International Journal of Antimicrobial Agents 33 (2009) 4–7

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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

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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.

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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

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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

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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. References [1] McDonald LC, Owings M, Jernigan DB. Clostridium difficile infection in patients discharged from US short-stay hospitals, 1996–2003. Emerg Infect Dis 2006;12:409–15. [2] Kyne L, Hamel MB, Polavaram R, Kelly CP. Health care costs and mortality associated with nosocomial diarrhea due to Clostridium difficile. Clin Infect Dis 2002;34:346–53. [3] Loo VG, Poirier L, Miller MA, Oughton M, Libman MD, Michaud S, et al. A predominantly clonal multi-institutional outbreak of Clostridium difficileassociated diarrhea with high morbidity and mortality. N Engl J Med 2005;353:2442–9 [Erratum. N Engl J Med 2006;354:2200]. [4] Bartlett JG, Chang TW, Gurwith M, Gorbach SL, Onderdonk AB. Antibioticassociated pseudomembranous colitis due to toxin-producing clostridia. N Engl J Med 1978;298:531–4. [5] Tedesco FL, Barton RW, Alpers DH. Clindamycin-associated colitis. A prospective study. Ann Intern Med 1974;8:429–33. [6] Pépin J, Saheb N, Coulombe MA, Alary ME, Corriveau MP, Authier S, et al. Emergence of fluoroquinolones as the predominant risk factor for Clostridium difficile-associated diarrhea: a cohort study during an epidemic in Quebec. Clin Infect Dis 2005;41:1254–60. [7] Weiss K, Bergeron L, Bernatchez H, Goyette M, Savoie M, Thirion D. Clostridium difficile-associated diarrhoea rates and global antibiotic consumption in five Quebec institutions from 2001 to 2004. Int J Antimicrob Agents 2007;30:309–14.

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