Full text of DOI:10.2165/00003495-200262100-00003

Drugs 2002; 62 (10): 1447-1461
0012-6667/02/0010-1447/$30.00/0
THERAPY IN PRACTICE
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Management Issues in Syphilis
1
2
1
David Pao, Beng T. Goh and James S. Bingham
1
2
Department of Genitourinary Medicine, Guy’s & St Thomas’ Hospitals, London, UK
Ambrose King Centre, The Royal London Hospital, London, UK
Contents
Abstract
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1447
1. Syphilis and HIV Co-Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1448
2. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1449
3. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1450
3.1 Penicillin in Early Infectious Syphilis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1451
3.2 Options if a Patient Declines Injectable Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . 1451
3.3 Penicillin Allergy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1452
3.4 Late Latent Syphilis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1452
3.5 Late Forms of Syphilis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1452
3.5.1 Gummatous Syphilis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1453
3.5.2 Neurosyphilis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1453
3.5.3 Cardiovascular Syphilis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1454
3.5.4 Ocular Syphilis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1454
4
5
. In Whom Should Evaluation of the Cerebrospinal Fluid Be Undertaken? . . . . . . . . . . . . . . . 1454
. Management of Special Situations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1455
5.1 Incubating Syphilis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1455
5.2 Syphilis with HIV Co-Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1455
5.3 Syphilis in Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1456
6. Reactions to Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1457
6.1 Anaphylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1457
6.2 The Jarisch-Herxheimer Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1457
6.3 The Procaine Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1457
7. Follow-Up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1458
8. Partner Notification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1458
9. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1458
Abstract
Syphilis is a sexually transmitted infection which is systemic from the outset
and has increased in incidence worldwide over the last decade. There has been
concern as to whether or not co-infection with HIV can modify the clinical pre-
sentation of syphilis and, as a genital ulcer disease, it can facilitate the transmis-
sion of HIV infection. Diagnosis is based on the microscopic identification of the
causative treponeme and serological testing.
Recommendations for the treatment of syphilis have been based on expert
opinion, case series, some clinical trials and 50 years of clinical experience.
Penicillin, given intramuscularly, is the mainstay of treatment and the favoured
preparations for early infectious syphilis are benzathine penicillin as a single
injection or a course of daily procaine penicillin injections for 10 to 14 days. The

1
448
Pao et al.
duration of treatment is longer for late syphilis. There has been concern that
benzathine penicillin may not prevent the development of neurosyphilis but that
is a rare outcome with this therapy. The main alternative to penicillin is doxycy-
cline, but the place of azithromycin and ceftriaxone is yet to be established.
It is not necessary to carry out examination of the cerebrospinal fluid in pa-
tients with early infectious syphilis but it should be performed in those with
neurological or ocular signs, psychiatric signs or symptoms, when there is evi-
dence of treatment failure and in those who are co-infected with HIV.
Follow-up is an essential part of management and should be particularly as-
siduous, for at least 24 months, in those co-infected with HIV. Partner notification
should be mandatory to try to contain the spread of infection.
Syphilis is a sexually transmitted infection (STI):
due to Treponema pallidum, (subspecies pallidum);
at 900 per 100 000 of the population aged between
20 to 29 years in 1996.[ In China between 1989
and 1998, the incidence of syphilis increased ap-
proximately 20-fold.[ The situation in an African
country, Zimbabwe, was even worse with a inci-
dence of 2300 per 100 000 of the population.[
Most industrialised countries have reported an in-
crease in incidence within certain populations (par-
ticularly men who have sex with men and individ-
uals infected with the human immunodeficiency
virus [HIV]) and a number of well defined out-
breaks have been identified in England.[
5]
‘
of great chronicity; systemic from the outset; capa-
ble of involving practically every structure of the
body in its course; distinguished by florid manifes-
tations on the one hand and years of completely
asymptomatic latency on the other; able to simu-
late many diseases in the fields of medicine and
surgery; transmissible to offspring in man [sic];
transmissible to certain laboratory animals; treat-
6]
7]
[
1]
able to the point of presumptive cure’.
8-10]
Syphilis may be either congenital (intrauterine
infection) or acquired. The stages are temporal and
are delineated in table I. Because of the rarity of
syphilis in the industrialised world in the last 30 to
1. Syphilis and HIV Co-Infection
4
0 years, many younger doctors are not acquainted
Syphilis, like many other sexually transmitted
infections (STIs), will increase the risk of sexual
transmission of HIV but HIV is unique in its ability
with its protean manifestations and may not be con-
versant with the serological tests for syphilis.
While syphilis has retained a relatively low
level of endemicity in the non-industrialised
world, after the advent of penicillin and the antibi-
otic era in the mid 1940s, it ceased to be a major
health problem in the industrialised world except
in particular high risk groups such as homosexual
men. However, there has been a recrudescence of
the infection over the last decade in many parts of
Europe and North America, particularly in the Rus-
sian Federation and its adjacent countries. In 1999,
the World Health Organization (WHO) estimated
that, worldwide, there were approximately 12 mil-
to modify the clinical presentations of other
STIs.[
11,12]
The former carries great implications
for the containment of the global HIV epidemic
through STI control, while the latter necessitates a
thorough re-evaluation of these genital tract infec-
tions in the context of HIV co-infection. Before
more definitive information is available, particular
attention is needed in the management of patients
with co-infection.
