511285

research-article2013

TAJ0010.1177/2040622313511285Therapeutic Advances in Chronic DiseaseK Mullane

Therapeutic Advances in Chronic Disease

Review

Fidaxomicin in Clostridium difficile infection: latest evidence and clinical guidance

Ther Adv Chronic Dis 2014, Vol. 5(2) 69­–84 DOI: 10.1177/ 2040622313511285 © The Author(s), 2013. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav

Kathleen Mullane

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.

Keywords:  Clostridium difficile associated diarrhea (CDAD), Clostridium difficile infection (CDI), fidaxomicin, metronidazole, vancomycin

Introduction Since the development of antimicrobials during the early years of the 20th century, gastrointestinal symptoms ranging from nausea, vomiting and abdominal discomfort, to diarrhea and colitis have been associated with the use of these agents. Many different mechanisms by which antibiotics can cause or contribute to the pathogenesis of diarrhea have been described, but the major cause of antibiotic associated diarrhea and colitis is Clostridium difficile infection (CDI) [Kelly et  al. 1994; Kelly and LaMont, 1998]. With the introduction of broad-spectrum antibiotics, CDI has emerged as an important entity. C. difficile, a Gram-positive anaerobic spore-forming bacillus, has been implicated in 20–30% of patients with antibiotic-associated diarrhea, in 50–70% of those with antibiotic-associated colitis and in more than 90% of those with antibiotic-associated pseudomembranous colitis [Kelly et al. 1994;

George et al. 1982]. Collectively, these conditions are commonly known as CDI. This infection is acquired via transmission of C. difficile spores from individuals with active CDI or those who are asymptomatically colonized and shed spores, individuals who have had contact with CDI patients and carry the spores on their hands, and from spore contaminated environmental exposure [McFarland et  al. 1989; Shaughnessy et  al. 2011]. C. difficile spores are resistant to stomach acid, however in the small intestine spores germinate into the vegetative form of the organism and produce large clostridial exotoxins, toxin A and B and, in approximately 10% of strains, a third toxin known as binary toxin. Germination of C. difficile is theorized to be controlled by the presence of an adequate normal intestinal microbiome [McFarland et al. 1989; Shaughnessy et al. 2011]. CDI, then, results from a combination of disruption of the normal intestinal microflora and

Correspondence to: Kathleen Mullane, DO Department of Medicine/ Division of Infectious Diseases, University of Chicago, 5841 South Maryland Avenue, MC 5065, Chicago, IL 60637, USA [email protected]. uchicago.edu

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Therapeutic Advances in Chronic Disease 5(2) overgrowth of native transient colonizing or newly acquired C. difficile spores [Rafii et  al. 2008; Jernberg et al. 2010; Mullane et al. 2011; Hensgens et al. 2012a]. In most instances, disruption of the normal intestinal flora is caused by exposure to antimicrobial agents. Complications initially reported to be associated with CDI were believed to be few and for many years it was considered a nuisance illness. However, over the past decade, CDI has become epidemic and is associated not only with an increase in incidence and severity, but also an increase in rates of CDI-related morbidity and a four-fold increase in CDI-related mortality between 1999 and 2011 [Pepin et  al. 2004; McDonald et  al. 2005; Loo et  al. 2005; Freeman et al. 2010]. Epidemiology of CDI The worldwide increased incidence and severity of CDI over the past 20 years may be the result of a combination of factors including the emergence of hyper-virulent strains such as BI/NAP1/027, the increased use and misuse of antibiotics, and the increase of susceptible at-risk populations [Pepin et  al. 2004; McDonald et  al. 2005; Loo et  al. 2005; Freeman et  al. 2010]. Studies performed in North America and Europe report increases of as much as two- to four-fold in the incidence of CDI in the past decade. In the United States, alone, there are an estimated 700,000 new cases of CDI per year. Compared with hospitalized persons without CDI, those having CDI as a secondary diagnosis have a threefold increased duration of hospitalization, have a 3.5-fold increase in hospital costs, and are six times as likely to die. Data from 28 community hospitals in the United States suggest that CDI has replaced methicillin-resistant Staphylococcus aureus as the most common cause of healthcareassociated infections ranking third behind catheter-associated urinary tract infections and surgical site infections [Miller et  al. 2011]. The national rate of C. difficile hospitalizations per 1000 nonmaternal, adult discharges increased from about 5.6 in 2001 to 11.5 in 2010 in the United States with this rate projected to continue to increase to about 12.5 in 2011 and 12.8 in 2012 [Steiner et al. 2012]. Reports from United States National Vital Records showed that from 1999 to 2008 death certificates listing C. difficile enterocolitis as the primary cause of death increased from 793 to 7483 with the majority of deaths from CDI occurring in persons >65 years of age [Minino et  al. 2010]. The burden of healthcare facility-acquired

