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International Journal of Antimicrobial Agents 33 (2009) 4–7
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International Journal of Antimicrobial Agents
journal homepage: http://www.elsevier.com/locate/ijantimicag
Review
Toxin-binding treatment for Clostridium difficile: a review including reports of
studies with tolevamer
Karl Weiss ∗
Department of Microbiology and Infectious Diseases, Maisonneuve-Rosemont Hospital, Faculty of Medicine, Université de Montréal,
5415 l’Assomption, Montreal, Quebec, Canada H1T 2M4
a r t i c l e
i n f o
Article history:
Received 14 July 2008
Accepted 15 July 2008
Keywords:
Clostridium difficile
Treatment
Toxin binding
Tolevamer
a b s t r a c t
Clostridium difficile represents an increasing threat to patients, mainly as a hospital-acquired infection
causing antibiotic-associated colitis (AAC). The emergence of a new more virulent strain in North America and Europe has been linked to increased morbidity and mortality. For a long period of time the only
available therapeutic options were oral vancomycin and metronidazole. However, both of these antibiotics
have limitations either in terms of efficacy, cost, formulation, side effects or the risk of emerging antibiotic
resistance among enterococci. Clostridium difficile produces two powerful toxins (A and B) that are responsible for the entire clinical spectrum associated with AAC. As this is exclusively a toxin-mediated disease,
agents with the potential of binding these targets have been tested. Data on polymer-based toxin-binding
agents such as cholestyramine, Synsorb 90 and tolevamer, designed to target specific bacterial toxins, will
be reviewed. Bovine colostrum and specific human monoclonal antibodies aimed at neutralising toxin A,
although still at an early stage of development, are also new avenues to be explored. Non-antibiotic-based
therapies might become the best available option for a condition almost always caused by antibiotics.
© 2008 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
1. Introduction
Clostridium difficile infection (CDI) is increasingly recognised
as a nosocomial infection with severe consequences [1,2]. Since
2002, the arrival of a new virulent clone designated as BI/NAP1
in North America and 027 in Europe has resulted in increased
research activity in the management of this disease [3]. Clostridium difficile was recognised as the cause of antibiotic-associated
colitis (AAC) in 1978 [4], when clindamycin was the main cause [5].
We know today that almost all antimicrobial agents can cause this
dreaded entity. There has been some debate regarding whether or
not fluoroquinolones might play a role in the current situation [6,7].
However, poor infection control measures, in particular deficient
hand hygiene, coupled with an increasing elderly, frail hospital population is likely one of the key explanations for C. difficile resurgence
[8,9].
Initially, hamster models of infection showed some protective and beneficial effect from oral vancomycin, which quickly
became the drug of choice [10]. Today it is still the only approved
drug for the treatment of C. difficile-associated diarrhoea (CDAD).
Metronidazole was subsequently used, although it was never
∗ Tel.: +1 514 252 3400x2693; fax: +1 514 252 3898.
E-mail address: [email protected].
endorsed with an official US Food and Drug Administration (FDA)approved indication. As a much cheaper alternative, and relatively
comparable in terms of efficacy, metronidazole became the de
facto first-line treatment thereafter. Clostridium difficile was an
orphan disease with few new developments until the mid 1990s
to early 2000 when the new virulent strain emerged as a great
threat.
2. Reasons for targeting C. difficile toxins
Clostridium difficile is a toxin-mediated disease in which two
main toxins, A and B, are responsible for the clinical picture [11].
For a long time toxin A was thought to be the key component in triggering the disease pathogenesis, but toxin B now appears to play
an equally important role. They both bind to receptors on intestinal epithelial cells thus triggering the production of cytokines
(interleukins 1–8, leukotrienes, histamine, etc.) [11]. The cytokines
released create local inflammation at the intestinal mucosa level,
and necrosis of the colonic border brush ensues. The massive cell
death will cause fluid secretion into the intestine, which manifests
as profuse watery diarrhoea. Blood is seldom present in the stool
in CDI and usually represents an ominous sign (perforation). Toxins A and B have the ability to disrupt tight junctions of epithelial
barriers and favour the migration of neutrophils into the lumen of
the large bowel.
0924-8579/$ – see front matter © 2008 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
doi:10.1016/j.ijantimicag.2008.07.011
K. Weiss / International Journal of Antimicrobial Agents 33 (2009) 4–7
Clostridium difficile does not invade the bloodstream or cause
infections at distant sites. It remains localised in the intestinal
lumen, thus any locally targeted treatment might be a therapeutic
option [12].
