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Promising New Drug for C difficile InfectionPosted: 02/17/2011
This is Andy Shorr from Washington, DC with the Pulmonary and
Critical Care Medicine literature update. I'd like to bring to your
attention an article that was recently published in The New England Journal of Medicine by Louie and colleagues, the February 3 edition.[1] It dealt with Clostridium difficile infection. We don't generally think of C difficile as a disease that we, as either pulmonologists or intensivists, own,
but it is, in fact, a disease that we deal with every day. The burden of C difficile in hospitalized patients is increasing, and it's
particularly noticeable in patients who are in the intensive care unit
(ICU). Patients in the ICU disproportionally consume antibiotic doses
that are often measured in tons and, therefore, are particularly at risk
for C difficile infection. Conversely, with the emergence of the epidemic strain of C difficile in North America, we are now seeing a level of severity of this disease that is leading to admission directly to the ICU because of C difficile infection. In terms of my own personal practice, on average I end up seeing about 1 patient every quarter who needs to go to the operating room for a colectomy or hemicolectomy because of C difficile infection. That certainly was not something we were seeing years ago. On top of that, epidemiologic data suggest that C difficile is going to become more, and not less, of an issue, and even with efforts to contain antibiotic abuse through antibiotic stewardship programs, C difficile is going to remain an issue for those of us who take care of inpatients and even, at times, outpatients. Traditionally we've had 2 choices. We've had metronidazole or oral vancomycin. These have not necessarily been the best choices, so there has been a huge effort to develop new molecules for this syndrome. Many of them have failed. In this article in The New England Journal of Medicine, these investigators present the data from 2 randomized controlled trials looking at a new antibiotic, a macrocyclic antibiotic, for its use in C difficile infection. Louie and colleagues conducted a series of randomized controlled trials that were designed to be noninferiority studies looking at fidaxomicin vs vancomycin in patients with C difficile infection, and overall cure or response was the primary endpoint. Pooled together, the 2 studies enrolled approximately 600 patients. Compared with oral vancomycin, fidaxomicin appeared to be similar or "noninferior." That's what this study was designed to show. The study was not powered to be a superiority study. A secondary endpoint in this study was recurrence rate. We know recurrent episodes of C difficile infection tend to be harder to treat and tend to be associated with the highest risk for mortality and more substantial morbidity. These investigators saw a very interesting and very promising signal, which was that rates of recurrent C difficile infection were reduced in an absolute sense by 10% between vancomycin and the novel intervention. If you do your evidence-based math, a 10% absolute risk reduction translates into a number needed to treat of only 10, so for every 10 patients treated with the intervention, the macrocyclic antibiotic, instead of our traditional standard oral vancomycin, you prevented 1 additional recurrence. When these investigators presented their data, one of the limitations is that in their published findings they don't tell us much about the patients who were enrolled in terms of their overall disease severity. There were some classification schema to describe the severity of C difficile infection, but they are unique to C difficile. They don't tell us how many patients were on ventilators or how many patients were critically ill. That gets to the external validity or generalizability of the study for those of us in the ICU. However, when they looked at outcomes, even in the patients with the most severe disease, there were fewer recurrences, so overall, that suggests that this molecule may be helpful to us. When they looked at safety (because we always balance the benefit vs safety risk in any intervention in the hospital), they did not see a difference in terms of overall tolerability or safety between the 2 drugs. The molecule is currently undergoing US Food and Drug Administration (FDA) review, so we'll have to see what happens. I think this article demonstrates that C difficile infection is such a challenge to us that novel therapies are being developed, and we need to start thinking about interventions in terms not only of their overall effects on cure, but what are the secondary endpoints we need to look at and embrace as we think about designing and interpreting clinical trials that are important to us as clinicians at the bedside? This may be a molecule for us to have available commercially if it's approved by the FDA in the United States or the European regulatory authorities for Europe, so we need to be aware of what's in the pipeline for this issue. We also need to be aware that C difficile infection is an issue on which we need to focus because, again, the best way to deal with C difficile is not to treat it but to prevent it. We need to think about preventive measures here as well, which include hand hygiene, patient cohorting, and infection control, along with good antibiotic stewardship. Again the article was in the February 3 issue of The New England Journal of Medicine. This is Andy Shorr from Washington, DC. http://www.medscape.com/viewarticle/737391
