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LONDON – Fidaxomicin was noninferior to vancomycin in achieving clinical cure of Clostridium difficile infection after 10 days of treatment but was superior to vancomycin in attaining lower recurrence rates and higher sustained response rates at 4 weeks.
The findings come from a multicenter, randomized, controlled, double-blind study conducted in seven European countries, Canada, and the United States. It was funded by Optimer Pharmaceuticals, manufacturer of fidaxomicin, a novel macrocyclic antibiotic with a narrow spectrum of activity against gram-positive bacteria and minimal activity against normal gut flora. It was approved for treatment of C. difficile infection in the United States in May 2011 and in Europe in December 2011. A previous phase III trial in Canada and the United States showed fidaxomicin to be noninferior to vancomycin for clinical cure and superior for sustained response at 4 weeks after treatment completion (N. Engl. J. Med. 2011;364:422-31).
The current study, identical in design and procedures, compared the efficacy of fidaxomicin in Europe as well as in the United States and Canada, said Dr. Oliver A. Cornely of University Hospital, Cologne, Germany. The findings were published online prior to the ECCMID meeting (Lancet Infect. Dis. 2012;12:281-9).
The 509 patients included in the intent to treat analysis were all aged 16 years or older, had more than three unformed bowel movements per 24 hours, had C. diff infection confirmed by toxin A and/or B in stool, and had a first episode or recurrence within 90 days. They were randomized to either twice-daily 200-mg doses of fidaxomicin with twice-daily intervening placebo or the standard 125-mg doses of vancomycin four times daily.
The 198 patients from Europe were slightly older than those from the United States and Canada (66.9 vs. 61.2 years), and fewer were women (54.5% vs. 65%). More of the European group were inpatients at the time of study enrollment (84.3% vs. 57.9%), but fewer in Europe had had a previous episode of C. diff within the prior 90 days (10.1% vs. 18.0%). As expected, the hypervirulent, fluoroquinolone-resistant C. difficile strain NAP1/BI/027 was more common in the U.S./Canada (45.9% vs. 10.4%).
Use of concomitant antibiotics to treat other infections was more common in Europe than in the United States during both treatment and follow-up (34.8% vs. 26.7% for either time period), Dr. Cornely reported.
For the primary study end point ("resolution of diarrhea and no further need for treatment"), fidaxomicin was noninferior to vancomycin, 87.7% vs. 86.8%, well within the prespecified 10% margin. However, fidaxomicin was superior in recurrence, defined as return of diarrhea within 4 weeks of completing therapy plus a positive toxin test (12.7% vs. 26.9%). Fidaxomicin was also superior for sustained response, defined as clinical cure maintained for 4 weeks (76.6% vs. 63.4%). The median time to resolution of diarrhea did not differ between fidaxomicin and vancomycin (56 vs. 58 hours, respectively). (Time to resolution was defined as the number of hours from the first dose of the study drug to the last unformed bowel movement preceding 2 days of three or fewer unformed stools per day.)
Resolution of diarrhea was significantly delayed among patients who received antibiotics to treat other infections at the same time as they were being treated for CDI (median time to resolution 92 hours vs. 54 hours). Among the patients who were receiving concomitant antibiotics, fidaxomicin was superior to vancomycin in clinical cure rate (90.2% of 51 vs. 73.3% of 45), Dr. Cornely reported.
When Europe and the U.S./Canada were analyzed separately, fidaxomicin remained noninferior for clinical cure and superior for recurrence and sustained response. However, recurrence rates overall were slightly higher and sustained response slightly lower in the U.S./Canada, compared with Europe, although the confidence intervals were broad. Early resolution (in less than 72 hours) was more common in Europe (51 vs. 60 hours), but the overall trend was not significantly different for Europe and North America, he said.
There were no significant differences in cure rates between fidaxomicin and vancomycin for other subgroups, including those stratified by age, prior C. diff. infection, inpatient/outpatient, severity, strain, or location.
No fidaxomicin-resistant clones were isolated at baseline or at the end of treatment, although a single isolate recovered at recurrence in Canada has reduced susceptibility, Dr. Cornely noted.
