Fidaxomicin is a macrocycle antibiotic6, 11, 14 classified as a macrolide.1, 26
Clostridioides difficile-associated Diarrhea
Fidaxomicin is used for the treatment of diarrhea caused by Clostridioides difficile (formerly known as Clostridium difficile ) infection (CDI; C. difficile -associated diarrhea [CDAD]) in adults 18 years of age or older.1, 2, 12, 16, 26, 28, 29, 30, 31, 32 Although safety and efficacy of fidaxomicin have not been established in children and adolescents,1 the drug is designated an orphan drug by FDA for the treatment of CDI in pediatric patients†.4
C. difficile can cause asymptomatic colonization in the intestinal tract ( C. difficile carriage) or symptomatic intestinal CDI that can range in severity from mild to moderate diarrhea without colitis to severe diarrhea that may be associated with potentially fatal pseudomembranous colitis requiring colectomy.7, 12, 15, 16, 17C. difficile is the most commonly recognized cause of infectious diarrhea in healthcare settings.12 There have been changes in the epidemiology of CDI, including an increased overall incidence of the disease worldwide, increased incidence in community populations previously considered at low risk (e.g., healthy peripartum women), increased morbidity and mortality rates, and reports of hospital outbreaks of severe and recurrent CDI associated with epidemic or hypervirulent strains of C. difficile (e.g., PCR ribotype 027, also known as NAP1 or B1).2, 7, 12, 15, 17 Risk factors for CDI include advanced age, duration of hospitalization, number of comorbidities, severity of underlying disease, immunosuppression as the result of disease or drug therapy, exposure to anti-infectives, and duration and degree of exposure to other patients with CDI.7, 11, 12, 15, 16, 17 The most important modifiable risk factor for development of CDI is exposure to anti-infectives.12, 15, 16, 17 Anti-infectives can alter normal intestinal flora and may lead to overgrowth of C. difficile .12, 17 CDI has been reported with nearly all systemic anti-infectives, and should be considered in the differential diagnosis in patients who develop diarrhea during or after anti-infective therapy.12, 17 The risk of CDI from disruption of intestinal flora is increased during anti-infective therapy and for 3 months after anti-infective therapy is discontinued.12 If CDI is suspected or confirmed, the inciting anti-infective should be discontinued as soon as possible.12, 15, 16, 17 Patients should be managed with appropriate supportive therapy (e.g., fluid and electrolyte management, protein supplementation), anti-infective therapy directed against C. difficile , and surgical evaluation as clinically indicated.7, 12, 15, 16, 17
Vancomycin, fidaxomicin, and metronidazole are considered the anti-infectives of choice for the treatment of CDI.3, 7, 10, 11, 12, 15, 16, 17, 19, 29 For the treatment of an initial episode of nonsevere CDI in adults, the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) recommend a 10-day regimen of oral vancomycin or oral fidaxomicin.12 These experts state that a 10-day regimen of oral metronidazole is an alternative for an initial episode of nonsevere CDI, but is recommended only if vancomycin and fidaxomicin are contraindicated or unavailable.12 For the treatment of an initial episode of severe CDI in adults, IDSA and SHEA state that a 10-day regimen of oral vancomycin or oral fidaxomicin can be used.12 However, vancomycin is the anti-infective of choice for the treatment of an initial episode of fulminant CDI (characterized by hypotension or shock, ileus, or megacolon) in adults and IDSA and SHEA recommend a regimen that includes vancomycin (given orally, by nasogastric tube, and/or rectally as clinically indicated) in conjunction with IV metronidazole for the treatment of such infections, especially if ileus is present.12 For the treatment of a first recurrence of CDI in adults who received a standard 10-day regimen of oral vancomycin initially, IDSA and SHEA recommend a more prolonged oral vancomycin regimen (tapered and pulsed) or a 10-day regimen of oral fidaxomicin.12 In those who received initial treatment with oral metronidazole and have a first recurrence of CDI, these experts recommend a standard 10-day regimen of oral vancomycin.12 Specialized references should be consulted for additional information on the management of CDI, including diagnosis, infection prevention and control, treatment of CDI in pediatric patients, and additional recommendations for treatment of initial, recurrent, or fulminant CDI in adults.12, 16
