Download Play your part in managing syphilis

The Pharmaceutical Journal 263
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Play your part in managing syphilis
Syphilis is not a disease of the past. Cases in the UK have been rising. This article gives an
overview of the disease and its treatment and discusses what pharmacists can do
LUCY HEDLEY PGDIPGPP, MRPHARMS, ROTATIONAL CLINICAL PHARMACIST, AND PREET PANESAR DIPCLINPHARM, MRPHARMS, LEAD PHARMACIST,
MICROBIOLOGY, UCLH NHS FOUNDATION TRUST
Reflect
SYPHILIS is a predominantly
sexually transmitted infection
caused by the spirochaete
bacterium Treponema pallidum.
In the early stages the disease
is usually easily treatable but
not all of those infected
experience symptoms and, if
untreated, serious complications,
including blindness, stroke,
aortic aneurysm and paralysis,
can arise.
Evaluate
Plan
Act
REFLECT
Numbers
The World Health Organization
estimates that around 12 million
new cases of syphilis occur
worldwide every year. The bulk
(eight million) of these are in
south-east Asia and subSaharan Africa but high
rates are also
observed in central
Asia and eastern
Europe.1
In western
Europe the
WHO estimates
there are
140,000 new
cases of syphilis
each year and
diagnosis has risen
substantially in the past decade
in the UK. In 2007, 3,762
diagnoses of infectious syphilis
were made — more than in any
other year since 1950.2 There
was a slight decrease in 2010
but by last year cases of
infectious syphilis had
increased by 10 per cent.3
The prevalence of new
infections is significantly
greater in men than in women,
with men accounting for 90 per
cent of new diagnoses.3
In the UK syphilis is largely
concentrated among men
who have sex with men
(MSM) — where sexual
orientation was recorded in male
cases, 75 per cent of diagnoses
was among this group. MSM
syphilis diagnoses in England
increased by 28 per cent from
2010 to 2011. A number of
factors are likely to have
contributed to this sharp rise.
1 What are the symptoms of
syphilis?
2 What are the treatment
options?
3 What role can pharmacists
play in the management of
syphilis?
Before reading on, think about
how this article may help you to
do your job better.
Left: primary syphilis chancre DR MA ANSARY/SPL ; Above: secondary
syphilis rash MARTIN M ROTKER/SPL
Use of
inaccurate
syphilis tests during
2011 may have led to
some patients being
incorrectly diagnosed with
syphilis, although this is likely to
have only marginally increased
the numbers. Reporting of sexual
orientation has improved in
recent years, leading to a greater
number of diagnoses being
assigned to MSM than
previously.3
A significant proportion of STI
diagnoses among MSM continue
to be in the younger age groups
and 14 per cent of syphilis cases
are in those aged between 15 and
24 years of age.3
In England there was an 85 per
cent increase in the numbers of
new diagnoses of primary,
secondary and early latent
syphilis in genitourinary
medicine clinics between 2002
and 2011.3 This rise has been
attributed to a number of local
outbreaks, the largest of which
was in London between 2001
and 2004.2
Transmission and risks
KEY POINTS
is a disease that has
• Syphilis
serious consequences if
•
undiagnosed and untreated.
Pharmacists can help slow the
increase in cases in the UK be
being aware of the disease
symptoms and promoting good
sexual health.
T pallidum is a human pathogen
that does not naturally appear in
other species. Transmission is by
penetration of through mucous
membranes by the spirochaete or
through abrasions on epithelial
surfaces. This usually occurs by
direct contact with an infectious
lesion or skin rash, (eg, during
sexual contact) but visible sores
or rash are not necessary for
transmission. The person
remains sexually infectious until
about two years after secondary
syphilis (see later) has cleared.
The infection can also be
transmitted in pregnancy
(vertical transmission) or via
infected blood products.
T pallidum cannot survive
drying or exposure to
disinfectants, so fomite
transmission (eg, from toilet
seats) is almost impossible.