The study was funded by Optimer Pharmaceuticals. Dr. Cornely disclosed that he has received research grants or lecture honoraria or is an adviser to Optimer and multiple other firms, including Actelion, Astellas, Basilea, Bayer, BioCryst, Celgene, F2G, Genzyme, Gilead, Merck, Miltenyi, Pfizer, Quintiles, and ViroPharma.
Vancomycin has hitherto been the best treatment option for Clostridium difficile infection (CDI). Of every 10 patients with this infection, about 9 usually respond to treatment. However, two or three have recurrent symptoms, primarily in the first month after therapy. Therefore, treatment is inadequate for roughly 4 of every 10 patients with C. difficile infection. Furthermore, elderly people – who often have comorbidities and acute illnesses for which antibiotics are prescribed – are most frequently infected and are most at risk of treatment failure.
Recurrence of CDI might be associated with the amount of perturbation of gut flora, possibly because C. difficile regrowth and toxin expression is not likely when disruption is low. Protective effects of treatment that causes little damage to the gut flora such as fidaxomicin might therefore decrease when baseline flora disruption is high. Patients infected with C. difficile who have several recurrences could be less likely to benefit from the few effects on gut flora associated with fidaxomicin.
Other patients at the greatest risk of recurrent CDI could benefit most from fidaxomicin as a new treatment option. Identification of these individuals is not straightforward but might include age greater than 65 years, severe disease, and receipt of concomitant antibiotics after treatment for CDI.
Generally, the baseline level of antibiotic susceptibility of C. difficile and clinical outcome are not associated. No resistance to either fidaxomicin or vancomycin was detected during treatment in phase III studies. Nevertheless, monitoring of emergence of fidaxomicin resistance will be important. Dedicated surveillance programs will be needed because susceptibility testing of C. difficile isolates is not routine practice.
Improvements are still to be made in treatment of CDI. A prospectively validated, simple but accurate scoring system, or laboratory test, is still needed to predict recurrent infections, to help clinicians to make informed treatment choices, and to justify the high cost of fidaxomicin. Shortened hospital stays or symptom duration, or reduction in excess mortality associated with CDI remain elusive treatment goals. The next new drug for treatment of this infection will probably not be licensed for the next 4-5 years. In the meantime, fidaxomicin could be a much needed step forward.
Dr. Mark H. Wilcox, microbiology department, Old Medical School, Leeds General Infirmary, and University of Leeds, England. He disclosed that in the past 2 years he has been a consultant to or has received research support or lecture honoraria from Optimer, which sponsored the study, as well as Actelion, Astellas, Merck, Novacta, Pfizer, Summit, the Medicines Company, Cubist, Optimer, Pfizer, and Sanofi Pasteur.
Vancomycin has hitherto been the best treatment option for Clostridium difficile infection (CDI). Of every 10 patients with this infection, about 9 usually respond to treatment. However, two or three have recurrent symptoms, primarily in the first month after therapy. Therefore, treatment is inadequate for roughly 4 of every 10 patients with C. difficile infection. Furthermore, elderly people – who often have comorbidities and acute illnesses for which antibiotics are prescribed – are most frequently infected and are most at risk of treatment failure.
Recurrence of CDI might be associated with the amount of perturbation of gut flora, possibly because C. difficile regrowth and toxin expression is not likely when disruption is low. Protective effects of treatment that causes little damage to the gut flora such as fidaxomicin might therefore decrease when baseline flora disruption is high. Patients infected with C. difficile who have several recurrences could be less likely to benefit from the few effects on gut flora associated with fidaxomicin.
Other patients at the greatest risk of recurrent CDI could benefit most from fidaxomicin as a new treatment option. Identification of these individuals is not straightforward but might include age greater than 65 years, severe disease, and receipt of concomitant antibiotics after treatment for CDI.
Generally, the baseline level of antibiotic susceptibility of C. difficile and clinical outcome are not associated. No resistance to either fidaxomicin or vancomycin was detected during treatment in phase III studies. Nevertheless, monitoring of emergence of fidaxomicin resistance will be important. Dedicated surveillance programs will be needed because susceptibility testing of C. difficile isolates is not routine practice.
Improvements are still to be made in treatment of CDI. A prospectively validated, simple but accurate scoring system, or laboratory test, is still needed to predict recurrent infections, to help clinicians to make informed treatment choices, and to justify the high cost of fidaxomicin. Shortened hospital stays or symptom duration, or reduction in excess mortality associated with CDI remain elusive treatment goals. The next new drug for treatment of this infection will probably not be licensed for the next 4-5 years. In the meantime, fidaxomicin could be a much needed step forward.