Fidaxomicin appears to offer some advantages over some other anti-infectives used for the treatment of CDI (e.g., minimal systemic absorption following oral administration, narrow spectrum of activity involving good activity against C. difficile and limited activity against normal intestinal flora).3, 6, 11, 15, 16, 21, 23, 25, 28 There is some evidence that oral fidaxomicin may be as effective or more effective than oral vancomycin in terms of resolution of diarrhea at the end of a 10-day treatment course and may be associated with lower recurrence rates than vancomycin when used for the treatment of initial episodes of CDI in adults.2, 3, 6, 7, 11, 12, 19, 28, 29, 30 Although there is some evidence from retrospective studies that oral fidaxomicin may be as effective as oral vancomycin for the treatment of recurrent or severe CDI in adults,31, 32 data are limited and additional study is needed to evaluate the relative efficacy and safety of fidaxomicin and vancomycin for the treatment of recurrent, severe, or fulminant CDI, including severe, life-threatening infections.3, 6, 11, 12, 15, 19, 28, 29, 31, 32
Efficacy of fidaxomicin for treatment of CDAD was evaluated in 2 randomized, double-blind, active-controlled, noninferiority phase 3 trials that compared use of oral fidaxomicin (200 mg twice daily for 10 days) and oral vancomycin (125 mg 4 times daily for 10 days) in more than 1000 adults with CDI.1, 2, 26 Enrolled patients were 18 years of age or older with a diagnosis of CDAD (defined by a change in bowel habits, with more than 3 unformed bowel movements [or more than 200 mL of unformed stool in those with rectal collection devices] in the 24-hour period before randomization and presence of C. difficile toxin A and/or B in a stool specimen obtained within 48 hours before randomization) and had a history of no prior episodes of CDAD or only a single prior episode in the previous 3 months and had received no more than 4 doses of metronidazole or vancomycin in the 24 hours prior to randomization.1, 2 Patients with life-threatening or fulminant CDI, hypotension, septic shock, peritoneal signs, substantial dehydration, toxic megacolon, previous exposure to fidaxomicin, or history of ulcerative colitis or Crohn's disease were excluded.1, 2 The demographic profile and baseline CDAD characteristics of enrolled patients were similar in the 2 trials (median age 64 years, 90% white, 58% female, 63% inpatients).1 The median number of bowel movements per day at baseline was 6,1 84% of patients had no prior episodes of CDAD, 45% reported diarrhea symptoms alone, and 37% had severe CDAD (defined as 10 or more unformed bowel movements per day or leukocyte count 15,000/mm3 or higher).1
The primary efficacy end point was the rate of clinical response (clinical cure) at the end of treatment (day 10-11).1, 2, 26 Clinical response was based on improvement in diarrhea (i.e., frequency of 3 or fewer unformed stools for 2 consecutive days) or other symptoms such that (in the investigator's judgment) further CDAD treatment was not needed;1, 2, 26 clinical failure was defined by persistence of diarrhea and/or need for additional treatment (according to the investigator's assessment).2, 26 An additional efficacy end point was sustained clinical response (global cure).1, 2, 26 Sustained clinical response (defined as clinical response at the end of treatment and survival without proven or suspected CDAD recurrence through 25 days beyond the end of treatment) was evaluated only in patients who had clinical success at the end of treatment.1 The primary analysis population was the modified intent-to-treat (mITT) population, comprising patients with documented CDAD (more than 3 unformed bowel movements in the 24-hour period prior to randomization and presence of C. difficile toxin A and/or B in a stool specimen obtained within 48 hours before randomization) who received at least 1 dose of study drug after randomization.2, 26
Results of both phase 3 trials indicated that oral fidaxomicin is noninferior to oral vancomycin for treatment of CDAD in adults and that fidaxomicin is superior to vancomycin in terms of sustained clinical response after treatment.1, 2, 26 The clinical response rate at the end of treatment in the mITT population was 88% in those who received fidaxomicin compared with 86 or 87% in those who received vancomycin.1, 26 Mortality rates were similar (approximately 6% in each group).1 During the follow-up period, substantially fewer patients in the fidaxomicin groups than in the vancomycin groups had recurrences of CDAD.1, 2 The sustained clinical response rate at 25 days after completion of treatment in the mITT population was 70 or 72% in those who received fidaxomicin compared with 57% in those who received vancomycin.1, 26 However, when subgroup analysis was performed to evaluate comparative efficacy of fidaxomicin and vancomycin in patients with baseline C. difficile isolates identified by restriction endonuclease analysis (REA) as belonging to the BI group (strains associated with increased rates and severity of CDAD), sustained clinical response rates were similar for both drugs (58 or 65% for fidaxomicin and 63 or 52% for vancomycin).1
