Tolemaver (GT160-246) binds Clostridium cytotoxins A/B and is associated with restoration of components of the anaerobic intestinal microflora during treatment of C. difficile-associated diarrhoea
Abstract number: 902_p855
During the conduct of a Phase 2 clinical trial on the efficacy of tolevamer 1 or 2 g TID for 14 days compared with vancomycin 125 mg QID for 10 days, we collected serial faecal samples on study entry, days 4, 7, 10, 14, 21, 28 and 42 to determine if non-antibiotic therapy can neutralise C. difficile toxin B in faecal filtrates, promote restoration of the normal microbiota and achieve clinical response.
33 patients were randomised into the study at Calgary study sites (out of 289 patients/58 centres). Faecal filtrate concentrations of C. difficile cytotoxin B, quantitative counts of C. difficile vegetative organisms, C. difficile spore counts were determined. Quantitative aerobic/anaerobic cultures using serial dilutions of faeces 10E-3,5,7,9,11 g-1 wet weight were performed using criteria as outlined in the Wadsworth Anaerobe Laboratory Manual. Stools from healthy donors served as normal microflora controls.
Thirty of 33 patients provided one or more samples, and 22/30 provided serial samples beyond 7 days and up to 42 days. Normal flora controls showed an average of four different Bacteroides species in counts of 1010-12 g-1 faeces wet weight, plus other anaerobic genera in a more inconsistent manner. Using Bacteroides species as a marker genus for the anaerobic microflora, 15, 8, and 7 patients had bacteroides counts below the limit of detection, between 103-8, or >108 CFU/g faeces, respectively, at study entry. Vancomycin treatment eliminated vegetative C. difficile with variable spore persistence, and the Bacteroides genera remained suppressed in the majority of patients during and after the course of therapy. On the other hand, response to tolemaver therapy appears to be accounted for by the inter-relationship between toxin neutralisation, C. difficile growth/persistence, and the pattern of recovery of the microflora. In general, patients who responded to toxin binding therapy exhibited non-emergence of toxin combined with increase in the numbers of anaerobic organisms. Recovery of the anaerobic microflora appeared not to be complete at 14 days in the majority of patients.
Patients with C. difficile diarrhoea have markedly depleted components of the normal intestinal microbiota. Non-antibiotic therapy of C. difficile associated diarrhoea should be further explored to optimise dosage and duration of toxin binding therapy."
|Session name:||XXIst ISTH Congress|
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