CDI has been associated with a high relapse rate, varying
between 15% and 25%, demonstrating the limitations of standard
conventional antibiotic therapy with metronidazole or vancomycin
[12]. Other antibiotics have been tried in the past (e.g. fusidic acid
and bacitracin) but never gained any popularity; only limited and
sketchy clinical data are available for these agents [13]. The use
of oral vancomycin must be limited because of its excessive price
and also to curtail the risk of emergence of vancomycin-resistant
enterococci (VRE). None the less, there is still controversy regarding this issue, as published data show that both vancomycin and
metronidazole might represent an ecological risk for VRE [14].
3. Toxin-binding molecules
Researchers and clinicians developed the concept that any substance potentially capable of binding C. difficile toxins might have
a relevant therapeutic role. Three compounds have been clinically
tested for the treatment of CDAD: cholestyramine; Synsorb 90; and
tolevamer. An additional compound, colestipol, a lipid-lowering
agent (bile salts binder), was briefly tried as a possible treatment
but never reached the level of a viable option.
3.1. Cholestyramine
Cholestyramine (Questran) is a bile acid sequestrant and was
the first to be studied. It was initially tested as an adjunct therapy
to vancomycin or as preventive therapy after a regular treatment
course of oral vancomycin [15]. It acts as a strong anion exchange
resin, exchanging its free chloride anion for anionic bile acids.
Cholestyramine is used in Crohn’s disease to prevent diarrhoea by
diminishing the amount of bile salts in the large bowel. Bile acids
are strong osmotic agents attracting water into the bowel lumen,
thus creating a watery diarrhoea.
The usual dose of cholestyramine is 4 g three or four times a day,
up to a maximum dose of 24 g. Apart from constipation, which may
be the aim in CDI episodes, it does not have any significant side
effects.
There is also a strong caveat with cholestyramine, namely its
potential ability to bind vancomycin [16]. It is recommended to
administer the drug at least 2 h after a dose of oral vancomycin.
So far, apart from a few anecdotal reports in the early 1980s, there
is no strong clinical evidence advocating its use in CDI. It can be
used in desperate situations such as numerous relapses, for which
there is no standard definition (four or more would probably be an
acceptable number).
3.2. Synsorb 90
Animal models showed that C. difficile toxin A binds to a specific trisaccharide receptor called Gal␣1–3Gal␤1–4GlcNAc situated
on intestinal cells [17]. Synsorb 90, an inert support carrying
this trisaccharide, was tested against C. difficile. It was developed by a Canadian-based company (Synsorb Biotech, Calgary,
Alberta, Canada) that had two major objectives: (i) the prevention
of haemolytic uremic syndrome in children who had verotoxigenic
Escherichia coli infections (including E. coli O157:H7); and (ii) the
treatment of CDAD. The compounds for the two indications were
labelled Synsorb Pk (R) and Synsorb Cd (R), respectively.
Initial animal models showed promising results with Synsorb Cd
(R) [18]. A phase II study demonstrated encouraging results with a
reduction of the C. difficile relapse rate [19]. However, development
5
of the drug was abandoned once it entered into phase III and no
clinical study with this compound has ever been published.
3.3. Tolevamer
Tolevamer, initially known as GT160-246, is a non-antibiotic
anionic polymer developed by Genzyme Corporation (Cambridge,
MA). It acts by binding to, and subsequently neutralising, C. difficile toxins A and B [20]. It is a high-molecular-weight compound
(>400 kDa) with no antimicrobial activity. This latter property was
initially appreciated as it does not interfere with the normal intraluminal bacterial flora. Initial animal models in dogs and rats showed
no intestinal absorption of the drug, which made it an ideal option
for CDI. Hamster models subsequently demonstrated its high activity against C. difficile [21].
Tolevamer was initially tested against specific strains of the
BI/027 clone. Recently published data suggest that the compound
neutralises the toxins produced by these specific strains [22].
In a phase II study (289 patients in 58 sites in the USA,
Canada and the UK) comparing tolevamer 3 g/day (n = 97), tolevamer 6 g/day (n = 95) and vancomycin 500 mg/day (n = 97), the
percentage of patients achieving the primary endpoint (resolution
of diarrhoea) in the per-protocol analysis was similar for vancomycin (73/80; 91%) and tolevamer 6 g/day (58/70; 83%) [23]. The
3 g/day dose of tolevamer was found to be significantly inferior to
vancomycin.
