Fidaxomicin: A Novel Macrocyclic Antibiotic for the Treatment of Clostridium difficile Infection

Tonya Crawford, Pharm.D; Emily Huesgen, Pharm.D; Larry Danziger, Pharm.D


Am J Health Syst Pharm. 2012;69(11):933-943. 

In This Article

Abstract and Introduction


Purpose The pharmacology, clinical efficacy, safety, dosage and administration, and place in therapy of fidaxomicin for the treatment of Clostridium difficile infection (CDI) are reviewed.
Summary Fidaxomicin, a macrocyclic antibiotic, has a narrow spectrum of activity against gram-positive anaerobes and is bactericidal against C. difficile. It has no activity against gram-negative bacteria. Fidaxomicin has minimal activity against Bacteroides species, which may be advantageous in maintaining colonization resistance and protecting the gastrointestinal tract from colonization by C. difficile. The minimum inhibitory concentration for 90% of organisms for fidaxomicin against C. difficile ranged from 0.0078 to 2 μg/mL in in vitro studies. After oral administration, fecal concentrations are detected and are directly proportional to the dose administered. Fidaxomicin resistance in vivo has not been reported. In clinical trials, fidaxomicin has been shown to be noninferior to vancomycin in the management of mild-to-moderately severe CDI. The adverse-effect profile of fidaxomicin is comparable to that of vancomycin. The recommended dosage for treatment of CDI is fidaxomicin 200 mg orally twice daily for 10 days. Fidaxomicin should be considered for patients who previously received treatment with metronidazole or vancomycin for CDI and who are diagnosed with recurrent CDI in which a non-NAP1/BI/027 strain is isolated. At institutions where strain typing is not available, fidaxomicin may be considered in patients with recurrent CDI who have not responded to treatment with the regimen used for the first episode of CDI.
Conclusion Fidaxomicin is a well-tolerated agent for the treatment of CDI and has been shown to be noninferior to vancomycin in the management of mild-to-moderately severe CDI.


Recent data suggest that Clostridium difficile has surpassed methicillin-resistant Staphylococcus aureus as the leading cause of nosocomial infections.[1] The severity and incidence of C. difficile-related disease have been on the rise over the past decade.[2] The emergence of a new hypervirulent, multidrug-resistant strain of C. difficile (NAP1/BI/027) has been linked to this increase in infection frequency, severity, and mortality worldwide.[3,4] The frequency of C. difficile infection (CDI) in the United States is currently estimated to be 450,000–700,000 cases annually.[2] Although CDI once primarily affected severely ill and older patients, it is becoming more common in otherwise healthy individuals with minimal exposure to the health care setting.[5] Until recently, CDI was mainly regarded as a nosocomial disease, but reports of community-acquired CDI raise concern for what could potentially become a common setting for CDI acquisition.[6,7] Reports of community-acquired CDI have led to investigations into the cause of CDI in this setting.[8]

C. difficile is a gram-positive, spore-forming, toxin-producing, anaerobic bacillus that is ubiquitous in nature and easily transmitted by the fecal-to-oral route.[9] Unlike most pathogens, C. difficile can persist as inert spores in extreme environmental conditions, a property that can increase rates of transmission and reinoculation. When the spores are ingested, they may germinate and colonize the large intestine or proliferate and release toxins. Most pathogenic strains produce toxins A and B, the primary virulence factors that cause CDI symptoms.[10–13] Chronic inflammation from toxin exposure leads to diarrhea, and the cycle continues as spores are shed back into the environment. Presentation of CDI may range from mild-to-moderate diarrhea to fulminant and sometimes fatal pseudomembranous colitis.[13]

Several factors are associated with the propagation of the hypervirulent NAP1/BI/027 strain of C. difficile. One of the issues associated with widespread dissemination of this hypervirulent strain is the overproduction of toxins A and B, which is thought to be due to a mutation in a gene (tcdC) encoding a negative regulator of toxin production.[4,14] This endemic strain is also known to produce a binary toxin, but the function of this toxin in the pathogenesis of CDI remains unknown.[15–17]

Antibiotic resistance is another characteristic of the NAP1/BI/027 strain. The use of broad-spectrum antibiotics has led to outbreaks of drug-resistant C. difficile strains that subside after antibiotic restriction. This is exemplified by the NAP1/BI/027 strain, which has acquired resistance to fluoroquinolones in response to their widespread use in health care settings.[4]

Excessive antibiotic use and the lack of available treatment options remain major challenges in the prevention and treatment of CDI. Antibiotic use is both a risk factor for CDI and the mainstay of treatment.[18] Unfortunately, use of broad-spectrum antibiotics disrupts normal bowel flora, priming the colonic environment for CDI through unopposed proliferation of C. difficile.

Metronidazole and oral vancomycin are the two mainstay antibiotic treatment options available, but the rates of CDI recurrence remain high for both agents. The rate of CDI recurrence after initial treatment is approximately 20–25%, with a 50–65% rate of subsequent CDI recurrences.[19,20] In addition, increased treatment-failure rates have recently been reported for metronidazole in the treatment of severe CDI (de-fined in CDI practice guidelines as a leukocytosis of at least 15,000 cells/μL, a serum creatinine concentration at least 1.5 times the baseline value, hypotension, shock, ileus, or megacolon).[18] Consequently, guidelines from the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA) recommend oral vancomycin for the treatment of severe infection.[18,21]

Due to the increase in severity and recurrence of CDI and the lack of alternative therapies, investigations into new treatment options are ongoing. In November 2010, Optimer Pharmaceuticals submitted a new drug application to the Food and Drug Administration (FDA) for use of fidaxomicin in the treatment of CDI and prevention of CDI recurrence in adults. In January 2011, fidaxomicin was granted orphan drug designation for the treatment of pediatric CDI.[22] On May 27, 2011, fidaxomicin was granted FDA-approval for the treatment of CDI in adults.[23] This review summarizes the pharmacology, clinical trials, efficacy, safety data, and place in therapy of fidaxomicin for the treatment of CDI.


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