Clostridium difficile: moving beyond antimicrobial therapy
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Lowy I, Molrine DC, Leav BA, Blair BM, Baxter R, Gerding DN, Nichol G, Thomas WD Jr, Leney M, Sloan S, Hay CA, Ambrosino DM: Treatment with monoclonal antibodies against Clostridium difficile toxins. N Engl J Med 2010, 362:197-205.
New therapies are needed to manage the increasing incidence, severity, and high rate of recurrence of Clostridium difficile infection.
To assess the ability of monoclonal antibodies directed against two toxins of C.difficile to prevent recurrence of disease.
Randomized, double-blind, placebo-controlled study
30 medical centers in the United States and Canada
200 subjects with diarrhea and a positive stool toxin assay for C.difficile being treating with metronidazole or vancomycin
Antibodies administered together as a single infusion, each at a dose of 10 mg per kilogram of body weight
The primary outcome was laboratory-documented recurrence of infection during the 84 days after the administration of monoclonal antibodies or placebo.
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).
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].)
Infection with Clostridium difficile places a significant burden on healthcare facilities. C. difficile 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. difficile-associated disease is the high rate of recurrence. Risk factors for recurrence include continued antibiotic use, antacid use, and older age . Anecdotal evidence supports the use of several different modalities, such as tapering doses of vancomycin, rifaxamin, and fecal transplant. Yet, to date none of these therapies have been shown to be effective. Myriad risk factors for C. difficile infection coalesce in intensive care units, making it a highly relevant condition for intensivists.
The present study sought to evaluate the efficacy of an infusion of monoclonal antibodies directed towards the two principle toxins that emanate from C. difficile at preventing relapse of infection . The study was a double blind, phase II, randomized, controlled trial at 30 medical centers in the US and Canada. This study enrolled 200 subjects between 2006 and 2008 with C. difficile 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. The proportion of the hypervirulent BI/NAPI strain of C. difficile was similar in both the treatment and placebo arms. The study results revealed a significant decrease in the relapse rate of C. difficile in the treatment arm. The 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). There was no difference 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. difficile infection or length of stay. All recurrences occurred in hospitalized subjects.
The study was well conducted and had few limitations. One limitation was that the study defined severity of C. difficile infection solely in terms of stool counts and may have unduly dismissed the benefit 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. difficile may have limited the generalizability of the study to acute care settings.
Recurrent C. difficile-associated disease is an important problem that not only affects the patient, but places others at risk from environmental contamination with the bacteria. The monoclonal antibodies studied in this paper provide hope that those plagued with recurrent infections can be treated effectively and safely. The utilization of monoclonal antibodies against infectious diseases is a crucial advance in developing specific therapies that are targeted at the organism of interest and not likely to inflict collateral damage to the patient's microbiome, an important point made in the editorial accompanying the study .
In conclusion, the addition of monoclonal antibodies did not alter the severity of Clostridium difficle-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-effectiveness of this approach remains to be seen.