Patients should be advised to
refrain from sexual contact of
any kind until the results of the
first follow-up blood tests
confirm they are clear of
infection.4 Those with lesions
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should also wait until these are
fully healed.
Unprotected sex, promiscuous
sex and intravenous drug use are
the major risk factors for
transmission of syphilis.
Ongoing high levels of high-risk
sexual behaviour have probably
contributed to the rise of the
disease in MSM and this group
remains a priority for targeted
STI prevention and health
promotion work.
Because it causes genital ulcers,
syphilis is associated with an
increased risk of HIV
transmission and acquisition.
Co-infection is common in those
with syphilis (27 per cent).2
As the number of syphilis cases
in women of reproductive age
has grown this has resulted in an
increase in cases of congenital
infection.1
Healthcare workers are at
potential risk of transmission
through needlestick injuries or
contact with lesions.
Late syphilis
Early syphilis
Primary
syphilis
Chancre(s)
Secondary
followed by
syphilis
lymphoedema
Rash, fever,
lymphoedema, Early latent syphilis
sore throat,
malaise,
weight loss,
hair loss,
headaches
Late latent syphilis
No symptoms
Tertiary syphilis
Gummatous syphilis,
cardiovascular syphilis,
neurosyphilis
0
3 months
2 years
Figure 1: Progression of acquired syphilis without treatment
PANEL 1: CLINICAL FEATURES OF TERTIARY SYPHILIS
Gummatous syphilis
Timing after infection
1–46 years
(average 15 years)
Cardiovascular syphilis
10–30 years
Neurosyphilis
Early
Late (4–25 years)
Signs and symptoms
Formation of chronic gummas, which are soft, tumour-like balls
of inflammation that vary in size. Gummas can occur anywhere
but commonly affect the skin and bones (often below the knee)
and can cause bone pain. They may also grow on organs.
Stages and symptoms
Syphilis is classified as acquired
or congenital. Acquired syphilis
is divided into early and late
disease. Early acquired syphilis
can be further subdivided into
primary, secondary and early
latent (less than two years of
infection) disease and late
acquired syphilis can be
subdivided into late latent (over
two years of infection) and
tertiary (including gummatous,
cardiovascular and neurological)
disease. Figure 1 provides a
summary.
Congenital syphilis is also
divided into early and late
disease, diagnosed in the first two
years of life and presenting after
two years of disease,1
respectively.
Syphilis was famously referred
to as “the great imitator” by Sir
William Osler because of its
varied presentations, which are
similar to many other conditions.
Acquired syphilis
Primary syphilis4–6 is usually
characterised by the appearance
of a single skin lesion (called a
chancre) which is typically firm,
small, round and painless,
occurring at the point of contact
with the infectious lesion(s) of
another person. However,
chancres may also be multiple,
painful and purulent. They do
not have to be genital. For
example, they may appear on the
lips or in the mouth (see image
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Inflammation around the aorta, resulting in aneurysm formation
and aortic valve dilation, leading to heart failure and heart
attacks.
Loss of mental and physical function, including changes in mood
and personality. Early neurosyphilis can be asymptomatic or
present as meningitis. Late neurosyphilis appears as
meningovascular syphilis, general paresis or tabes dorsalis
(inflammation of spinal dorsal column), which is associated with
poor balance and lightning pains in the lower extremities.
Adapted from National guidelines on the management of syphilis 20084
on p263). Multiple lesions are
more common when a patient is
co-infected with HIV.
The time from initial exposure
to start of initial symptoms can
range from 10 to 90 days
(average 21 days). Swelling
(lymphoedema) frequently
occurs (80 per cent) around the
area of infection, usually seven to
10 days after chancre formation.
The chancre lasts three to six
weeks without treatment.
Untreated, primary syphilis will
always progress to secondary
syphilis. This occurs four to 10
weeks after first exposure.4,6,8
Secondary syphilis typically
involves the skin, mucous
membranes and lymph nodes.
