Fidaxomicin versus vancomycin for Clostridium difficile infection.

BACKGROUND Clostridium 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. METHODS Adults 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). RESULTS A 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. CONCLUSIONS The 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.)

[1]  C. Kelly,et al.  Clostridium difficile--more difficult than ever. , 2008, The New England journal of medicine.

[2]  T. Louie,et al.  A new macrocyclic antibiotic, fidaxomicin (OPT-80), causes less alteration to the bowel microbiota of Clostridium difficile-infected patients than does vancomycin. , 2010, Microbiology.

[3]  M. Owings,et al.  Clostridium difficile Infection in Patients Discharged from US Short-stay Hospitals, 1996–2003 , 2006, Emerging Infectious Diseases.

[4]  R. Preston,et al.  Safety, Tolerance, and Pharmacokinetic Studies of OPT-80 in Healthy Volunteers following Single and Multiple Oral Doses , 2008, Antimicrobial Agents and Chemotherapy.

[5]  C. Donskey,et al.  Both Oral Metronidazole and Oral Vancomycin Promote Persistent Overgrowth of Vancomycin-Resistant Enterococci during Treatment of Clostridium difficile-Associated Disease , 2008, Antimicrobial Agents and Chemotherapy.

[6]  D. Musher,et al.  Relatively poor outcome after treatment of Clostridium difficile colitis with metronidazole. , 2005, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[7]  Stuart Johnson,et al.  An epidemic, toxin gene-variant strain of Clostridium difficile. , 2005, The New England journal of medicine.

[8]  M. Owings,et al.  Clostridium difficile Infection in Patients Discharged from US , 2006 .

[9]  P. Puri.  Faecal metronidazole concentrations during oral and intravenous therapy for antibiotic associated colitis due to clostridium difficile , 1987 .

[10]  G. D'Angelo,et al.  Attributable Outcomes of Endemic Clostridium difficile–associated Disease in Nonsurgical Patients , 2008, Emerging infectious diseases.

[11]  S. Maroo,et al.  Recurrent clostridium difficile. , 2006, Gastroenterology.

[12]  J. Gerberding,et al.  Severe Clostridium difficile-associated disease in populations previously at low risk--four states, 2005. , 2005, MMWR. Morbidity and mortality weekly report.

[13]  T. Louie,et al.  OPT-80 Eliminates Clostridium difficile and Is Sparing of Bacteroides Species during Treatment of C. difficile Infection , 2008, Antimicrobial Agents and Chemotherapy.

[14]  Sandra Romero-Steiner,et al.  The Second International Conference on Women and Infectious Diseases , 2006 .

[15]  R. Nelson,et al.  Antibiotic treatment for Clostridium difficile-associated diarrhea in adults. , 2007, The Cochrane database of systematic reviews.

[16]  P. Appelbaum,et al.  Activity of OPT-80, a Novel Macrocycle, Compared with Those of Eight Other Agents against Selected Anaerobic Species , 2004, Antimicrobial Agents and Chemotherapy.

[17]  J. Mossong,et al.  Update of Clostridium difficile infection due to PCR ribotype 027 in Europe, 2008. , 2008, Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin.

[18]  K. Osawa,et al.  Molecular analysis of Clostridium difficile at a university teaching hospital in Japan: a shift in the predominant type over a five-year period , 2007, European Journal of Clinical Microbiology & Infectious Diseases.

[19]  J. Bartlett.  The case for vancomycin as the preferred drug for treatment of Clostridium difficile infection. , 2008, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[20]  M. Osterman.  Outcomes of Clostridium difficile-Associated Disease Treated With Metronidazole or Vancomycin Before and After the Emergence of NAP1/027 , 2008 .

[21]  L. Peterson,et al.  Recurrences of Clostridium difficile diarrhea not caused by the original infecting organism. , 1989, The Journal of infectious diseases.

[22]  Mark A. Miller,et al.  Clinical Outcomes, Safety, and Pharmacokinetics of OPT-80 in a Phase 2 Trial with Patients with Clostridium difficile Infection , 2008, Antimicrobial Agents and Chemotherapy.

[23]  P. Polgreen,et al.  Clostridium difficile-associated diarrhea: an emerging threat to pregnant women. , 2008, American journal of obstetrics and gynecology.

[24]  J. Pépin,et al.  Increasing risk of relapse after treatment of Clostridium difficile colitis in Quebec, Canada. , 2005, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[25]  D. Gerding,et al.  In Vitro Activities of 15 Antimicrobial Agents against 110 Toxigenic Clostridium difficile Clinical Isolates Collected from 1983 to 2004 , 2007, Antimicrobial Agents and Chemotherapy.

[26]  L. Peterson,et al.  Development of a rapid and efficient restriction endonuclease analysis typing system for Clostridium difficile and correlation with other typing systems , 1993, Journal of clinical microbiology.

[27]  T. Louie,et al.  Molecular Analysis of Clostridium difficile PCR Ribotype 027 Isolates from Eastern and Western Canada , 2006, Journal of Clinical Microbiology.

[28]  C. Woods,et al.  Comparison of Seven Techniques for Typing International Epidemic Strains of Clostridium difficile: Restriction Endonuclease Analysis, Pulsed-Field Gel Electrophoresis, PCR-Ribotyping, Multilocus Sequence Typing, Multilocus Variable-Number Tandem-Repeat Analysis, Amplified Fragment Length Polymorphis , 2007, Journal of Clinical Microbiology.

[29]  S. Finegold,et al.  In Vitro Activities of OPT-80 and Comparator Drugs against Intestinal Bacteria , 2004, Antimicrobial Agents and Chemotherapy.

[30]  M. Kollef,et al.  Increase in Adult Clostridium difficile–related Hospitalizations and Case-Fatality Rate, United States, 2000–2005 , 2008, Emerging infectious diseases.

[31]  N. Verlander,et al.  Clinical Severity of Clostridium difficile PCR Ribotype 027: A Case-Case Study , 2008, PloS one.

[32]  L. Peterson,et al.  Clostridium Difficile-Associated Diarrhea and Colitis , 1995, Infection Control & Hospital Epidemiology.

[33]  J. Karlowsky,et al.  In Vitro Activity of OPT-80 Tested against Clinical Isolates of Toxin-Producing Clostridium difficile , 2008, Antimicrobial Agents and Chemotherapy.

[34]  L. Mascola,et al.  Increase in Clostridium difficile–related Mortality Rates, United States, 1999–2004 , 2007, Emerging infectious diseases.

[35]  Melinda B Davis,et al.  A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. , 2007, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[36]  M. Hu,et al.  Clostridium difficile strain NAP-1 is not associated with severe disease in a nonepidemic setting. , 2009, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[37]  J. Stockman.  A Predominantly Clonal Multi-Institutional Outbreak of Clostridium difficile—Associated Diarrhea With High Morbidity and Mortality , 2007 .

[38]  A. Rodloff,et al.  In Vitro Activity of OPT-80 against Clostridium difficile , 2004, Antimicrobial Agents and Chemotherapy.