As a genital ulcer disease, syphilis increases the
rate of HIV transmission by up to five times[ and,
furthermore, it has been demonstrated that treat-
ment of STIs early in an HIV epidemic can be as-
sociated with a decline in the incidence of HIV
12]
[
3]
lion new cases of syphilis among adults. In West-
ern Europe, taking England as an example, the in-
cidence was 0.3 per 100 000 of the population,
whereas in Russia the incidence was much higher
[
4]
[13]
infection. Most often the clinical picture is little
different between HIV-infected and HIV-unin-
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Management Issues in Syphilis
1449
Table I. Classification of syphilis
Acquired syphilis
Early infectious syphilis
Primary syphilisa
An often painless anogenital chancre (ulcer) with dependent lymphadenopathy
Can persist into the secondary stage
Incubation period of 9-90d but usually 3-4 wks
Secondary syphilisa
Early latent syphilis
Multisystem involvement due to bacteraemia, resulting in generalised rash (+/- condylomata lata),
and lymphadenopathy, systemic malaise and fever, buccal and genital mucosal erosions; may also
cause patchy alopecia, hepatitis, meningitis, cranial nerve palsies, uveitis, periostitis and
glomerulonephritis
4-8 wks after appearance of chancre
From the end of the secondary stage to the end of a 2y period after the appearance of chancre
Positive STS but without symptoms or signs
Classified as infectious because relapse to the secondary stage is possible up to 2y
Late non-infectious syphilis
Late latent
From the 2y point onwards
Asymptomatic with positive STS
Most untreated patients would remain in this stage
Rare but described in patients recently co-infected with HIV;[2] can be infiltrative or ulcerative
Gummatous syphilis
Neurosyphilis
Rare but rapid progress to this stage, described in patients co-infected with HIV; meningovascular,
tabes dorsalis and general paresis
Cardiovascular syphilis
Rare; aortic regurgitation or aneurysm, coronary ostiitis
Congenital syphilis
Early congenital syphilis (< 2y)
Late congenital syphilis including stigmata
Some patients do not notice the primary and secondary stages, and infection is only detected on STS.
a
STS = serological tests for syphilis.
fected hosts. There are studies and case reports,
however, suggesting an influence by HIV infec-
tion on the clinical presentation of syphilis (table
II).
not standardised, but is likely to be used more
in the future.
• Indirect detection through serological testing.
There are two groups of tests available: (i)
treponemal tests, i.e. treponemal enzyme im-
munoassay (EIA with immunoglobulin [Ig]G or
IgM), T. pallidum particle agglutination test
2
. Diagnosis
Diagnosis of primary and secondary syphilis is
based on:
(
TPPA) or the T. pallidum haemagglutination
assay (TPHA), fluorescent treponemal anti-
body-absorbed test (FTA-Abs); and (ii) ‘non-
treponemal’ cardiolipin (reaginic) tests, i.e.
Venereal Diseases Reference Laboratory test
•
Clinical appearances - in those with symptoms
and/or signs.
•
Direct detection of the causative organism, T.
pallidum (subspecies pallidum). This may be
either by visualisation using a dark field micro-
scope or by the direct fluorescent antibody
technique (DFA-TP). This latter technique
identifies T. pallidum in a direct lesion smear
by immunofluorescence using polyclonal anti-
serum but is very labour intensive. A newer mol-
ecular technique, polymerase chain reaction
(
VDRL) or the rapid plasma reagin test (RPR).
Many laboratories now use EIA (IgG or IgM)
as a screening test, although the TPPA or TPHA
together with VDRL or RPR can also be used.[
Should the EIA be positive, the laboratory will
then go on and perform other treponemal tests such
as the TPPA or TPHA. In cases of doubt, the FTA-
Abs is done too. In addition, a cardiolipin test such
14]
(
PCR), is not widely available at present and is
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1
450
Pao et al.
Table II. Clinical aspects of syphilis and HIV co-infection
syphilis is generally based on clinical appearances
with positive STS and biopsy of the lesion to ex-
clude other causes. Symptomatic neurosyphilis is
diagnosed on the neurological signs and symptoms
along with positive STS and examination of the
cerebrospinal fluid (CSF). In patients with neuro-
syphilis, examination and investigation should be
carried out to exclude cardiovascular and ocular
syphilis.
Primary syphilis may present with larger or more numerous
chancres
A primary syphilitic chancre and chronic mucocutaneous herpes
(an AIDS-defining diagnosis) may be similar clinically
Secondary syphilis and primary HIV infection can be similar
clinically
‘Malignant syphilis’ (accelerated ulcerating secondary syphilis)
More frequent ocular syphilis
Rapid progression to the late stages of syphilis, particularly
neurosyphilis
Atypical presentations of neurosyphilis
Unusual manifestations of gummatous syphilis
3
. Treatment
Treatment for syphilis has been available from
early times but, until the first arsenical became
available in 1909, treatment had been predomi-
nantly with mercury, given by mouth, injection,
inunction or inhalations. Other treatments had in-
cluded guaiacum, iodides and fever therapy.[ Ar-
senicals were augmented by bismuth in the 1920s
as the VDRL or RPR should be carried out. These
are useful for quantitating the activity of an infec-
tion and in monitoring treatment, i.e. following
treatment, the VDRL/RPR titre should fall to neg-
ativity or close to it. Failure for that to happen may
indicate either a treatment failure, re-infection or,
at a low titre the patient may be ‘sero-fast’. The
treponemal tests are not usually quantitated. Bio-
logical false-positive reactions can occur with the
15]
[16]
and this combination was used until Mahoney
demonstrated that penicillin was effective in 1943.