There is often a symmetrical,
reddish brown rash on the trunk
and extremities, including the
palms and soles of the feet (see
image on p263). The rash is
classically non-itchy but can be
itchy, particularly in darkskinned patients. It may become
maculopapular or pustular and
form wart-like lesions (known as
condylomata lata) on mucous
membranes.
Other symptoms can include
fever, lymphoedema, sore throat,
malaise, weight loss, hair loss and
headaches. The acute symptoms
usually resolve after six weeks,
but about 25 per cent of people
experience a recurrence of
secondary symptoms.
Latent syphilis4,9 (both early
latent and late latent) has no
signs and symptoms and can last
for years. The distinction
between early latent and late
latent is for treatment purposes
(see later). It is difficult to tell
exactly how long someone has
had the infection, but serological
tests and medical and sexual
histories can help clinicians make
a good estimate.
In around a third of cases
tertiary (or late symptomatic)
syphilis4,6 can occur three to 15
years after infection. It can
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PANEL 2: TREATMENT REGIMENS FOR DIFFERENT STAGES OF SYPHILIS
Clinical stage
Recommended regimens
Early syphilis (primary,
secondary and early latent)
Benzathine penicillin 2.4MU IM (single dose) Doxycycline 100mg po bd for 14 days
Procaine penicillin 600,000units IM od for
Azithromycin 2g po stat or 500mg od
10 days
for 10 days
Erythromycin 500mg po qds for 14 days
Ceftriaxone 500mg IM od for 10 days
Amoxicillin 500mg PO qds plus
probenecid* 500mg qds for 14 days
Late latent, cardiovascular
or gummatous syphilis†
Benzathine penicillin 2.4MU IM weekly
(three doses)
Procaine penicillin 600,000units IM od
for 17 days
Alternative regimens
Doxycycline 100mg po bd for 28 days
Amoxicillin 2g po tds plus probenecid
500mg qds for 28 days
Neurosyphilis, including
Benzylpenicillin 18–24MU od in divided
neurological/ophthalmic
doses for 17 days
involvement in early syphilis Procaine penicillin 1.8–2.4MU IM od plus
probenecid 500mg po qds for 17 days
Doxycycline 200mg po bd for 28 days
Amoxicillin 2g po tds plus probenecid
500mg po qds for 28 days
Ceftriaxone 2g IM or IV for 10–14 days
Early syphilis in pregnancy‡
In the first or second trimester, benzathine
penicillin 2.4MU IM (single dose) but where
treatment is given in the third trimester
a second dose should be given after a week
Procaine penicillin 600,000units IM od for
for 10 days
Amoxicillin 500mg po qds plus
probenecid 500mg po qds for 14 days
Erythromycin 500mg po qds for14 days
Ceftriaxone 500mg IM od for 10 days
Azithromycin 500mg po od for 10 days
Late syphilis in pregnancy
Manage as in non-pregnant patients but
without doxycycline
Congenital syphilis§
Benzylpenicillin sodium 100,000–150,000
units/kg IV daily (in divided doses given as
50,000units/kg 12 hourly in the first seven
days of life and eight hourly thereafter) for
10 days
Procaine penicillin 50,000units/kg IM od for
10 days
*Probenecid increases serum concentration of the antibiotic (patients are unable to tolerate very large antibiotic
doses due to adverse effects); †Steroid cover should be used when treating cardiovascular syphilis; ‡ Management
should be in close liaison with obstetric, midwifery and paediatric teams. Appropriate follow-up is required after
birth; § In children, IV therapy may be preferred rather than intramuscular injections, which are painful.
present as gummatous syphilis
(15 per cent), cardiovascular
syphilis (10 per cent) or
neurosyphilis (6.5 per cent),
which are described in Panel 1.
Congenital syphilis
Infection with congenital
syphilis1, 10 can occur during
pregnancy or at birth. If the baby
is infected during pregnancy and
is untreated, there is a high risk
of stillbirth, prematurity or
neonatal death. If infected during
delivery, the baby will develop a
number of symptoms over time.