Dr. Mark H. Wilcox, microbiology department, Old Medical School, Leeds General Infirmary, and University of Leeds, England. He disclosed that in the past 2 years he has been a consultant to or has received research support or lecture honoraria from Optimer, which sponsored the study, as well as Actelion, Astellas, Merck, Novacta, Pfizer, Summit, the Medicines Company, Cubist, Optimer, Pfizer, and Sanofi Pasteur.
Vancomycin has hitherto been the best treatment option for Clostridium difficile infection (CDI). Of every 10 patients with this infection, about 9 usually respond to treatment. However, two or three have recurrent symptoms, primarily in the first month after therapy. Therefore, treatment is inadequate for roughly 4 of every 10 patients with C. difficile infection. Furthermore, elderly people – who often have comorbidities and acute illnesses for which antibiotics are prescribed – are most frequently infected and are most at risk of treatment failure.
Recurrence of CDI might be associated with the amount of perturbation of gut flora, possibly because C. difficile regrowth and toxin expression is not likely when disruption is low. Protective effects of treatment that causes little damage to the gut flora such as fidaxomicin might therefore decrease when baseline flora disruption is high. Patients infected with C. difficile who have several recurrences could be less likely to benefit from the few effects on gut flora associated with fidaxomicin.
Other patients at the greatest risk of recurrent CDI could benefit most from fidaxomicin as a new treatment option. Identification of these individuals is not straightforward but might include age greater than 65 years, severe disease, and receipt of concomitant antibiotics after treatment for CDI.
Generally, the baseline level of antibiotic susceptibility of C. difficile and clinical outcome are not associated. No resistance to either fidaxomicin or vancomycin was detected during treatment in phase III studies. Nevertheless, monitoring of emergence of fidaxomicin resistance will be important. Dedicated surveillance programs will be needed because susceptibility testing of C. difficile isolates is not routine practice.
Improvements are still to be made in treatment of CDI. A prospectively validated, simple but accurate scoring system, or laboratory test, is still needed to predict recurrent infections, to help clinicians to make informed treatment choices, and to justify the high cost of fidaxomicin. Shortened hospital stays or symptom duration, or reduction in excess mortality associated with CDI remain elusive treatment goals. The next new drug for treatment of this infection will probably not be licensed for the next 4-5 years. In the meantime, fidaxomicin could be a much needed step forward.
Dr. Mark H. Wilcox, microbiology department, Old Medical School, Leeds General Infirmary, and University of Leeds, England. He disclosed that in the past 2 years he has been a consultant to or has received research support or lecture honoraria from Optimer, which sponsored the study, as well as Actelion, Astellas, Merck, Novacta, Pfizer, Summit, the Medicines Company, Cubist, Optimer, Pfizer, and Sanofi Pasteur.
LONDON – Fidaxomicin was noninferior to vancomycin in achieving clinical cure of Clostridium difficile infection after 10 days of treatment but was superior to vancomycin in attaining lower recurrence rates and higher sustained response rates at 4 weeks.
The findings come from a multicenter, randomized, controlled, double-blind study conducted in seven European countries, Canada, and the United States. It was funded by Optimer Pharmaceuticals, manufacturer of fidaxomicin, a novel macrocyclic antibiotic with a narrow spectrum of activity against gram-positive bacteria and minimal activity against normal gut flora. It was approved for treatment of C. difficile infection in the United States in May 2011 and in Europe in December 2011. A previous phase III trial in Canada and the United States showed fidaxomicin to be noninferior to vancomycin for clinical cure and superior for sustained response at 4 weeks after treatment completion (N. Engl. J. Med. 2011;364:422-31).
The current study, identical in design and procedures, compared the efficacy of fidaxomicin in Europe as well as in the United States and Canada, said Dr. Oliver A. Cornely of University Hospital, Cologne, Germany. The findings were published online prior to the ECCMID meeting (Lancet Infect. Dis. 2012;12:281-9).