At first, injectable benzylpenicillin (penicillin
G) was used, but this needed to be given frequently
and was very painful if given intramuscularly. One
of the first long acting injectable penicillins was
procaine penicillin in oil with aluminium monoste-
arate (PAM) which was used extensively in the
yaws eradication campaign of the 1950s and
‘
non-treponemal’ cardiolipin tests so it is essential
always to perform treponemal tests. In primary
syphilis, EIA IgM and FTA-abs are usually the first
tests to be positive and should be requested if a
chancre is suspected.
Because it is possible for specimen mix-ups to
occur, either with the healthcare provider or in the
laboratory, a second serum sample should always
be sent to confirm a result.
It is important to note that both treponemal and
non-treponemal serological tests for syphilis (STS)
are also positive in the non-venereal treponemato-
ses such as bejel or endemic syphilis (T. pallidum
subspecies endemicum), in yaws (T. pallidum sub-
species pertenue) and in pinta (T. pallidum subspe-
cies carateum). The distinction between venereal
and non-venereal treponematoses is based on the
clinical history, the age and the country of origin
of the patient, as well as whether or not there are
any signs, often on the skin, of these infections.
The diagnosis of latent syphilis is based on the
STS results and a clinical history of when infection
might have taken place. A diagnosis of gummatous
1
960s, only one injection being needed. An early
oral penicillin, phenoxymethylpenicillin (penicil-
lin V), proved to be unreliably absorbed and, there-
fore, was dismissed as a suitable agent with which
to treat syphilis, although a more recent study in
[17]
Sweden did show some efficacy.
When the
newer oral penicillins such as ampicillin and
amoxicillin were introduced they were not exten-
sively investigated as the incidence of syphilis, by
that time, was very low in the industrialised world
and, therefore, the evidence base for their use is
limited. Nevertheless, the efficacy of penicillin in
the treatment of syphilis was well established
through clinical experience prior to the value of
randomised, controlled clinical trials being
recognised. Thus, most of the recommendations
for the treatment of syphilis have been based on
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Management Issues in Syphilis
1451
expert opinion, case series, some clinical trials and
half a century of clinical experience.
of late syphilis by using aqueous penicillin. Of
course, whether there is penicillin in the CSF does
not establish that it is not present in the brain tissue
itself.
3
.1 Penicillin in Early Infectious Syphilis
This led to a plethora of studies investigating
penicillin concentrations in the CSF after benzath-
ine and procaine penicillin administration and, at
least for neurosyphilis, led to a higher dose being
recommended. The inner layer of the bacterial
membrane contains peptidoglycan which makes T.
pallidum highly sensitive to penicillin. From early
days a serum penicillin concentration of >0.018
mg/L has been considered treponemicidal, al-
though this is far lower than the maximally effec-
tive in vitro level of concentration at 0.36 mg/L.[
Benzathine penicillin has a peak plasma con-
centration at 13 to 24 hours with an effective con-
centration maintained for 7 to 10 days. Procaine
penicillin, on the other hand, has a peak plasma
concentration in 1 to 4 hours with an effective con-
centration maintained for 12 to 24 hours. To be
effective, the treponemicidal concentration should
be maintained for at least 7 days to cover a number
of division times (30 to 33 hours) of the trepo-
nemes in early syphilis, with a sub-treponemicidal
There is a dearth of adequately conducted com-
parative trials to guide the selection of an optimal
penicillin regimen - not for dose, duration or prep-
aration. Parenteral benzylpenicillin has been used
effectively for 5 decades to achieve local cure –
healing of lesions and prevention of sexual trans-
mission - and it remains the recommended drug for
[
18-22]
the treatment of syphilis in most countries.
However, the preparation used varies from re-
gion to region. In North America, in the Center for
Disease Control (CDC) guidelines, the preferred
preparation is benzathine penicillin, (the tetrahy-
drate salt of benzylpenicillin), 2.4 million units in-
tramuscularly in a single dose. In Europe, while the
benzathine preparation is also recommended, the
procaine salt of penicillin, 600 000 units intramus-
26-28]
cularly for 10 to 14 days, is preferred in some coun-
tries.[
19-21]
There are obvious advantages to the use
of a single injection; the patient does not have to
be persuaded to return for daily penicillin admin-
istration and it is, in effect, a one-off directly ob-
served therapy (DOT). Daily procaine penicillin
by intramuscular injection is, of course, also DOT.
The WHO recommends intramuscular benzathine
penicillin as first line therapy, with injectable pro-
[26]
interval of not more than 24 to 30 hours. So both
benzathine and procaine preparations should be
satisfactory, but benzathine penicillin injections
can be very painful and to minimise this should be
reconstituted with lidocaine and the dose divided
between both buttocks. Because the treponemes
probably divide more slowly in late disease, a
longer duration of treatment is advisable as the du-
ration of infection increases.
[
22]
caine penicillin as an alternative.