Two-thirds of syphilitic infants
are born without signs of the
disease. Early congenital syphilis
develops over the first two years
of life and common symptoms
include hepatosplenomegaly (70
per cent), rash (70 per cent),
fever (40 per cent), neurosyphilis
(20 per cent) and pneumonitis
(20 per cent).
Left untreated, late congenital
syphilis occurs in 40 per cent of
babies. Symptoms include saddle
nose deformation (loss of height
of nose due to collapse of the
bridge), Higoumenakis sign
(unilateral enlargement of the
sternoclavicular portion of the
clavicle), saber shin
(malformation of tibia) and
Clutton’s joints (symmetrical
joint swelling).
Congenital syphilis kills more
than a million babies a year
worldwide but is preventable if
infected mothers are identified
early and treated appropriately.7
The World Development Report
cites antenatal screening and
treatment for syphilis as one of
the most cost-effective health
interventions available. In
The authors will be available
to answer questions on this
topic until 24 September 2012
Ask the
expert
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England in 2005, 95 per cent of
pregnant women were screened
for syphilis, although uptake
varied from 77 to 100 per cent
between regions.2
Diagnosis and investigation
Syphilis can be difficult to
diagnose in the early stages.
Confirmation is required with
blood tests or direct visual
microscopy.4,6,11
For all suspected cases a full
sexual health screen, including
HIV testing, should be
performed.
A thorough investigation should
be undertaken for the clinical
manifestations of syphilis,
including full examinations of
skin and mucosal surfaces, lymph
nodes, cardiovascular and
neurological systems.
In addition, history of travel to
or living in countries where
syphilis or other treponemal
infections are endemic should be
established. In women an
obstetric history, including
potential complications such as
still births and miscarriages,
should be taken.
Serological tests
Blood tests are routine. They can
be divided into treponemal and
non-treponemal.
Non-treponemal tests are used
initially and include the venereal
disease research laboratory
(VDRL) test and rapid plasma
reagin test. These are widely used
for syphilis screening but falsepositive reactions can occur with
viral infections (such as varicella
and measles), autoimmune
disorders, infections (such as
malaria, tuberculosis, and
endocarditis) and pregnancy.
Treponemal specific tests
detect antibodies to antigenic
components of T pallidum. These
tests are primarily used to
confirm the diagnosis of syphilis
in patients with a reactive nontreponemal test. They have
sensitivities and specificities
equal to or higher than nontreponemal tests but are more
difficult and expensive, which
limits their usefulness as
screening tests.
Direct testing
Dark-field microscopy is the
most specific technique for
diagnosing syphilis when a
chancre or condylomata are
present. Serous exudate from the
lesion is examined under a
microscope equipped with a
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dark-field condenser. T pallidum
is identified by its characteristic
corkscrew appearance.
Direct fluorescent testing can
also be done on samples from the
lesions using antibodies tagged
with fluorescein, which attach to
specific syphilis proteins.
Another test is nucleic acid
amplification to detect the
presence of specific syphilis
genes.
Treatment
Syphilis is curable when identified
early — a single dose of penicillin
is sufficient to cure the infection
in those with primary, secondary
or early latent disease. Additional
doses will be required in those
who have had the disease for
longer.
Although treatment kills the
bacterium and prevents further
damage, it will not repair damage
already done. And in
cardiovascular syphilis, lesions
can progress despite treatment.
Panel 2 summarises the
treatment regimens for different
stages of the disease, including
alternative regimens.4
Both benzathine- and procainepenicillin are unlicensed in the
UK, probably due to low
demand. They are given by
injection into a large muscle. The
gluteal muscle is usually
preferred because the injection is
least painful. Prescribers should
be aware of the uses and actions
of these products and be assured
of their quality and source.
Reactions to treatment
Penicillin is the gold standard
treatment — other antibiotics are
not as efficacious and failures
have been reported in the
literature. However, penicillin is
the most common cause of
anaphylaxis, and facilities for
appropriate treatment should be
available. Patients should be
monitored for immediate adverse
reactions for 15 minutes after
receiving their first injection. In
addition they should be advised
to seek urgent medical attention
if they later experience shortness
of breath, itchy wheals on their
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skin, facial swelling or tightness
in their chest or throat.
