Human Monoclonal Antibodies Directed against Toxins A and B Prevent
            <i>Clostridium difficile</i>
            -Induced Mortality in Hamsters

Babcock, Gregory J.; Broering, Teresa J.; Hernández, Héctor J.; Mandell, Robert B.; Donahue, Katherine C; Boatright, Naomi K.; Stack, Anne M.; Lowy, Israel; Graziano, Robert F.; Molrine, Deborah C.; Ambrosino, Donna M.; Thomas, William D.

doi:10.1128/iai.00982-06

Cited by 230 publications

(256 citation statements)

References 37 publications

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“…Passive or active immunization against C. difficile toxins A and B is protective in animals that are challenged with toxigenic C. difficile, [7][8][9] which underscores the key importance of the toxins in causing the symptoms of C. difficile infection. The relative biologic importance of toxins A and B in C. difficile infection is controversial, but it may be host species-dependent.…”

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confidence: 99%

Bezlotoxumab for Prevention of RecurrentClostridium difficileInfection

et al. 2017

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BACKGROUNDClostridium difficile is the most common cause of infectious diarrhea in hospitalized patients. Recurrences are common after antibiotic therapy. Actoxumab and bezlotoxumab are human monoclonal antibodies against C. difficile toxins A and B, respectively. METHODSWe conducted two double-blind, randomized, placebo-controlled, phase 3 trials, MODIFY I and MODIFY II, involving 2655 adults receiving oral standard-of-care antibiotics for primary or recurrent C. difficile infection. Participants received an infusion of bezlotoxumab (10 mg per kilogram of body weight), actoxumab plus bezlotoxumab (10 mg per kilogram each), or placebo; actoxumab alone (10 mg per kilogram) was given in MODIFY I but discontinued after a planned interim analysis. The primary end point was recurrent infection (new episode after initial clinical cure) within 12 weeks after infusion in the modified intention-to-treat population. RESULTSIn both trials, the rate of recurrent C. difficile infection was significantly lower with bezlotoxumab alone than with placebo (MODIFY I In prespecified subgroup analyses (combined data set), rates of recurrent infection were lower in both groups that received bezlotoxumab than in the placebo group in subpopulations at high risk for recurrent infection or for an adverse outcome. The rates of initial clinical cure were 80% with bezlotoxumab alone, 73% with actoxumab plus bezlotoxumab, and 80% with placebo; the rates of sustained cure (initial clinical cure without recurrent infection in 12 weeks) were 64%, 58%, and 54%, respectively. The rates of adverse events were similar among these groups; the most common events were diarrhea and nausea.: CONCLUSIONSAmong participants receiving antibiotic treatment for primary or recurrent C. difficile infection, bezlotoxumab was associated with a substantially lower rate of recurrent infection than placebo and had a safety profile similar to that of placebo. The addition of actoxumab did not improve efficacy. 306T h e ne w e ngl a nd jou r na l o f m e dicine I n high-income countries, Clostridium difficile is the most common cause of infectious diarrhea in hospitalized patients. 1,2 After completing initial antibiotic therapy, up to 35% of patients have recurrent C. difficile infection, 3,4 which is more difficult to treat and is associated with more hospitalizations, more severe outcomes, and higher costs than the first infection and a 50 to 60% chance of repeat recurrent infections. 5,6 Currently, no therapy has been approved to prevent recurrent C. difficile infection.Passive or active immunization against C. difficile toxins A and B is protective in animals that are challenged with toxigenic C. difficile, 7-9 which underscores the key importance of the toxins in causing the symptoms of C. difficile infection. The relative biologic importance of toxins A and B in C. difficile infection is controversial, but it may be host species-dependent. 10-12 Neutralization of both toxins appears to be necessary for maximal protection in rodents, but neutralization of toxin...

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confidence: 99%

Bezlotoxumab for Prevention of RecurrentClostridium difficileInfection

et al. 2017

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“…Toxin dosing was based on in vitro cell based assays with purified rTcdA and rTcdB, which indicate that the toxicity of rTcdB is at least 10-fold greater than rTcdA. 9 The human monoclonal antiTcdA antibodies used in this study were developed by Massachusetts Biologic Laboratories and Medarex, Inc, 12 and were provided for this study and currently licensed by Merck, Inc. The anti-TcdA antibodies were administered to piglets at a dose of 10 mg/kg, based on the dosing in human studies.…”

Section: Methodsmentioning

confidence: 99%

“…The human monoclonal antibodies used here were kindly provided by Merck, Inc and were developed using the C. difficile strain VPI 10463. 12 The human monoclonal anti-TcdA antibodies were administered to 2 gnotobiotic piglets at 5 d of age, and then 2 μg of purified rTcdA was administered the following day. The dose of rTcdA was reduced from the previous experiment given the extreme toxicity observed with the 10 μg dose and our desire to not overwhelm the antibodies.…”

Section: Systemic Administration Of Tcda With Human Monoclonalmentioning

confidence: 99%

The roles of toxin A and toxin B inClostridium difficileinfection

2013

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“…For example, antibodies against Shiga toxin were shown to protect against Shiga toxinproducing E. coli (STEC) in a piglet model of acute gastroenteritis [35]. Similarly, efficacy was demonstrated in mouse and hamster infection models by combining human antibodies against C. difficile toxins A and B [36]. The potential use of B. anthracis as a bioweapon has made this and other high threat pathogens the focus of intense efforts to develop antibodies and vaccines [37].…”

Section: Targeting Toxinsmentioning

confidence: 99%