A new macrocyclic antibi-otic, fidaxomicin (OPT-80): causes less alteration to the bowel microbiota of Clostridium difficile-infected patients than does vancomycin

Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand.
Microbiology (Impact Factor: 2.56). 11/2010; 156(Pt 11):3354-9. DOI: 10.1099/mic.0.042010-0
Source: PubMed


Clostridium difficile infection (CDI) is the most common identifiable cause of diarrhoea in hospitalized patients. Current therapies rely on the administration of metronidazole or vancomycin, which reduce vegetative populations of C. difficile in the bowel. Recurrence of the disease when treatment with these antibiotics ceases indicates that metronidazole and vancomycin affect not only C. difficile but also commensal populations that normally mediate competitive exclusion. Fidaxomicin is a new antibiotic that inhibits C. difficile. Our study shows that fidaxomicin had little effect on the composition of the faecal microbiota in terms of its major phylogenetic clusters. Notably, clostridial clusters XIVa and IV, and Bifidobacterium, were much less affected by fidaxomicin compared to vancomycin treatment. These findings help to explain the substantially reduced rates of relapse following treatment of CDI with fidaxomicin in recent clinical trials.

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    • ". Fidaxomicin has a very narrow spectrum of antimicrobial activity when compared with vancomycin and metronidazole; therefore, it has less of an impact on the normal intestinal microbiota, predominantly on the members of clostridial clusters XIVa and IV, the Bacteroides/Prevotella group and it has an indifferent effect on bifidobacteria [Babakhani et al. 2013; Louie et al. 2012; Nerandzic et al. 2012; Tannock et al. 2010]. "
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    ABSTRACT: The incidence of Clostridium difficile infection (CDI) has risen 400% in the last decade. It currently ranks as the third most common nosocomial infection. CDI has now crossed over as a community-acquired infection. The major failing of current therapeutic options for the management of CDI is recurrence of disease after the completion of treatment. Fidaxomicin has been proven to be superior to vancomycin in successful sustained clinical response to therapy. Improved outcomes may be due to reduced collateral damage to the gut microflora by fidaxomicin, bactericidal activity, inhibition of Clostridial toxin formation and inhibition of new sporulation. This superiority is maintained in groups previously reported as being at high risk for CDI recurrence including those: with relapsed infection after a single treatment course; on concomitant antibiotic therapy; aged >65 years; with cancer; and with chronic renal insufficiency. Because the acquisition cost of fidaxomicin far exceeds that of metronidazole or vancomycin, in order to rationally utilize this agent, it should be targeted to those populations who are at high risk for relapse and in whom the drug has demonstrated superiority. In this manuscript is reviewed the changing epidemiology of CDI, current treatment options for this infection, proposed benefits of fidaxomicin over currently available antimicrobial options, available analysis of cost effectiveness of the drug, and is given recommendations for judicious use of the drug based upon the available published literature.
    Therapeutic Advances in Chronic Disease 03/2014; 5(2):69-84. DOI:10.1177/2040622313511285
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    • "Fidaxomicin, is a novel narrow spectrum, oral macrocyclic antibiotic which has bactericidal activities against C. difficile.94,118 It has no activity against gram-negative bacteria and has minimal activity against Bacteroides species, which allows for the normal flora to be somewhat suitably maintained.119 In two phase 3 clinical trials in which patients with CDI were treated with either fidaxomicin or vancomycin, fidaxomicin has been shown to be non-inferior to vancomycin in the management of mild-to-moderately severe CDI.120,121 Subgroup analyses also show that there were significantly fewer CDI recurrences in patients who received fidaxomicin than those treated with vancomycin. "
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    ABSTRACT: Clostridium difficile is a spore-forming gram-positive bacillus, and the leading cause of antibiotic-associated nosocomial diarrhea and colitis in the industrialized world. With the emergence of a hypervirulent strain of C. difficile (BI/NAP1/027), the epidemiology of C. difficile infection has rapidly changed in the last decade. C. difficile infection, once thought to be an easy to treat bacterial infection, has evolved into an epidemic that is associated with a high rate of mortality, causing disease in patients thought to be low-risk. In this review, we discuss the changing face of C .difficile infection and the novel treatment and prevention strategies needed to halt this ever growing epidemic.
    Emerging Microbes and Infections 09/2013; 2(9). DOI:10.1038/emi.2013.62 · 2.26 Impact Factor
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    • "Vancomycin is the drug of choice for severe CDI [27,28]. However, its use has been associated with clinical recurrence of infection in up to 20% of cases, which has been attributed to antibiotic-induced changes of gut microbiota [29]. In the mouse model of infection, recurrence of disease and late mortality has also been observed to occur in 40-60% of mice treated with vancomycin [24,30]. "
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    ABSTRACT: Background Activation of the A2A adenosine receptor (A2AAR) decreases production of inflammatory cytokines, prevents C. difficile toxin A-induced enteritis and, in combination with antibiotics, increases survival from sepsis in mice. We investigated whether A2AAR activation improves and A2AAR deletion worsens outcomes in a murine model of C. difficile (strain VPI10463) infection (CDI). Methods C57BL/6 mice were pretreated with an antibiotic cocktail prior to infection and then treated with vancomycin with or without an A2AAR agonist. A2AAR-/- and littermate wild-type (WT) mice were similarly infected, and IFNγ and TNFα were measured at peak of and recovery from infection. Results Infected, untreated mice rapidly lost weight, developed diarrhea, and had mortality rates of 50-60%. Infected mice treated with vancomycin had less weight loss and diarrhea during antibiotic treatment but mortality increased to near 100% after discontinuation of antibiotics. Infected mice treated with both vancomycin and an A2AAR agonist, either ATL370 or ATL1222, had minimal weight loss and better long-term survival than mice treated with vancomycin alone. A2AAR KO mice were more susceptible than WT mice to death from CDI. Increases in cecal IFNγ and blood TNFα were pronounced in the absence of A2AARs. Conclusion In a murine model of CDI, vancomycin treatment resulted in reduced weight loss and diarrhea during acute infection, but high recurrence and late-onset death, with overall mortality being worse than untreated infected controls. The administration of vancomycin plus an A2AAR agonist reduced inflammation and improved survival rates, suggesting a possible benefit of A2AAR agonists in the management of CDI to prevent recurrent disease.
    BMC Infectious Diseases 12/2012; 12(1):342. DOI:10.1186/1471-2334-12-342 · 2.61 Impact Factor
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