Original Article Fidaxomicin versus Vancomycin for Clostridium difficile InfectionN Engl J Med 2011; 364:422-431February 3, 2011 BackgroundClostridium difficile infection is a serious diarrheal illness associated with substantial morbidity and mortality. Patients generally have a response to oral vancomycin or metronidazole; however, the rate of recurrence is high. This phase 3 clinical trial compared the efficacy and safety of fidaxomicin with those of vancomycin in treating C. difficile infection. MethodsAdults with acute symptoms of C. difficile infection and a positive result on a stool toxin test were eligible for study entry. We randomly assigned patients to receive fidaxomicin (200 mg twice daily) or vancomycin (125 mg four times daily) orally for 10 days. The primary end point was clinical cure (resolution of symptoms and no need for further therapy for C. difficile infection as of the second day after the end of the course of therapy). The secondary end points were recurrence of C. difficile infection (diarrhea and a positive result on a stool toxin test within 4 weeks after treatment) and global cure (i.e., cure with no recurrence). ResultsA total of 629 patients were enrolled, of whom 548 (87.1%) could be evaluated for the per-protocol analysis. The rates of clinical cure with fidaxomicin were noninferior to those with vancomycin in both the modified intention-to-treat analysis (88.2% with fidaxomicin and 85.8% with vancomycin) and the per-protocol analysis (92.1% and 89.8%, respectively). Significantly fewer patients in the fidaxomicin group than in the vancomycin group had a recurrence of the infection, in both the modified intention-to-treat analysis (15.4% vs. 25.3%, P=0.005) and the per-protocol analysis (13.3% vs. 24.0%, P=0.004). The lower rate of recurrence was seen in patients with non–North American Pulsed Field type 1 strains. The adverse-event profile was similar for the two therapies. ConclusionsThe rates of clinical cure after treatment with fidaxomicin were noninferior to those after treatment with vancomycin. Fidaxomicin was associated with a significantly lower rate of recurrence of C. difficile infection associated with non–North American Pulsed Field type 1 strains. (Funded by Optimer Pharmaceuticals; ClinicalTrials.gov number, NCT00314951.) Drs. Louie, Miller, Mullane, Weiss, Lentnek, and Golan report that their respective institutions received per-case funding from Optimer Pharmaceuticals to support patient expenses. Drs. Louie, Miller, Mullane, and Golan report receiving support from Optimer Pharmaceuticals for travel to meetings for the conduct of the clinical trial or presentation of the results of the clinical trial, and Drs. Louie, Miller, and Mullane report receiving honoraria from Optimer Pharmaceuticals for participation in additional meetings related to investigative planning for fidaxomicin. In addition, Dr. Louie reports receiving honoraria or consulting fees from Merck, Cubist Pharmaceuticals, ViroPharma, Cempra, and Iroko Pharmaceuticals, and being listed on a fidaxomicin patent; Dr. Miller, receiving honoraria or consulting fees from Merck, Iroko Pharmaceuticals, and Salix Pharmaceuticals; Dr. Weiss, receiving honoraria or consulting fees from Abbott, Bayer, Pfizer, and Genzyme; Dr. Shue, being an employee of and owning stock options in Optimer Pharmaceuticals; Dr. Sears, being an employee of and owning stock options in Optimer Pharmaceuticals and being listed as an inventor on a fidaxomicin patent; and Dr. Gorbach, being a part-time employee of Optimer Pharmaceuticals, receiving honoraria from and owning stock options in Cempra, and holding a patent on lactobacillus GG probiotic and β-glucan. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. No other potential conflict of interest relevant to this article was reported. Source InformationFrom the University of Calgary, Calgary, AB, Canada (T.J.L.); McGill University (M.A.M.) and the University of Montreal (K.W.) — both in Montreal; the University of Chicago, Chicago (K.M.M.); Wellstar Infectious Disease, Marietta, GA (A.L.); Tufts Medical Center, Boston (Y.G., S.G.); and Optimer Pharmaceuticals, San Diego, CA (S.G., P.S., Y.-K.S.). Address reprint requests to Dr. Louie at the Division of Infectious Diseases, Departments of Medicine and Microbiology and Infectious Diseases, University of Calgary, Foothills Hospital, 1403 29 St. NW, Calgary, AB T2N 4J8, Canada, or at thomas.louie@albertahealthservices.ca. Additional investigators in the OPT-80-003 Clinical Study Group are listed in the Supplementary Appendix, available at NEJM.org. |