The 509 patients included in the intent to treat analysis were all aged 16 years or older, had more than three unformed bowel movements per 24 hours, had C. diff infection confirmed by toxin A and/or B in stool, and had a first episode or recurrence within 90 days. They were randomized to either twice-daily 200-mg doses of fidaxomicin with twice-daily intervening placebo or the standard 125-mg doses of vancomycin four times daily.
The 198 patients from Europe were slightly older than those from the United States and Canada (66.9 vs. 61.2 years), and fewer were women (54.5% vs. 65%). More of the European group were inpatients at the time of study enrollment (84.3% vs. 57.9%), but fewer in Europe had had a previous episode of C. diff within the prior 90 days (10.1% vs. 18.0%). As expected, the hypervirulent, fluoroquinolone-resistant C. difficile strain NAP1/BI/027 was more common in the U.S./Canada (45.9% vs. 10.4%).
Use of concomitant antibiotics to treat other infections was more common in Europe than in the United States during both treatment and follow-up (34.8% vs. 26.7% for either time period), Dr. Cornely reported.
For the primary study end point ("resolution of diarrhea and no further need for treatment"), fidaxomicin was noninferior to vancomycin, 87.7% vs. 86.8%, well within the prespecified 10% margin. However, fidaxomicin was superior in recurrence, defined as return of diarrhea within 4 weeks of completing therapy plus a positive toxin test (12.7% vs. 26.9%). Fidaxomicin was also superior for sustained response, defined as clinical cure maintained for 4 weeks (76.6% vs. 63.4%). The median time to resolution of diarrhea did not differ between fidaxomicin and vancomycin (56 vs. 58 hours, respectively). (Time to resolution was defined as the number of hours from the first dose of the study drug to the last unformed bowel movement preceding 2 days of three or fewer unformed stools per day.)
Resolution of diarrhea was significantly delayed among patients who received antibiotics to treat other infections at the same time as they were being treated for CDI (median time to resolution 92 hours vs. 54 hours). Among the patients who were receiving concomitant antibiotics, fidaxomicin was superior to vancomycin in clinical cure rate (90.2% of 51 vs. 73.3% of 45), Dr. Cornely reported.
When Europe and the U.S./Canada were analyzed separately, fidaxomicin remained noninferior for clinical cure and superior for recurrence and sustained response. However, recurrence rates overall were slightly higher and sustained response slightly lower in the U.S./Canada, compared with Europe, although the confidence intervals were broad. Early resolution (in less than 72 hours) was more common in Europe (51 vs. 60 hours), but the overall trend was not significantly different for Europe and North America, he said.
There were no significant differences in cure rates between fidaxomicin and vancomycin for other subgroups, including those stratified by age, prior C. diff. infection, inpatient/outpatient, severity, strain, or location.
No fidaxomicin-resistant clones were isolated at baseline or at the end of treatment, although a single isolate recovered at recurrence in Canada has reduced susceptibility, Dr. Cornely noted.
The study was funded by Optimer Pharmaceuticals. Dr. Cornely disclosed that he has received research grants or lecture honoraria or is an adviser to Optimer and multiple other firms, including Actelion, Astellas, Basilea, Bayer, BioCryst, Celgene, F2G, Genzyme, Gilead, Merck, Miltenyi, Pfizer, Quintiles, and ViroPharma.
LONDON – Fidaxomicin was noninferior to vancomycin in achieving clinical cure of Clostridium difficile infection after 10 days of treatment but was superior to vancomycin in attaining lower recurrence rates and higher sustained response rates at 4 weeks.
The findings come from a multicenter, randomized, controlled, double-blind study conducted in seven European countries, Canada, and the United States. It was funded by Optimer Pharmaceuticals, manufacturer of fidaxomicin, a novel macrocyclic antibiotic with a narrow spectrum of activity against gram-positive bacteria and minimal activity against normal gut flora. It was approved for treatment of C. difficile infection in the United States in May 2011 and in Europe in December 2011. A previous phase III trial in Canada and the United States showed fidaxomicin to be noninferior to vancomycin for clinical cure and superior for sustained response at 4 weeks after treatment completion (N. Engl. J. Med. 2011;364:422-31).
The current study, identical in design and procedures, compared the efficacy of fidaxomicin in Europe as well as in the United States and Canada, said Dr. Oliver A. Cornely of University Hospital, Cologne, Germany. The findings were published online prior to the ECCMID meeting (Lancet Infect. Dis. 2012;12:281-9).