Concern arose about benzathine penicillin in
976 when two articles appeared in the same issue
1
[
23,24]
of JAMA,
one showing persistence of trep-
onemes in CSF after treatment with benzathine
penicillin and the other showing that no penicillin
was detected in the CSF when two patients who
had had positive STS were treated with benzathine
penicillin. The editorial which accompanied these
papers opined that while the benzathine prepara-
tion should be adequate therapy for primary syph-
ilis, once spirochaetaemia has occurred in the sec-
ondary stage of syphilis, it must be assumed that
the organism will reach the brain and that if
Finally, persistent spiral organisms/treponemes
have been identified despite apparently adequate
[29,30]
treatment.
Whether or not these can cause a
relapse of the infection is not known but is a pos-
sibility in immunosuppressed patients.
3
.2 Options if a Patient Declines
Injectable Therapy
In the industrialised world some patients have
an aversion to injectable therapy and, if procaine
penicillin is to be used, it necessitates multiple vis-
[
25]
benzathine penicillin does not enter the CSF,
then we ought to change the method of treatment
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1
452
Pao et al.
its for administration. The opposite is true in some
regions of the developing world where it is a com-
mon belief that medication by injection is superior.
There is most experience with the tetracycline
group of drugs, especially tetracycline itself at a
for evidence of late/tertiary disease to ensure that
a misdiagnosis is not being made. Thus, a careful
history and examination should be undertaken
looking for gummata (rare at present), neurologi-
cal, cardiovascular and ocular complications, and
aortitis (on a chest radiograph). This might be par-
ticularly important in patients co-infected with
HIV. Five decades of experience seem to support
the effectiveness of therapy but there is little evi-
dence upon which to base decisions regarding spe-
cific regimens. The evidence available is in sup-
port of penicillin containing regimens but there is
little evidence for the use of non-penicillin re-
gimens for the treatment of this stage of the disease.
The same drugs used for early infectious syph-
ilis should be administered, but for a longer dura-
tion because of the slower division of treponemes
in late disease. Thus, benzathine penicillin 2.4 mil-
[
18,20]
dose of 500mg four times daily for 14 days.
There is less experience with doxycycline but
compliance is likely to be better than with tetracy-
cline as it is administered four times daily. Doxy-
cycline can be administered at either 100mg
twice daily or as a single dose of 200 mg/day for
18,19,21,30]
1
4 days.[
It has also the advantage that
dairy products do not have to be avoided. Erythro-
mycin at a dose of 500mg four times daily for 14
days has also been used but the efficacy may be
less.[
18-21]
The well absorbed amoxicillin ought to
be effective and has been found to penetrate the
CSF well.[
31,32]
Azithromycin, a newer macrolide
antibiotic with a long half life (approximately 68
hours) which is used to treat other STIs (chlamy-
lion units should be given intramuscularly at days
1, 8 and 15.[
18-21]
Procaine penicillin needs to be
given for 17 to 21 days. The CDC guidelines do not
recommend this but it has been standard practice
[
33-35]
dia) has also been investigated.
are not effective against T. pallidum.
Quinolones
[
36]
in many European countries, usually at a daily dose
3
.3 Penicillin Allergy
[19-21]
of 600 000 units intramuscularly.
Some phy-
sicians recommend a large dose of procaine peni-
cillin (1.2 million units) and this may be best for
heavier patients.[
Where there is penicillin allergy or intramuscu-
lar treatment is refused, then doxycycline 200
Doxycycline, tetracycline and erythromycin are
the choices, as discussed in section 3.2. Some may
wish to consider azithromycin and, if the patient is
not averse to injectable therapy, then ceftriaxone
may be considered, but most of the evidence for its
efficacy is with neurosyphilis (see section 3.5.2).
Although a third generation cephalosporin, there is
still a slight risk of cross reactivity with penicillin
and it should not be used if a patient has a history
of anaphylaxis with penicillin. The suggested re-
gimens are azithromycin 500 mg/day and intra-
muscular ceftriaxone 500 mg/day, both for 14
days. Another option would be to offer penicillin
21]
mg/day (either 100mg twice daily or a single 200mg
dose) can be given over 21 to 30 days.[
18,19,21]
Tet-
racycline 500mg four times daily for 28 to 30 days
or erythromycin 500mg four times daily for 28
days may also be considered.[
21,22]
These recom-
mendations tend to be passed on from one set of
guidelines to another without the support of mean-
ingful clinical trials.
desensitisation, a strategy often recommended for
pregnant mothers.[18]
3.5 Late Forms of Syphilis
The definitions of the late forms of syphilis may
vary. Gummatous syphilis is sometimes referred to
as benign tertiary syphilis, but the CDC guidelines
state that tertiary syphilis includes gummatous
syphilis and cardiovascular syphilis. Others refer
to quaternary syphilis, which includes cardiovas-
3
.4 Late Latent Syphilis
The rationale behind the treatment of this stage
of infection is to prevent progression to the late
forms of syphilis. Certainly, those who apparently
have latent syphilis should be carefully examined
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Management Issues in Syphilis
1453
cular and neurosyphilis. Some degree of overlap
may occur and it is possible to have all three forms
of late syphilis. There had been anxiety in the
rosyphilis and CSF pleocytosis persisted after the
use of the standard regimens of that time. How-
ever, an increased dose of procaine penicillin re-
sulted in symptomatic improvement in these pa-
tients, although a few patients went on to develop
general paresis. Numerous dose ranging studies
1
960s that, with the aura of antibiotics in the gen-
eral population, early syphilis would be partially
treated by happenstance and that there would be a
risk of the late forms of syphilis developing. This
has not come to pass. Cardiovascular syphilis re-
mains rare but neurosyphilis continues to be
recognised in individuals not infected with HIV
were performed thereafter, summarised well by
[29]
Dunlop,
to establish what doses were actually
needed to produce treponemicidal penicillin con-
centrations in the CSF.
