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January 20, 2010 — Adding human monoclonal antibodies to antibiotics significantly reduces the recurrence of Clostridium difficile infection, an infection with increasing incidence in the United States, Canada, and Europe, according to a study published in the January 21 issue of the New England Journal of Medicine.
"We developed one fully human monoclonal antibody targeted against C. difficile toxin A (CDA1) and a second against toxin B (CDB1)," write Israel Lowery, MD, PhD, from Medarex, Princeton, New Jersey, and Deborah Molrine, MD, MPH, from the University of Massachusetts Medical School, Boston, and colleagues. "We have found significant efficacy for the combined antibodies in an established hamster model of C. difficile infection, as well as safety in a phase 1 study in healthy volunteers."
This goal of this randomized, double-blind, placebo-controlled trial was to investigate the ability of CDA1 and CDB1 to prevent C difficile from returning; to examine the antibodies' safety and the length and severity of the infection's first episode; and to determine the infection's effect on hospital stay.
Cohort and Comparative Results
Researchers selected 200 patients in 30 locations in the United States and Canada, all of whom had diarrhea (3 or more unformed stools per day for at least 2 consecutive days, or more than 6 in 1 day) that tested positive for C difficile during the 14-day period before enrollment. The authors noted that the "epidemic of C. difficile isolates have been identified as group BI on restriction enodnucleasae analysis, and 027 on ribotyping (BI/NAP1/027) with the use of polymerase-chain-reaction."
A single intravenous dose of the antibody-infused antibiotics (10 mg/kg of body weight) was administered to 101 participants; 99 received placebo treatment. Results were measured using JMP software, version 7.0 (SAS Institute), and StatXact (Cytel Software), and were compared after 84 days.
For all patients, the recurrence of C difficile was 7% among those who received the antibodies compared with 25% for the placebo group (95% confidence interval, 7 - 29; P < .001). Among those with the (BI/NAP1/027) epidemic strain, recurrence rate was 8% for the antibody group and 32% for the placebo group (P = .06). Of the patients who had 1 or more prior C difficile infection, the rates were 7% for those who received the antibodies and 38% for those who did not (P = .006).
The length of hospital stays did not vary significantly between groups (9.5 days for the antibody group vs 9.4 days for those receiving placebo). Regarding safety, 18 patients receiving antibodies reported at least 1 serious adverse event (including atrial fibrillation, cardiorespiratory arrest, and sepsis or septic shock) compared with 28 patients in the placebo group (P = .09).
"Our results are consistent with those of previous studies that correlated serum levels of antitoxin antibodies with protection against C. difficile infections," the authors write. "Although recent evidence in a hamster model of disease indicated that toxin B is essential for virulence and toxin A may not be, the treatment of human disease may benefit from the presence of high-affinity antibodies against both toxins."
Tempered Praise, Future Applications
Calling the trial results "impressive" in an editorial, Lorraine Kyne, MD, MPH, from Misericordiae University Hospital, Dublin, Ireland, noted that the researchers did not record several common disease severity markers, including serum leukocyte counts, creatinine levels, and intensive care unit admission.
"The lack of efficacy for monoclonal antibodies in attenuating the severity of initial episodes may be related to the definition of severe infection used by the study investigators: the occurrence of at least five unformed stools for at least 2 consecutive days," Dr. Kyne said.
The researchers stated no limitations to their trial, but they acknowledged the need for larger studies to confirm its findings.
They observed that the 1-dose aspect of the combined antibodies-antibiotic treatment may, in and of itself, have future implications for some patients.
"Furthermore, the administration of a single intravenous dose of antibody may be advantageous, depending on the patient's ability to take oral medications," the authors write.
Mass Biologics and Medarex supported the study. Several study authors reported receiving lecture fees, consulting fees, advisory board fees, grants, patent royalties, and equity from Mass Biologics and/or Medarex, or are employees of Medarex. A full list of disclosures is available at the end of the journal article.
N Engl J Med. 2010;362:197-205, 264-265.
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