Clostridium difficile: moving beyond antimicrobial therapy

Background 
New therapies are needed to manage the increasing incidence, severity, and high rate of recurrence of Clostridium difficile infection. 
 
Methods 
Objective 
To assess the ability of monoclonal antibodies directed against two toxins of C.difficile to prevent recurrence of disease. 
 
Design 
Randomized, double-blind, placebo-controlled study 
 
Setting 
30 medical centers in the United States and Canada 
 
Subjects 
200 subjects with diarrhea and a positive stool toxin assay for C.difficile being treating with metronidazole or vancomycin 
 
Intervention 
Antibodies administered together as a single infusion, each at a dose of 10 mg per kilogram of body weight 
 
Outcomes 
The primary outcome was laboratory-documented recurrence of infection during the 84 days after the administration of monoclonal antibodies or placebo. 
 
Results 
Among the 200 patients who were enrolled (101 in the antibody group and 99 in the placebo group), the rate of recurrence of C. difficile infection was lower among patients treated with monoclonal antibodies (7% vs. 25%; 95% confidence interval, 7 to 29; P < 0.001). The absolute risk reduction (ARR) was 16%, yielded a number needed to treat (NNT) of 5.5. The recurrence rates among patients with the epidemic BI/NAP1/027 strain were 8% for the antibody group and 32% for the placebo group (P = 0.06); among patients with more than one previous episode of C. difficile infection, recurrence rates were 7% and 38%, respectively (P = 0.006). The mean duration of the initial hospitalization for inpatients did not differ significantly between the antibody and placebo groups (9.5 and 9.4 days, respectively). At least one serious adverse event was reported by 18 patients in the antibody group and by 28 patients in the placebo group (P = 0.09). 
 
Conclusions 
The addition of monoclonal antibodies against C. difficile toxins to antibiotic agents significantly reduced the recurrence of C. difficile infection. (ClinicalTrials.gov number, NCT00350298 [ClinicalTrials.gov].)


Background
New therapies are needed to manage the increasing incidence, severity, and high rate of recurrence of Clostridium diffi cile infection.

Methods
Objective: To assess the ability of monoclonal antibodies directed against two toxins of C.diffi cile to prevent recurrence of disease. Design: Randomized, double-blind, placebo-controlled study Setting: 30 medical centers in the United States and Canada Subjects: 200 subjects with diarrhea and a positive stool toxin assay for C.diffi cile being treating with metronidazole or vancomycin Intervention: Antibodies administered together as a single infusion, each at a dose of 10 mg per kilogram of body weight Outcomes: Th e primary outcome was laboratorydocumented recurrence of infection during the 84 days after the administration of monoclonal antibodies or placebo.

Results
Among the 200 patients who were enrolled (101 in the antibody group and 99 in the placebo group), the rate of recurrence of C. diffi cile infection was lower among patients treated with monoclonal antibodies (7% vs. 25%; 95% confi dence interval, 7 to 29; P <0.001). Th e absolute risk reduction (ARR) was 16%, yielded a number needed to treat (NNT) of 5.5. Th e recurrence rates among patients with the epidemic BI/NAP1/027 strain were 8% for the antibody group and 32% for the placebo group (P = 0.06); among patients with more than one previous episode of C. diffi cile infection, recurrence rates were 7% and 38%, respectively (P = 0.006). Th e mean duration of the initial hospitalization for inpatients did not diff er signifi cantly between the antibody and placebo groups (9.5 and 9.4 days, respectively). At least one serious adverse event was reported by 18 patients in the antibody group and by 28 patients in the placebo group (P = 0.09).

Conclusions
Th e addition of monoclonal antibodies against C. diffi cile toxins to antibiotic agents signifi cantly reduced the recurrence of C. diffi cile infection. (ClinicalTrials.gov number, NCT00350298 [ClinicalTrials.gov] .)

Commentary
Infection with Clostridium diffi cile places a signifi cant burden on healthcare facilities. C. diffi cile has been shown to substantially increase hospital costs, hospital length of stay, and contribute to mortality [1,2]. One of the major factors hindering successful treatment of C. diffi cile -associated disease is the high rate of recurrence. Risk factors for recurrence include continued antibiotic use, antacid use, and older age [3]. Anecdotal evidence supports the use of several diff erent modalities, such as tapering doses of vancomycin, rifaxamin, and fecal transplant. Yet, to date none of these therapies have been shown to be eff ective. Myriad risk factors for C. diffi cile infection coalesce in intensive care units, making it a highly relevant condition for intensivists.
Th e present study sought to evaluate the effi cacy of an infusion of monoclonal antibodies directed towards the two principle toxins that emanate from C. diffi cile at preventing relapse of infection [4]. Th e study was a double blind, phase II, randomized, controlled trial at 30 medical centers in the US and Canada. Th is study enrolled 200 subjects between 2006 and 2008 with C. diffi cile infection in both inpatient and outpatient settings. All subjects were followed up for 84 days. Both study groups received antibiotic treatment with either metronidazole or vancomycin. Th e proportion of the hypervirulent BI/NAPI strain of C. diffi cile was similar in both the treatment and placebo arms. Th e study results revealed a signifi cant decrease in the relapse rate of C. diffi cile in the treatment arm. Th e absolute risk reduction (ARR) was 18% and the number needed to treat (NNT) is 5.5. In those with more than one recurrence, the ARR of a recurrence was even greater (ARR = 31% and NNT = 3.2). Th ere was no diff erence in the rates of serious adverse events between the placebo and treatment groups. However, the infusion failed to impact the severity of the initial episode of C. diffi cile infection or length of stay. All recurrences occurred in hospitalized subjects.
Th e study was well conducted and had few limitations. One limitation was that the study defi ned severity of C. diffi cile infection solely in terms of stool counts and may have unduly dismissed the benefi t of the antibodies against the initial infection. Utilizing other parameters, such as quality of life and ability to tolerate meals, may have provided more information concerning the impact on the initial episode. Additionally, the exclusion of the sickest patients with C. diffi cile may have limited the generalizability of the study to acute care settings.
Recurrent C. diffi cile -associated disease is an important problem that not only aff ects the patient, but places others at risk from environmental contamination with the bacteria. Th e monoclonal antibodies studied in this paper provide hope that those plagued with recurrent infections can be treated eff ectively and safely. Th e utilization of monoclonal antibodies against infectious diseases is a crucial advance in developing specifi c therapies that are targeted at the organism of interest and not likely to infl ict collateral damage to the patient's microbiome, an important point made in the editorial accompanying the study [5].

Recommendation
In conclusion, the addition of monoclonal antibodies did not alter the severity of Clostridium diffi cle-associated disease. However, monoclonal antibodies will reduce the recurrence of disease and should be routinely administered to those at highest risk for recurrence. Determining the cost-eff ectiveness of this approach remains to be seen.