[
37]
but especially those who are infected.
Currently, the advice is that penicillin should be
given either intravenously or, if patient compli-
ance can be relied on and the patient does not re-
quire hospitalisation, by intramuscular injection of
procaine penicillin. The data concerning the effec-
tiveness of using a procaine penicillin and proben-
ecid combination to produce treponemicidal
CSF penicillin concentrations is conflicting.[
The concern that the CSF penicillin concentration
3.5.1 Gummatous Syphilis
As gummatous syphilis is such a rare disease it
is difficult to evaluate therapy since there are no
controlled studies of penicillin in any large series
of patients. The last review of treatment by St John
in 1976[ found no therapeutic trials subsequent
to the 1940s and advised that a recommendation
made in 1948 still stood - that ‘at least 2 million
units of penicillin if not more’ would be neces-
sary.[ While the current WHO guidelines do not
mention treatment of gummatous syphilis, the
CDC guidelines do.[ There the recommended
therapy regimen is intramuscular benzathine pen-
icillin 7.2 million units in total, administered as
three doses of 2.4 million units at 1-week intervals.
European guidelines[ concur with this but also
suggest the use of intramuscular procaine penicil-
38]
42,45]
is increased at the expense of the CNS tissue con-
39]
[42,46]
centration
may not be relevant because con-
centrations in both the CSF and in CNS tissue are
higher with probenecid than without, with a much
higher concentration, relatively, in the CSF.[
However, anecdotally, the use of the procaine pen-
icillin/probenecid combination has been success-
ful in the UK, although the availability of proben-
ecid in some countries is now becoming a problem.
Thus, the recommendations for first-line ther-
apy for the treatment of neurosyphilis are now in-
travenous aqueous (crystalline) benzyl penicillin
18]
29]
21]
[
19-21]
lin 600 000 units daily for 17 to 21 days.
3.5.2 Neurosyphilis
The advent of penicillin completely changed
the management of neurosyphilis; it simplified it
1
2 to 24 million units daily as 3 to 4 million units
[
18-22]
[
40,41]
every 4 hours over 10 to 21 days.
The dose
and dramatically improved the outcome.
may also be estimated on a basis of 0.15 million
Most patients in these trials had initially received
less than 6 million units of penicillin. Thus, in the
units/kg/day intravenously, spread over six doses
20,46]
(
every 4 hours) for 10 to 14 days.[
An alterna-
1
960s and 1970s, three doses of benzathine peni-
tive is intramuscular procaine penicillin 1.8 to 2.4
million units daily plus probenecid 500mg four
times daily for 10 to 21 days.[
cillin (total of 7.2 million units) or a 21-day course
of procaine penicillin at 600 000 units daily was
18-21,45,47]
used (total of 12 million units). But reports in the
22,23,42]
1
970s,[
showed that treponemes could per-
Where a patient is penicillin allergic or paren-
teral treatment is refused then doxycycline 200mg
twice daily over 28 to 30 days has been recom-
sist in the CSF and that penicillin was not detected
in the fluid following the use of benzathine peni-
[
23,24,43]
[44]
[19-21,48]
[22]
cillin.
Hooshmand et al.
reported pa-
mended.
The WHO guidelines also rec-
tients with tabes dorsalis or meningovascular
syphilis where clinical evidence of active neu-
ommend oral tetracycline 500mg four times daily
for 30 days.
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Pao et al.
There remains a need for effective alternatives
would suggest that this might help. Syphilitic uve-
itis of short duration, usually occurring in the sec-
to penicillin, apart from the tetracyclines. The pro-
longed half-life, adequate CNS penetration and
satisfactory activity against T. pallidum of
ceftriaxone suggest that this drug should be suita-
ble. However, studies in both humans and animal
models suggest that ceftriaxone may not be any
ondary stage, may be treated with parenteral
benzathine penicillin,[
neurosyphilis.
55,56]
but preferably as for
4
. In Whom Should Evaluation of the
[
49-52]
more efficacious than high-dose penicillin.
Cerebrospinal Fluid Be Undertaken?
Patients with auditory disturbances, caused by
syphilis, should be treated as described for neuro-
syphilis. Corticosteroids have been used as adjunc-
tive therapy in otologic syphilis and often resolve
the associated tinnitus, sometimes permanently,
but usually do not induce a lasting benefit with the
hearing loss.
There is a 30 to 40% likelihood of CSF abnor-
malities in primary and secondary stage syphi-
lis.[ This has never been shown to predict pro-
57]
gression to neurological complications but the
studies previously mentioned,[
22,23,42]
where
treponemes were found to persist following peni-
cillin therapy and where no penicillin was detected
in the CSF after administration of benzathine pen-
icillin, have certainly caused concern.
