabey; 2) Figures 5 and 6 provided to us
by Dr. Ming-Zhi Wu from the Suzhou Fifth People’s Hospital, Suzhou,
China. Patient consent obtained (or parental consent) for each photo.
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