The 509 patients included in the intent to treat analysis were all aged 16 years or older, had more than three unformed bowel movements per 24 hours, had C. diff infection confirmed by toxin A and/or B in stool, and had a first episode or recurrence within 90 days. They were randomized to either twice-daily 200-mg doses of fidaxomicin with twice-daily intervening placebo or the standard 125-mg doses of vancomycin four times daily.
The 198 patients from Europe were slightly older than those from the United States and Canada (66.9 vs. 61.2 years), and fewer were women (54.5% vs. 65%). More of the European group were inpatients at the time of study enrollment (84.3% vs. 57.9%), but fewer in Europe had had a previous episode of C. diff within the prior 90 days (10.1% vs. 18.0%). As expected, the hypervirulent, fluoroquinolone-resistant C. difficile strain NAP1/BI/027 was more common in the U.S./Canada (45.9% vs. 10.4%).
Use of concomitant antibiotics to treat other infections was more common in Europe than in the United States during both treatment and follow-up (34.8% vs. 26.7% for either time period), Dr. Cornely reported.
For the primary study end point ("resolution of diarrhea and no further need for treatment"), fidaxomicin was noninferior to vancomycin, 87.7% vs. 86.8%, well within the prespecified 10% margin. However, fidaxomicin was superior in recurrence, defined as return of diarrhea within 4 weeks of completing therapy plus a positive toxin test (12.7% vs. 26.9%). Fidaxomicin was also superior for sustained response, defined as clinical cure maintained for 4 weeks (76.6% vs. 63.4%). The median time to resolution of diarrhea did not differ between fidaxomicin and vancomycin (56 vs. 58 hours, respectively). (Time to resolution was defined as the number of hours from the first dose of the study drug to the last unformed bowel movement preceding 2 days of three or fewer unformed stools per day.)
Resolution of diarrhea was significantly delayed among patients who received antibiotics to treat other infections at the same time as they were being treated for CDI (median time to resolution 92 hours vs. 54 hours). Among the patients who were receiving concomitant antibiotics, fidaxomicin was superior to vancomycin in clinical cure rate (90.2% of 51 vs. 73.3% of 45), Dr. Cornely reported.
When Europe and the U.S./Canada were analyzed separately, fidaxomicin remained noninferior for clinical cure and superior for recurrence and sustained response. However, recurrence rates overall were slightly higher and sustained response slightly lower in the U.S./Canada, compared with Europe, although the confidence intervals were broad. Early resolution (in less than 72 hours) was more common in Europe (51 vs. 60 hours), but the overall trend was not significantly different for Europe and North America, he said.
There were no significant differences in cure rates between fidaxomicin and vancomycin for other subgroups, including those stratified by age, prior C. diff. infection, inpatient/outpatient, severity, strain, or location.
No fidaxomicin-resistant clones were isolated at baseline or at the end of treatment, although a single isolate recovered at recurrence in Canada has reduced susceptibility, Dr. Cornely noted.
The study was funded by Optimer Pharmaceuticals. Dr. Cornely disclosed that he has received research grants or lecture honoraria or is an adviser to Optimer and multiple other firms, including Actelion, Astellas, Basilea, Bayer, BioCryst, Celgene, F2G, Genzyme, Gilead, Merck, Miltenyi, Pfizer, Quintiles, and ViroPharma.
FROM THE EUROPEAN CONGRESS OF CLINICAL MICROBIOLOGY AND INFECTIOUS DISEASES
Major Finding: Fidaxomicin was noninferior to vancomycin in curing C. difficile, 87.7% vs. 86.8%. However, fidaxomicin was superior in terms of lower recurrence at 4 weeks (12.7% vs. 26.9%) and in sustained response at 4 weeks (76.6% vs. 63.4%).
Data Source: The findings come from a multicenter, randomized, controlled, double-blind study of 509 patients with CDI, conducted in Europe (seven countries), Canada, and the United States.
Disclosures: The study was funded by Optimer Pharmaceuticals. Dr. Cornely disclosed that he has received research grants or lecture honoraria or is an advisor to Optimer, as well as Actelion, Astellas, Basilea, Bayer, Biocryst, Celgene, F2G, Genzyme, Gilead, Merck, Miltenyi, Pfizer, Quintiles, and Viropharma.