CDI in Europe, based on data collected prospectively from 38 hospitals in 14 different countries in 2005, reported 30-day mortality rates from CDI ranging from 2.8% to 29.8% [Barbut et al. 2007]. In these hospitals, the mortality rates from CDI more than doubled from 1999 to 2004, and continued to rise until 2007. Recurrent CDI was reported to vary from 1% (France) to 36% (Ireland). Despite being classically described as a nosocomial process, community-acquired cases of CDI are now more common than reported previously [Lambert et  al. 2009; Fellmeth et  al. 2010; Khanna and Pardi, 2010; Khanna et  al. 2012a, 2012b; Lessa et  al. 2012]. Populations such as children and peripartum women previously considered being of low risk for CDI and populations without the established risk factors for CDI such as recent hospitalization, antibiotic exposure, known contact with persons at risk for CDI, or travel, are now being identified as having this infection [Bouttier et al. 2010; Centers for Disease Control and Prevention, 2005; Zilberberg et  al. 2010]. In livestock and household pets, C. difficile has been reported to be both a pathogen and a commensal. C. difficile spores have been reported to be present in foods such as fresh vegetables, meat, and shellfish [Keel et  al. 2007; Goorhuis et  al. 2008; Rupnik et  al. 2008; Avbersek et  al. 2009; Bakri et  al. 2009; Bouttier et  al. 2010; Metcalf et  al. 2010; Hensgens et  al. 2012b]. Published reports from North America and Europe indicate that community-associated CDI cases accounted for approximately 20–27% of cases of infection with an estimated incidence of 20–30 cases per 100,000 population [Wilcox et al. 2008; Lambert et al. 2009; Kutty et al. 2010]. Not only is the incidence of community-acquired CDI increasing, but adverse outcomes have been reported in up to 40% of this population who require hospitalization for the management of their infection [Khanna et al. 2012a]. Current treatment options for CDI Oral metronidazole and oral vancomycin have been the primary treatment options in the management of CDI for the past 30 years. Widespread use of metronidazole over vancomycin was advocated in the 1995 HICPAC guidelines in an effort to reduce the spread of vancomycin-resistant enterococci (VRE), however VRE colonization was shown to arise from exposure to either agent [Centers for Disease Control and