Penicillin desensitisation may
be considered for patients
reporting penicillin allergy.
Jarisch-Herxheimer reaction
The Jarisch-Herxheimer reaction
is an acute febrile illness with
headache, myalgia, chills and
rigors that resolves within 24
hours. It is common in the
treatment of patients with early
syphilis (a figure of 50 per cent
has been reported) but is usually
not important unless there is
neurological or ophthalmic
involvement, or in pregnancy
when it may cause fetal distress
and premature labour. The
reaction is thought to occur as a
result of destruction of
spirochetes and activation of a
pro-inflammatory cytokine
cascade.
It is uncommon in late syphilis
but can potentially be life
threatening if there is
involvement of coronary ostia,
the larynx or the nervous system.
Steroids are recommended when
there is neurological or
cardiovascular involvement and
may also be used in pregnancy
(additional fetal monitoring is
required).
Procaine psychosis Inadvertent
intravenous injection of procaine
penicillin can result in a reaction
characterised by fear of
impending death and may cause
hallucinations or fits immediately
after injection, lasting less than
20 minutes. Calm and verbal
reassurance is required, and
diazepam can be used if fits
occur.
A single dose of
penicillin is
sufficient to cure
the infection in
those with primary,
secondary or early
latent disease
Resources
British Association for
• The
Sexual Health and HIV (BASHH)
website (www.bashh.org) has
links to various guidelines for
sexually transmitted infections.
Role for pharmacists
Pharmacists, especially those
working in community settings,
are in a prime position to
provide advice and signpost
people to sexual health services.
For example, women coming
into the pharmacy requesting
emergency contraception should
always be advised that this does
not protect against the risks of
STIs and be referred for
screening where appropriate.
Emergency contraception
consultations are also ideal
opportunities to engage patients
in discussions about future, more
appropriate methods of
contraception.
People might also visit a
pharmacy requesting products
for lesions that could be
PRACTICE POINTS
Reading is only one way to
undertake CPD and the
regulator will expect to see
various approaches in a
pharmacist’s CPD portfolio.
1. Emphasise to patients,
where appropriate, the
importance of compliance
with their course of
antibiotics and follow-up
appointments.
2. Refer at-risk patients for
sexual health screening.
Consider making this activity
one of your nine CPD entries
this year.
syphilitic. If syphilis cannot be
excluded, these people should be
referred to a GUM clinic or their
GP.
In hospitals patients may
be seen on wards or, more likely,
in an outpatient clinic where
prescriptions will need
screening. This will involve
checking the appropriateness
and duration of therapy and
potential interactions, and
titrating doses for renal or
hepatic impairment. There is also
an important role for
pharmacists in counselling
patients on their therapy,
and discussing any compliance
issues and the importance of
completing the course and
attending follow-up
appointments for monitoring.
Some patients may be
prescribed long-term intravenous
antibiotic courses. In such cases
it is important to establish how
the medicine will be prepared,
how it will be administered and
who will be administering it.
This will require detailed
discussions with the outpatient
intravenous antibiotic therapy
(OPAT) team, community
nurses or homecare services.
GUM clinics often have patient
group directives for treatment of
STIs and pharmacists are
involved in the development of
such services.
Despite intensive efforts, the
unusual nature of T pallidum has
hindered progress towards the
development of a vaccine to
prevent infection.11 Good sexual
health is a key component of the
prevention of syphilis and
pharmacists have a part to play
in reinforcing this. In particular,
people at risk should be
encouraged to:
barrier contraceptives
• Use
aware of the symptoms of
• Be
infection and seek early medical
•
advice
Get tested regularly
(Consulting clinical services
regularly increases the
chances that infection can be
identified, even if there are no
symptoms. HIV testing should
be considered every three
months to annually for patients
in high-risk groups.)
To avoid reinfection, partners
of infected individuals should be
advised to be screened and, if
necessary, treated.
References available online