However, years of experience with benzathine
and procaine penicillin in early infectious syphilis
are reassuring. In addition, in a study of CSF ab-
normalities in early stage syphilis, although they
were found to be common, they were not predictive
3.5.3 Cardiovascular Syphilis
Some experts treat all patients who have cardio-
vascular syphilis with a neurosyphilis regimen and
this may involve parenteral therapy.[18] The man-
agement, other than antibiotic therapy, of the three
main problems in cardiovascular syphilis, aortic
aneurysm, coronary artery disease and aortic valve
disease are beyond the scope of this article but, in
general terms, involve a surgical approach. It is
said that a Jarisch-Herxheimer Reaction (JHR)
consequent upon antibiotic therapy may result in
coronary ostial occlusion or even in rupture of a
syphilitic aneurysm. Thus, some authorities have
recommended the use of corticosteroids to modify
this response but there is little evidence to support
such a strategy.
[
58]
of treatment failure.
CSF abnormalities are
common in HIV infection anyway,[ and in 1987,
two papers showing rapid progression from the
early stage to neurosyphilis caused alarm.[
Subsequent reports have included similar findings.
Whether or not risk can be stratified by the CD4+
count or by the reagin test titre remains to be dem-
onstrated. However, experts now advise that cer-
59]
60,61]
tain individuals co-infected with HIV should have
a CSF examination,[
18,21]
particularly those with
3.5.4 Ocular Syphilis
Ocular manifestations are probably uncommon
in untreated syphilis, not being mentioned at all in
latent or late syphilis.
Thus, it might reasonably be suggested that, in
individuals who are not infected with HIV and who
have early infectious syphilis, it should not be nec-
essary to perform lumbar puncture as long as the
individuals do not have neurological symptoms or
signs. But in those with any of the forms of late
syphilis, especially those with neurological symp-
toms and signs, CSF examination should be carried
out. Patients with positive syphilis serology and
psychiatric symptoms should be checked.[ It is
difficult to justify a lumbar puncture for every pa-
tient with latent syphilis, apart from those men-
[
53]
the Oslo study of untreated syphilis,
but optic
atrophy was found in about 3% of patients in the
Tuskagee study.[ Where there is serious ocular
involvement as optic neuritis or neuroretinitis,
treatment should be as for neurosyphilis, probably
54]
[
18,21]
using parenteral therapy.
Some experts would
also give corticosteroid cover to ameliorate the
JHR, because of reports of deterioration following
treatment. In addition, corticosteroids may already
be used in the management of these conditions,
unrelated to syphilis, and biological plausibility
62]
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Drugs 2002; 62 (10)

Management Issues in Syphilis
1455
tioned above including those in whom it is in-
tended to use non-penicillin therapy.[63] However,
if lumbar puncture is not performed to exclude
CSF involvement, one should consider treating pa-
tients with regimen as for neurosyphilis. It has not
been shown that those with a reagin titre of >1 : 32
are more likely to have CSF abnormalities sugges-
tive of neurosyphilis,[63] however, if a high titre
does not decline by 12 to 24 months after therapy,
such a patient requires evaluation for neu-
rosyphilis (including CSF examination) and re-
treatment. Should the reagin titre increase 4-fold
5. Management of Special Situations
.1 Incubating Syphilis
5
As a result of partner notification activity, sex-
ual partners of those with early infectious syphilis
may appear for evaluation and treatment. Some
may wish to be followed up through the incubation
period (up to 3 months) and, if seronegative and
asymptomatic at the end of the that time, treatment
will not be necessary. However, many wish to be
treated epidemiologically/presumptively and in-
tramuscular benzathine penicillin 2.4 million units
as a single dose has been recommended.[
18]
(
2 dilutions) after treatment then this should be re-
Azithromycin 1g orally as a single dose has also
been investigated in this situation and none of the
participants developed syphilis. However, in the
study most index patients had early latent and not
garded as a treatment failure and re-treatment
should be planned after examination of the CSF.
Indications for lumbar puncture are summarised in
table III.
[65]
primary or secondary syphilis.
The CDC guidelines recommend that if a CSF
pleocytosis was present initially, CSF examination
should be repeated every 6 months until the cell
count is normal. However, non-relevant CSF find-
ings suggesting aggravation due to the so-called
paradoxical response may cause unnecessary con-
fusion.[64] In meningovascular neurosyphilis the
number of mononuclear cells in the CSF generally
normalises faster (6 to 12 months) than parenchy-
matous neurosyphilis (1 to 2 years). The mononu-
clear cell count should be normal within 1 to 2
years, but other measurements such as the TPHA-
index may remain abnormal and the CSF reagin
test may remain positive. For these reasons, follow
up CSF examination should not be performed ear-
5
.2 Syphilis with HIV Co-Infection
The issue of interaction between syphilis and
HIV became topical after two reports in 1987 of
co-infected individuals where the syphilis was, ap-
parently, refractory to standard therapy or dis-
[60,61]
played a rapid progression to neurosyphilis.
Manifestations of syphilis and HIV can mimic
each other. Numerous other reports have described
more severe manifestations of syphilis, acceler-
[2,66-83]
ated progression to late syphilis
especially
neuro, ocular[
well summarised by Czelusta and colleagues
see also table II). A study by Rolfs et al.[
66-81]
and gummatous syphilis,
[2,82,83]
[
84]
58]
(
showed no increase in the incidence of neu-
rosyphilis in either HIV positive or negative pa-
tients treated for early syphilis, although the fol-
low-up period was short. However, the drop-out
rate was high with only 52% followed up for 1
year.
