Tolevamer, a novel nonantibiotic polymer, compared with vancomycin in the treatment of mild to moderately severe Clostridium difficile-associated diarrhea.
BACKGROUND
Current antibiotic therapies for Clostridium difficile-associated diarrhea have limitations, including progression to severe disease, recurrent C. difficile-associated diarrhea, and selection for nosocomial pathogens. Tolevamer, a soluble, high-molecular weight, anionic polymer that binds C. difficile toxins A and B is a unique nonantibiotic treatment option.


METHODS
In this 3-arm, multicenter, randomized, double-blind, active-controlled, parallel-design phase II study, patients with mild to moderately severe C. difficile-associated diarrhea were randomized to receive 3 g of tolevamer per day (n = 97), 6 g of tolevamer per day (n = 95), or 500 mg of vancomycin per day (n = 97). The primary efficacy parameter was time to resolution of diarrhea, defined as the first day of 2 consecutive days when the patient had hard or formed stools (any number) or < or = 2 stools of loose or watery consistency.


RESULTS
In the per-protocol study population, resolution of diarrhea was achieved in 48 (67%) of 72 patients receiving 3 g of tolevamer per day (median time to resolution of diarrhea, 4.0 days; 95% confidence interval, 2.0-6.0 days), in 58 (83%) of 70 patients receiving 6 g of tolevamer per day (median time to resolution of diarrhea, 2.5 days; 95% confidence interval, 2.0-3.0 days), and in 73 (91%) of 80 patients receiving vancomycin (median time to resolution of diarrhea, 2.0 days; 95% confidence interval, 1.0-3.0 days). Tolevamer administered at a dosage of 6 g per day was found to be noninferior to vancomycin administered at a dosage of 500 mg per day with regard to time to resolution of diarrhea (P = .02) and was associated with a trend toward a lower recurrence rate. Tolevamer was well tolerated but was associated with an increased risk of hypokalemia.


CONCLUSIONS
Tolevamer, a novel polystyrene binder of C. difficile toxins A and B, effectively treats mild to moderate C. difficile diarrhea and merits further clinical development.
Louie
Thomas J
TJ
University of Calgary, Calgary, Alberta, Canada. louie@ucalgary.ca
Peppe
Jennifer
J
Watt
C Kevin
CK
Johnson
David
D
Mohammed
Rasheed
R
Dow
Gordon
G
Weiss
Karl
K
Simon
Stuart
S
John
Joseph F
JF
Garber
Gary
G
Chasan-Taber
Scott
S
Davidson
David M
DM
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000890:Anti-Infective Agents / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000378:metabolism; D001427:Bacterial Toxins / Q000378:metabolism; D016360:Clostridioides difficile; D003967:Diarrhea / Q000188:drug therapy / Q000382:microbiology; D004311:Double-Blind Method; D004761:Enterocolitis, Pseudomembranous / Q000188:drug therapy* / Q000382:microbiology; D004768:Enterotoxins / Q000378:metabolism; D005260:Female; D006801:Humans; D007477:Ions / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011108:Polymers / Q000627:therapeutic use*; D011137:Polystyrenes / Q000627:therapeutic use*; D013451:Sulfonic Acids; D014640:Vancomycin / Q000627:therapeutic use
D000890:Anti-Infective Agents; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D004768:Enterotoxins; D007477:Ions; D011108:Polymers; D011137:Polystyrenes; D013451:Sulfonic Acids; C041348:tcdA protein, Clostridium difficile; C031815:toxB protein, Clostridium difficile; D014640:Vancomycin; C077114:styrenesulfonic acid polymer