Fidaxomicin is administered orally without regard to food.1
Clostridioides difficile-associated Diarrhea
The recommended dosage of fidaxomicin for the treatment of diarrhea caused by Clostridioides difficile (formerly known as Clostridium difficile ) infection (CDI; C. difficile -associated diarrhea [CDAD]) in adults 18 years of age or older is 200 mg orally twice daily for 10 days.1, 12
While the manufacturer makes no specific recommendations regarding dosage in adults with hepatic impairment, fidaxomicin pharmacokinetics are not expected to be affected by hepatic impairment.1 (See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)
Dosage adjustment is not recommended in adults with mild, moderate, or severe renal impairment.1 (See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)
Dosage adjustment is not recommended in geriatric patients 65 years of age and older.1 (See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)
Fidaxomicin is contraindicated in patients hypersensitive to the drug or any ingredient in the formulation.1
Acute hypersensitivity reactions (e.g., dyspnea, rash, pruritus, angioedema of the mouth, throat, and face) have been reported in patients receiving fidaxomicin.1 Some patients with such reactions also reported a history of allergy to other macrolides.1
Clinicians should consider the possibility of hypersensitivity reactions if fidaxomicin is prescribed for a patient with known macrolide allergy.1
If a severe hypersensitivity reaction occurs, fidaxomicin should be discontinued and appropriate therapy administered.1
Fidaxomicin should only be used for the treatment of diarrhea caused by Clostridioides difficile (formerly known as Clostridium difficile ).1 Because only minimal systemic absorption occurs following oral administration of fidaxomicin,1, 20 the drug is not effective for the treatment of other types of infections.1
Selection and Use of Anti-infectives
To reduce development of drug-resistant bacteria and maintain effectiveness of fidaxomicin and other antibacterials, fidaxomicin should be used only for the treatment of infections proven or strongly suspected to be caused by C. difficile .1
Prescribing fidaxomicin in the absence of proven or strongly suspected C. difficile infection (CDI) is unlikely to provide benefit to the patient and increases the risk of development of drug-resistant bacteria.1
When selecting or modifying anti-infective therapy, results of culture and in vitro susceptibility testing should be used.1 In the absence of such data, local epidemiology and susceptibility patterns should be considered when selecting anti-infectives for empiric therapy.1
Available data regarding use of fidaxomicin in pregnant women are insufficient to inform any drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes.1
In embryofetal reproduction studies in rats and rabbits, there was no evidence of harm to the fetus when IV fidaxomicin was administered during organogenesis at dosages resulting in fidaxomicin and OP-1118 (its main metabolite) exposures that were at least 65-fold higher than human exposures reported with the recommended dosage of the drug.1
It is not known whether fidaxomicin or its main metabolite (OP-1118) is distributed into human milk, affects the breast-fed infant, or affects milk production.1
The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for fidaxomicin and potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.1
The manufacturer states that safety and efficacy of fidaxomicin have not been established in patients younger than 18 years of age.1 Fidaxomicin is designated an orphan drug by FDA for treatment of CDI in pediatric patients†.4
In a phase 2a clinical trial that evaluated the safety and pharmacokinetics of oral fidaxomicin in pediatric patients 6 months of age or older† with C. difficile -associated diarrhea, the safety profile of the drug was similar to that reported in adults.33 The most common adverse effects reported in these pediatric patients were vomiting, fever, upper abdominal pain, and C. difficile colitis requiring hospitalization after study enrollment.33
In controlled trials evaluating safety and efficacy of fidaxomicin, 50% of enrolled patients were 65 years of age and older and 31% were 75 years of age and older.1 No overall differences in efficacy or safety of fidaxomicin compared with vancomycin were observed in geriatric adults 65 years of age or older compared with younger adults.1
Although data from controlled trials indicate that plasma concentrations of fidaxomicin and its main metabolite (OP-1118) are higher in patients 65 years of age or older than in younger adults, concentrations remain in the ng/mL range.1 This is not considered clinically important and dosage adjustments are not recommended in geriatric patients.1