STS can mostly be interpreted the same as in
individuals without HIV infection, but there have
been reports of a higher rate of biological false
positive reactions with ‘non-treponemal’ cardio-
lipin tests.[
titres will generally fall 4-fold and individuals with
HIV infection usually follow this normal pattern.
lier than 1 to 2 years after treatment of neu-
rosyphilis.[21]
Table III. Indications for cerebrospinal fluid (CSF) examination in
patients with syphilis
In those with positive STS and neurological or ocular
signs/symptoms, the presence of gummata or aortitis
In those with positive STS and psychiatric signs/symptoms
In those with evidence of treatment failure
85-87]
Following treatment the reagin
In those with concomitant HIV infection (late latent syphilis or
unknown duration)
STS = serological tests for syphilis.
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456
Pao et al.
However, there have been reports of a delayed se-
5.3 Syphilis in Pregnancy
[
58,88-90]
rological titre response after treatment,
of
[80,91,92]
Congenital syphilis is preventable and its occur-
rence is a reflection of the inadequacy of antenatal
services in any country. It has been rare in the in-
dustrialised world in recent years, although more
prevalent in some resource-poor countries. Its in-
cidence is increasing in countries where the medi-
cal infrastructure is in decline, such as in the Rus-
sian Federation.[ In some Western countries there
has been debate as to whether or not to abandon
antenatal screening for syphilis but it ought to be
performed even if only 1 in 10 000 is expected to
be positive.[ All women identified as having
syphilis should be offered HIV testing.[
cases of seronegative syphilis
and of the re-
turn of positive STS to negativity as immune sup-
pression advances.[
68,93]
Thus, if the clinical find-
ings are suggestive of syphilis and the STS are
unreactive or unclear, alternative methods of diag-
nosis should be implemented such as darkfield ex-
amination, biopsy and direct fluorescent antibody
staining or PCR examination of material from the
lesion.[18]
5]
Progression to neurosyphilis despite apparently
appropriate therapy has prompted the recommen-
dation to perform CSF examination in latent or late
syphilis.[ Therapy might then be modified, de-
pendent upon the findings. However, most physi-
cians would treat all stages of syphilis in the same
97]
98]
18]
The risk of intrauterine infection is greatest in
the early infectious stages of the disease in the
mother, and rarely occurs after that. Seventy to
manner as in those who are not infected with
1
00% of infants born to mothers with early infec-
HIV.[
18,20-22]
Whether this is effective over time
tious syphilis will be infected, with stillbirths in up
to one third. If there has been documented proof of
adequate treatment and follow-up, demonstrated
by a fall in reagin titre prior to pregnancy, it ought
not to be necessary to re-treat during the pregnancy
unless there is concern about relapse of the infec-
tion or re-infection (evidenced by a greater than
one dilution or 2-fold rise in reagin titre). However,
some mothers prefer the reassurance of re-treat-
ment and physicians concerned for the welfare of
the newborn may require similar reassurance.
The preferred treatment of syphilis in pregnancy
remains penicillin and it should be administered as
in the non-pregnant state, although there is insuf-
ficient evidence to support the recommended re-
remains to be seen as patients treated with standard
therapy have not been followed up for a sufficient
period of time. If HIV treatment fails and patients
become progressively immunosuppressed, there is
concern that persisting treponemes may reactivate.
Furthermore, as neurological complications and
CSF abnormalities are common in HIV infection
per se, should neurological symptoms or signs oc-
cur in patients treated with standard therapy, the
possibility of neurosyphilis resulting from subopti-
mal treatment arises. In view of this, and of reports
of progression to neurosyphilis in patients treated
with benzathine penicillin, some physicians would
treat all patients infected with HIV as for those
with neurosyphilis.
[99]
gimens. In a recent study, a single intramuscular
There is concern that serological relapse is more
injection of benzathine penicillin 2.4 million units
given to mothers with early infectious syphilis pro-
duced a 98% success rate in the prevention of con-
genital syphilis. Treatment failures with benza-
[
94]
frequent in patients co-infected with HIV
but
other studies have shown no significant difference
[
95,96]
from those without HIV co-infection.
Never-
theless, because of these anxieties, assiduous fol-
low-up for clinical and serological evaluation for
treatment failure at 3, 6, 9, 12 and 24 months after
therapy is sensible. Although of unproven benefit,
some experts recommend CSF examination 6
months after therapy in early infectious syphi-
lis.[
thine penicillin in pregnant women have been
One study showed that a single
injection did not prevent preterm birth, intrauterine
reported.[
100-102]
death and congenital syphilis, but a second dose of
2.4 million units did.[
102]
Treponemicidal activity
of less than 3 weeks (the estimated optimal dura-
tion of 2.4 million units of benzathine penicillin)
18,21]
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Management Issues in Syphilis
1457
was felt to be insufficient to protect the newborn.