As a secondary objective, the median time to resolution of diarrhoea, was also analysed and tolevamer 6 g/day (median 2.5 days,
95% confidence interval (CI) 2–3 days) and vancomycin (median
2 days, 95% CI 1–3 days) were similar. An interesting fact was
the trend towards a lower recurrence rate among the 6 g/day
tolevamer-treated group compared with vancomycin (10% vs. 19%;
P = 0.19).
In terms of side effects, an unexpected finding was a higher rate
of hypokalaemia, which appears to be dose-related, in the tolevamer arm: 23% in the 6 g/day group and 17% in the 3 g/day group
compared with 7% for vancomycin. The exact mechanism of action
for this has not been elucidated.
Two phase III studies followed, one in North America (GD3-170301) [24], and one in Europe, Australia and Canada (GD3-170-302)
[25]. These were designed to be three-limb studies comparing
vancomycin, metronidazole and tolevamer, randomised in a 1:1:2
fashion. Both studies represent the largest ever clinical trials done
in the field of C. difficile and also gave crucial information on the
comparative efficacy of vancomycin and metronidazole, which was
lacking until recently.
In the two studies, tolevamer was found to be inferior to both
comparators and further development of the drug was stopped. A
summary of both studies is presented in Table 1. However, a key
point was the significantly lower recurrence rate with tolevamer
among patients who had a successful clinical response and were
categorised as cured at the end of treatment. Despite initial clinical failure of the drug, the lower recurrence rate opens potential
avenues for the compound as a supplemental adjunctive treatment
or for patients known to have frequent relapses.
3.4. Immunoglobulin-directed therapy
The capability to neutralise C. difficile toxins by immunoglobulins has been investigated [26]. Immunoglobulins able to bind
toxin A were seen as potentially capable of preventing the clinical
consequences of the infection.
Bovine colostrum has often been targeted as a viable treatment
[27,28]. It is a pre-milk substance produced in cows’ mammary glands within 24–48 h of giving birth and contains a high
6
K. Weiss / International Journal of Antimicrobial Agents 33 (2009) 4–7
Table 1
Summary of clinical efficacy and recurrence rates for tolevamer phase III clinical studies
Study
Agent
a
GD3-170-301 [24]
GD3-170-301 [24]
GD3-170-301 [24]
GD3-170-302 [25]b
GD3-170-302 [25]
GD3-170-302 [25]
a
b
c
d
Tolevamer (n = 266)
Vancomycin (n = 134)
Metronidazole (n = 143)
Tolevamer (n = 268)
Vancomycin (n = 125)
Metronidazole (n = 135)
Clinical success (%)
c
46
81
72
42c
81
73
Recurrence rate (%)
3d
23
27
6
18
19
n = 574; n = 543 available for full analysis.
n = 528.
P < 0.001.
P < 0.001.
concentration of immunoglobulins. Cows are immunised with
an antigen with the intention of producing a high immune
response resulting in an abnormally high concentration of specific
immunoglobulins in their colostrum. The ecological appeal of this
approach has stimulated some interest lately.
Knowing that specific anti-toxin A antibodies offer protection
against symptomatic disease and relapses, a more recent approach
involves neutralising human monoclonal antibody against this particular structure. Still in its infancy, this model may open new ways
in the treatment and prevention of CDI [29].
4. Conclusion
CDI is a condition with many interesting therapeutic options.
New drugs being evaluated, or ‘old’ compounds, are stimulating interest in the field, with rifaximin, nitazoxanide, OPT-80
(difimicin) and ramoplanin being good examples. Intravenous
immunoglobulins as well as vaccines are being investigated to
improve the patient’s ability to fight this dreaded entity that has
made an unexpected comeback with a vengeance. To date, none
of the toxin-binding agents fully meet our expectations, however
tolevamer might still play a role in the future at a higher dosage
or as an adjunctive therapy in patients with frequent relapses of
infection.
Funding: Health-Canada, Valorisation-Recherche Québec,
Abbott, Bayer, Bristol-Myers Squibb, Genzyme, GSK, Merck Frosst,
Roche, Pfizer, Theravance and Wyeth.
Competing interests: None declared.
Ethical approval: Not required.
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