Although the effect of hepatic impairment on the pharmacokinetics of fidaxomicin has not been formally studied, elimination is not expected to be substantially affected by hepatic impairment since fidaxomicin and its main metabolite (OP-1118) do not appear to undergo substantial hepatic metabolism.1
In clinical trials in patients with mild, moderate, or severe renal impairment (based on creatinine clearance) receiving fidaxomicin (200 mg orally twice daily for 10 days), plasma concentrations of fidaxomicin and its main metabolite (OP-1118) did not vary by severity of renal impairment.1 Dosage adjustments are not recommended in patients with renal impairment.1
Adverse effects reported in 2% or more of patients receiving fidaxomicin in clinical trials include nausea (11%), vomiting (7%), abdominal pain (6%), GI hemorrhage (4%), anemia (2%), and neutropenia (2%).1 Abdominal distension, abdominal tenderness, dyspepsia, dysphagia, flatulence, intestinal obstruction, megacolon, increased blood alkaline phosphatase, decreased blood bicarbonate, increased hepatic enzymes, decreased platelet count, hyperglycemia, metabolic acidosis, drug eruption, pruritus, and rash were reported in less than 2% of patients.1
Drugs Metabolized by Hepatic Microsomal Enzymes
Metabolism of fidaxomicin and formation of its main metabolite (OP-1118) are not dependent on cytochrome P-450 (CYP) isoenzymes.1 Drug interaction studies using a CYP3A4 substrate (midazolam), CYP2C9 substrate (warfarin), or CYP2C19 substrate (omeprazole) indicate that fidaxomicin has no clinically important effect on the pharmacokinetics of these drugs.1 Based on these results, the manufacturer states that dosage adjustments are not warranted if fidaxomicin is used concomitantly with drugs that are CYP isoenzyme substrates.1
Drugs Affecting or Affected by P-glycoprotein Transport
Fidaxomicin and its main metabolite (OP-1118) are substrates of the efflux transporter, P-glycoprotein (P-gp), which is expressed in the GI tract.1
When cyclosporine (a P-gp inhibitor) was administered 1 hour before fidaxomicin, plasma concentrations of fidaxomicin and OP-1118 were substantially increased but remained in the ng/mL range.1 Although it is possible that concentrations of fidaxomicin and OP-1118 may be decreased at the site of action (i.e., GI tract) via P-gp inhibition, data from controlled clinical trials indicate that concomitant use of P-gp inhibitors in patients receiving fidaxomicin has no attributable effect on safety or treatment outcome.1 A drug interaction study using digoxin (a P-gp substrate) indicated that fidaxomicin has no clinically important effect on digoxin pharmacokinetics.1 Based on these results, the manufacturer states that dosage adjustments are not warranted if fidaxomicin is used concomitantly with P-gp inhibitors or P-gp substrates.1
In vitro, the antibacterial effects of fidaxomicin and its main metabolite (OP-1118) and the antibacterial effects of rifamycin antibiotics (i.e., rifampin, rifaximin) are synergistic against Clostridioides difficile (formerly known as Clostridium difficile ).1, 26, 27 Some synergism also was demonstrated in vitro between fidaxomicin and OP-1118 and ampicillin, clindamycin, and metronidazole.26, 27
There was no in vitro evidence of antagonism between fidaxomicin and OP-1118 and other anti-infectives (e.g., ampicillin, azithromycin, clindamycin, metronidazole, rifampin, rifaximin, telithromycin, vancomycin).1, 26, 27
Fidaxomicin, a macrocycle antibiotic6, 11, 14 that has been classified as a macrolide,1, 26 is a fermentation product obtained from the Actinomycete Dactylosporangium aurantiacum .1 While other commercially available macrolides have 14- or 15-member lactone ring structures, fidaxomicin has an 18-member macrocyclic ester structure.6, 11
Fidaxomicin has a narrow spectrum of antibacterial activity.6, 11, 13, 15, 22, 23, 24, 25 The drug is active against certain gram-positive bacteria and has only limited or no activity against gram-negative bacteria and is inactive against Candida albicans .6, 11, 13, 15, 23, 25, 26, 27 Fidaxomicin is active in vitro and in vivo against Clostridioides difficile (formerly known as Clostridium difficile ), a spore-forming, gram-positive anaerobe.1, 6, 11, 13, 21, 23, 25 The MIC90 of fidaxomicin for C. difficile generally ranges from 0.125-0.5 mcg/mL.6, 11, 21, 23, 24 Although the clinical importance is unclear, there is some evidence that PCR ribotype 027 strains of C. difficile (also known as NAP1 or B1) may have slightly higher fidaxomicin MICs than non-027 strains.6, 21 Fidaxomicin appears to have greater in vitro activity against C. difficile and may have a more minimal impact in vivo on normal intestinal flora than some other anti-infectives used for treatment of C. difficile infection (CDI; C. difficile -associated diarrhea [CDAD]);3, 6, 15 however, additional study is needed to more fully evaluate the effect of fidaxomicin on normal intestinal flora.3 Although fidaxomicin has in vitro activity against some other gram-positive anaerobes (e.g., C. perfringens and other Clostridium species, Peptostreptococcus ) and has limited in vitro activity against certain gram-positive aerobes (e.g., Staphylococcus aureus , coagulase-negative staphylococci, Enterococcus faecalis , E. faecium ),6, 11, 22, 23, 27 the drug is not effective for the treatment of systemic infections.1