Thus CDC and European guidelines recommend two
intramuscular doses of benzathine penicillin 2.4
million units, 1 week apart, for early infectious syph-
ilis or intramuscular procaine penicillin 600 000 or
pearing or becoming more prominent. It is more
common in those treated for early infectious syph-
ilis, and it often starts within 2 hours of adminis-
tration of the treatment and effects have usually
resolved within 24 hours. It is not important unless
there is neurological or ophthalmic involvement,
and in the second half of pregnancy when it can
cause fetal distress and preterm labour. While rare
in late syphilis, it could be a problem if the coro-
nary ostia, the larynx or the nervous system includ-
ing cranial nerves are involved, because of local
swelling. Prednisolone at a dose of 10 to 20mg
three times daily for 3 days may abolish fever but
is unproven in reducing local inflammation,[
and is given 24 hours before commencing anti-
syphilitic treatment. As deterioration of affected
lesions such as anterior uveitis and optic neuritis
following antisyphilitic treatment have been re-
ported and corticosteroids had been used to treat
such lesions particularly if ‘idiopathic’, biological
plausibility suggests that it might be useful to re-
duce inflammation. Systemic treatment with a tu-
mour necrosis factor (TNF) antagonist may be
[
18,21]
1
.2 million units daily for 10 to 14 days,
and
this seems reasonable.
If the patient is penicillin allergic the options
are limited. Congenital syphilis has occurred in ba-
bies born to mothers given erythromycin, and tet-
racyclines cannot be used in pregnancy. Some feel
that penicillin allergic individuals should be de-
sensitised using escalating doses of phenoxy-
methylpenicillin and this is clearly described in the
103]
CDC guidelines.[
18]
Ceftriaxone can also be con-
sidered if no alternative is available. If erythromy-
cin is used, the baby must be treated with penicillin
at birth as erythromycin does not penetrate the pla-
cental barrier and consideration given to retreat the
mother with doxycycline after delivery.
It is often difficult to be certain when the mother
might have acquired syphilis but contact tracing
should be undertaken.
The management of congenital syphilis is de-
[
18,21]
[104]
lineated in the CDC and European guidelines.
. Reactions to Treatment
more effective than a corticosteroid.
6
6
.3 The Procaine Reaction
The three reactions of concern are anaphylaxis,
the JHR and the procaine reaction. Patients being
treated for early infectious syphilis should be
warned about the JHR.
The procaine reaction (procaine psychosis, pro-
caine mania or Hognié syndrome) is a rare event
and is believed to occur as a result of inadvertent
intravenous injection of procaine penicillin during
intramuscular administration. The risk of it occur-
ring may be reduced by aspiration into the syringe
following insertion of the needle prior to injection.
Should there be any evidence of blood the needle
should be replaced in a different site. It is a most
alarming reaction and the patient may experience
fear of impending death, may hallucinate or even
seizure immediately after the injection. They may
become violent and possessed of unusual strength
and require physical restraint. The reaction rarely
lasts more than 15 to 20 minutes. If the patient is
convulsing then intravenous, intramuscular or rec-
tal diazepam may be given.
6
.1 Anaphylaxis
Facilities for the treatment of anaphylaxis
should be available, as penicillin is one of its com-
mon precipitating causes. Management is with epi-
nephrine (adrenaline) 1 : 1000 0.5mls intramuscu-
larly followed by an antihistamine such as
chlorpheniramine 10mg and hydrocortisone 100mg,
both either intramuscularly or intravenously.
6
.2 The Jarisch-Herxheimer Reaction
The JHR is an acute febrile illness with rigors,
headache, muscle aches and a secondary rash ap-
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Drugs 2002; 62 (10)

1
458
Pao et al.
7
. Follow-Up
sion of syphilis, immediate epidemiological treat-
ment should be given.
Follow-up is advised to establish that treatment
9
. Conclusion
has been effective and to look for evidence of re-
infection or reactivation. Apart from clinical as-
sessment, the quantitated non-treponemal (reagin)
test should be repeated (VDRL/RPR). In patients
with early infectious syphilis, the titre should de-
cline by two dilution steps (4-fold) within 6
months, and perhaps more slowly in patients co-
infected with HIV. Thus, follow-up at 1, 3, 6 and
Syphilis is an STI which is treatable to the point
of presumptive cure. The mainstay of treatment is
injectable penicillin, either as the benzathine or
procaine salts. Treatments are efficacious but evi-
dence for their use is based mainly on 50 years of
clinical experience rather than controlled clinical
trials. For the penicillin allergic, where other anti-
biotics have to be used, there is even less evidence
of efficacy but doxycycline is the preferred alter-
native. Pilot studies with azithromycin have shown
efficacy in incubating syphilis and a multicentre
study is now underway in the US to assess the ef-
ficacy of a single oral dose of azithromycin 1g in
patients with early infectious syphilis. Those with
syphilis and HIV co-infection can be treated with
the same regimen as is used for those without co-
infection but a more prolonged follow-up is advis-
able.
1
2 months is recommended in early infectious
syphilis. If the serological response is not satisfac-
tory, additional treatment should be given. The
CDC guidelines recommend further intramuscular
benzathine penicillin 2.4 million units on days 1, 8
and 15,[ or a further course of procaine penicillin
may be given over 10 to 14 days.
18]
In late latent syphilis, the non-treponemal test
may have been negative prior to treatment, and fol-
low-up is usually not necessary. In the late forms
of syphilis follow-up might be at 1, 3, 6, 12, 18 and
2
4 months with CSF examination at 24 months in
patients with neurosyphilis. As the serological
tests can remain positive for life (serofast) despite
effective treatment, it is important to document this
to prevent unnecessary retreatment. Follow-up in
those co-infected with HIV has already been dis-
cussed in section 5.2.
Acknowledgements
No sources of funding were used to assist in the prepara-
tion of this manuscript and there are no potential conflicts of
interest that are directly relevant to the contents of this
manuscript.
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E-mail: james.bingham@gstt.sthames.nhs.uk
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