[en] Two recently completed phase 3 trials (003 and 004) showed fidaxomicin to be noninferior to vancomycin for curing Clostridium difficile infection (CDI) and superior for reducing CDI recurrences. In both studies, adults with active CDI were randomized to receive blinded fidaxomicin 200 mg twice daily or vancomycin 125 mg 4 times a day for 10 days. Post hoc exploratory intent-to-treat (ITT) time-to-event analyses were undertaken on the combined study 003 and 004 data, using fixed-effects meta-analysis and Cox regression models. ITT analysis of the combined 003/004 data for 1164 patients showed that fidaxomicin reduced persistent diarrhea, recurrence, or death by 40% (95% confidence interval [CI], 26%-51%; P < .0001) compared with vancomycin through day 40. A 37% (95% CI, 2%-60%; P = .037) reduction in persistent diarrhea or death was evident through day 12 (heterogeneity P = .50 vs 13-40 days), driven by 7 (1.2%) fidaxomicin versus 17 (2.9%) vancomycin deaths at <12 days. Low albumin level, low eosinophil count, and CDI treatment preenrollment were risk factors for persistent diarrhea or death at 12 days, and CDI in the previous 3 months was a risk factor for recurrence (all P < .01). Fidaxomicin has the potential to substantially improve outcomes from CDI.
McDonald LC, Killgore GE, Thompson A, et al. An epidemic, toxin genevariant strain of Clostridium difficile. N Engl J Med 2005; 353:2433-41. (Pubitemid 41770164)
Loo VG, Poirier L, Miller MA, et al. A predominantly clonal multiinstitutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality. N Engl J Med 2005; 353:2442-9. (Pubitemid 41770165)
Muto CA, Pokrywka M, Shutt K, et al. A large outbreak of Clostridium difficile-associated disease with an unexpected proportion of deaths and colectomies at a teaching hospital following increased fluoroquinolone use. Infect Control Hosp Epidemiol 2005; 26:273-80. (Pubitemid 40445086)
Musher DM, Aslam S, Logan N, et al. Relatively poor outcome after treatment of Clostridium difficile colitis with metronidazole. Clin Infect Dis 2005; 40:1586-90. (Pubitemid 40720807)
Pepin J, Alary M-E, Valiquette L, et al. Increasing risk of relapse after treatment of Clostridium difficile colitis in Quebec, Canada. Clin Infect Dis 2005; 40:1591-7. (Pubitemid 40720808)
Zar FA, Bakkanagari SR, Moorthi KM, Davis MB. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis 2007; 45:302-7. (Pubitemid 47101025)
Muto CA, Blank MK, Marsh JW, et al. Control of an outbreak of infection with the hypervirulent Clostridium difficile BI strain in a university hospital using a comprehensive "bundle" approach. Clin Infect Dis 2007; 45:1266-73. (Pubitemid 351411898)
Teasley DG, Gerding DN, Olson MM, et al. Prospective randomised trial of metronidazole versus vancomycin for Clostridium difficileassociated diarrhoea and colitis. Lancet 1983; 2:1043-6. (Pubitemid 14235361)
Wenisch C, Parschalk B, Hasenhündl M, Hirschl AM, Graninger W. Comparison of vancomycin, teicoplanin, metronidazole, and fusidic acid for the treatment of Clostridium difficile-associated diarrhea. Clin Infect Dis 1996; 22:813-8. (Pubitemid 26255600)
Johnson S. Recurrent Clostridium difficile infection: a review of risk factors, treatments, and outcomes. J Infect 2009; 58:403-10.
Johnson AP. Drug evaluation: OPT-80, a narrow-spectrum macrocyclic antibiotic. Curr Opin Investig Drugs 2007; 8:168-73. (Pubitemid 46438471)
Ackermann G, Loffler B, Adler D, Rodloff AC. In vitro activity of OPT-80 against Clostridium difficile. Antimicrob Agents Chemother 2004; 48:2280-2. (Pubitemid 38691631)
Credito KL, Appelbaum PC. Activity of OPT-80, a novel macrocycle, compared with those of eight other agents against selected anaerobic species. Antimicrob Agents Chemother 2004; 48:4430-4. (Pubitemid 39434908)
Finegold SM, Molitoris D, Vaisanen ML, Song Y, Liu C, Bolanos M. In vitro activities of OPT-80 and comparator drugs against intestinal bacteria. Antimicrob Agents Chemother 2004; 48:4898-902. (Pubitemid 39577704)
Hecht DW, Galang MA, Sambol SP, Osmolski JR, Johnson S, Gerding DN. In vitro activities of 15 antimicrobial agents against 110 toxigenic Clostridium difficile clinical isolates collected from 1983 to 2004. Antimicrob Agents Chemother 2007; 51:2716-9. (Pubitemid 47206204)
Karlowsky JA, Laing NM, Zhanel GG. In vitro activity of OPT-80 tested against clinical isolates of toxin-producing Clostridium difficile. Antimicrob Agents Chemother 2008; 52:4163-5.
Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med 2011; 364:422-31.
Cornely OA, Crook DW, Esposito R, et al. Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomised controlled trial. Lancet Infect Dis 2012; 12:281-9.
Hill A, Sabin C. Designing and interpreting HIV noninferiority trials in naive and experienced patients. AIDS 2008; 22:913-21. (Pubitemid 351681499)
Phillips AN, Walker AS. Drug switching and virologic-based endpoints in trials of antiretroviral drugs for HIV infection. AIDS 2004; 18:365-70. (Pubitemid 38365862)
Wittkop L, Smith C, Fox Z, et al. Methodological issues in the use of composite endpoints in clinical trials: examples from the HIV field. Clin Trials 2010; 7:19-35.
Babakhani F, Robert N, Shangle S, et al. Antimicrobial activity and post-antibiotic effect (PAE) of OPT-80, a new macrocyclic compound, against Clostridium difficile, Vol 44. Washington, DC: ICAAC, 2004; Abstract E-2048.
Louie TJ, Emery J, Krulicki W, Byrne B, Mah M. OPT-80 eliminates Clostridium difficile and is sparing of bacteroides species during treatment of C. difficile infection. Antimicrob Agents Chemother 2009; 53:261-3.
Tannock GW, Munro K, Taylor C, et al. A new macrocyclic antibiotic, fidaxomicin (OPT-80), causes less alteration to the bowel microbiota of Clostridium difficile-infected patients than does vancomycin. Microbiology 2010; 156:3354-9.
Naggara O, Raymond J, Guilbert F, Altman DG. The problem of subgroup analyses: an example from a trial on ruptured intracranial aneurysms. AJNR Am J Neuroradiol 2011; 32:633-6.
Miller M, Gravel D, Mulvey M, et al. Health care-associated Clostridium difficile infection in Canada: patient age and infecting strain type are highly predictive of severe outcome and mortality. Clin Infect Dis 2010; 50:194-201.
Dubberke ER, Sadhu J, Gatti R, et al. Severity of Clostridium difficileassociated disease (CDAD) in allogeneic stem cell transplant recipients: evaluation of a CDAD severity grading system. Infect Control Hosp Epidemiol 2007; 28:208-11. (Pubitemid 46374164)
Henrich TJ, Krakower D, Bitton A, Yokoe DS. Clinical risk factors for severe Clostridium difficile-associated disease. Emerg Infect Dis 2009; 15:415-22.
McFarland LV, Elmer GW, Surawicz CM. Breaking the cycle: treatment strategies for 163 cases of recurrent Clostridium difficile disease. Am J Gastroenterol 2002; 97:1769-75. (Pubitemid 34761404)