Fidaxomicin and its main metabolite (OP-1118) are bactericidal against C. difficile in vitro,1, 6, 13 and exert a postantibiotic effect against the organism.5, 6 Although the exact mechanism of action has not been fully determined, the drug acts as an RNA polymerase inhibitor.1, 6, 27 Fidaxomicin appears to inhibit RNA synthesis in susceptible bacteria by binding to the DNA-RNA polymerase complex prior to formation of the open DNA-RNA polymerase complex needed for initiation of transcription.6, 27 This mechanism of action is distinct from that of other commercially available macrolides, which interfere with translation in susceptible bacteria by acting at the ribosomal level of protein synthesis.27
Although in vitro studies indicate a low frequency of spontaneous resistance to fidaxomicin in C. difficile ,1, 6 fidaxomicin-resistant strains of C. difficile have been produced in vitro1, 6, 34 and reduced susceptibility to the drug has been reported rarely in clinical specimens.1, 21, 34 Point mutations in the gene encoding the β subunit of RNA polymerase, rpo B, were identified in C. difficile mutants with reduced susceptibility to fidaxomicin that were produced in vitro.35, 36 A single mutation (Val-1143-Gly) in the β subunit of RNA polymerase was identified in C. difficile obtained from a patient who had recurrence of CDAD after fidaxomicin treatment.1 Although C. difficile isolated from this patient at baseline had a fidaxomicin MIC of 0.06 mcg/mL, the MIC was 16 mcg/mL at the time of recurrence.1, 21 Cross-resistance between fidaxomicin and other anti-infectives has not been reported to date.1, 6, 11
Following oral administration of fidaxomicin, only minimal systemic absorption occurs and the drug remains mainly confined to and acts locally in the GI tract.1, 20 Although plasma concentrations of fidaxomicin and its main metabolite (OP-1118) are approximately 2-6 times higher in patients with CDI than in healthy adults, plasma concentrations remain in the ng/mL range.1 Administration with a high-fat meal decreases peak plasma concentrations of fidaxomicin and OP-1118 by approximately 22 and 33%, respectively, but AUC is not affected and the effect of food is not considered clinically important.1 More than 92% of an oral dose is recovered in feces as fidaxomicin and OP-1118;1 less than 1% of a dose is recovered in urine as OP-1118.1 In patients treated with fidaxomicin (200 mg twice daily for 10 days), concentrations of fidaxomicin and OP-1118 in feces obtained within 24 hours of the last dose have ranged from 639-2710 mcg/g and 213-1210 mcg/g, respectively.1 Fidaxomicin is mainly transformed by hydrolysis at the isobutyryl ester to form OP-1118;1 although OP-1118 has antibacterial activity against C. difficile ,1, 5, 13, 27 it is less active than fidaxomicin.5, 13, 27 Metabolism of fidaxomicin and formation of OP-1118 are not dependent on cytochrome P-450 (CYP) isoenzymes.1 The plasma elimination half-lives of fidaxomicin and OP-1118 in adults are approximately 12 and 11 hours, respectively.1
Advise patients that antibacterials (including fidaxomicin) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold).1 Importance of advising patients that fidaxomicin is used only to treat diarrhea associated with Clostridioides difficile (formerly known as Clostridium difficile ) infection (CDI; C. difficile -associated diarrhea [CDAD]) and should not be used to treat any other infection.1
Importance of completing full course of therapy, even if feeling better after a few days.1
Advise patients that skipping doses or not completing the full course of therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with fidaxomicin or other antibacterials in the future.1
Advise patients that fidaxomicin may be taken with or without food.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
1. Merck Sharp & Dohme Corp. Dificid® (fidaxomicin) tablets prescribing information. Whitehouse Station, NJ; 2019 Mar.
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36. Schwanbeck J, Riedel T, Laukien F et al. Characterization of a clinical Clostridioides difficile isolate with markedly reduced fidaxomicin susceptibility and a V1143D mutation in rpoB. J Antimicrob Chemother . 2019; 74:6-10. [PubMed 30247587]