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K Mullane Prevention, 1995; Al-Nassir et  al. 2008]. Vancomycin has been shown to be superior to metronidazole in those with severe CDI [Louie et  al. 2007; Zar et  al. 2007]. The current Infectious Diseases Society of America/Society of Healthcare Epidemiologists (IDSA/SHEA) and European Society of Clinical Microbiology and Infectious Diseases (ESCMID) published CDI guidelines, developed prior to the release of the newest agent approved for treatment of CDI, fidaxomicin, advocate oral metronidazole in cases of mild to moderate disease, oral vancomycin for serious CDI, and combination therapy with enteral vancomycin and intravenous metronidazole in cases of ileus or toxic megacolon [Bauer et al. 2009; Cohen et al. 2010]. For first relapse, these guidelines recommend using the same therapy as the initial regimen unless the white blood cell count is ≥15,000 cells/µl or in cases where there is rising creatinine in which case vancomycin is recommended. Other agents that have been reported as having activity in treating CDI are listed in Tables 1 and 2. Recently published guidelines by the American Society of Gastroenterology mirror those of the previously published guidelines, as noted above, for treatment of initial and recurrent CDI with the additional recommendation of fecal microbiota transplant (FMT) for third recurrence of CDI [Surawicz et al. 2013]. Reports of metronidazole treatment failures have become a concern [Aslam et al. 2005]. C. difficile strains with reduced susceptibility to metronidazole have been reported and treatment failures have increased from a reported 3% prior to the year 2000 to 16–38% after 2000 [Aslam et  al. 2005; Baines et al. 2008; Rupnik et al. 2009]. In addition, following successful cure (relief of symptoms at the end of therapy with no need for further CDI treatment) recurrence is common with both metronidazole and vancomycin. In recent studies, the recurrence of CDI (diarrhea with a positive diagnostic test for the presence of C. difficile or its toxins) has been reported to occur in up to 35% of cases within 30 days following treatment [Aslam et  al. 2005; Louie et  al. 2007, 2011; Cornely et  al. 2012a; Rege et  al. 2012]. With one recurrence, the rate of further CDI recurrences increases to 45–65% [McFarland et al. 1994, 2002; Huebner and Surawicz, 2006]. Identified risk factors that have been reported to place individuals at high risk for recurrent CDI are listed in Table 3. Although there are many small uncontrolled studies evaluating different

agents in managing second recurrence or higher, there is only one published randomized clinical trial and based on this data, tapering or pulsed dosing of vancomycin are currently recommended for the management of these cases in published treatment guidelines [McFarland et al. 2002]. FMT has also been reported as a treatment option in individuals with recurrent CDI. In a systematic review of the literature which included case series and reports, FMT was shown to be an effective treatment for recurrent CDI [Gough et al. 2011]. FMT was more successful if delivered by colonoscopy or enema, was from a related donor, had a donor specimen of >50 g, and was delivered in a diluents volume >500 ml. Duodenal infusion of donor feces following a 3-day course of vancomycin in individuals with recurrent CDI in whom vancomycin had failed was compared with a 14-day course of vancomycin with or without bowel lavage by van Nood and colleagues [van Nood et al. 2013]. The study was discontinued after 43 of a planned 120 subjects were enrolled because at the study’s first interim analysis the cure rates in the study arm who received donor fecal infusion was significantly higher (81%) than either of the vancomycin arms (31% vancomycin alone and 23% vancomycin plus bowel lavage). This study was unblinded and neither vancomycin arm was treated with a tapering or pulsed dose of vancomycin for comparison, but the significant improvement in subject outcomes should encourage the design of other trials comparing pharmacologic therapies with FMT. Standardization issues regarding donor screening procedures for potential transmissible infections and the manufacturing processes for feces will also need to be developed for FMT. Fidaxomicin In May 2011, the United States Food and Drug Administration (FDA) approved fidaxomicin making it only the second agent, after vancomycin, to be approved by this agency for the treatment of CDI. Soon afterwards, in December 2011, the European Medicines Agency (EMA) granted marketing authorization throughout the European Union followed by Japan, Australia, and Canada. Fidaxomicin is a first-in-class 18-membered macrocyclic antibiotic [Parenti et  al. 1975; Theriault et  al. 1987; Mullane and Gorbach, 2011] previously known as OPT-80, PAR-101, and difimicin (Figure 1). In the United States and in Japan, fidaxomicin is classified as a macrolide antibiotic.

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200 mg po bid for 10 days

125 mg po qid for 10 days or ‘taper/pulse’ for recurrence: 125 mg po qid for 10–14 days, then 125 mg po bid per day for 1 week, then 125 mg po daily for 1 week, then 125 mg po every 2 or 3 days for 2–8 weeks 500 mg po tid for 10 days or 250 mg po qid for 10 days

Fidaxomicin

Vancomycin

400 mg po tid for 10 days or ‘chaser’ regimen 400 mg po bid for 14 days

400 mg po bid for 10 days

50 mg iv every 12 hours for 10 days

25,000 units po qid for 10 days

250 mg po tid for 10 days

Rifaximin

Teicoplanin

Tigecycline

Bacitracin

Fusidic acid

++

+

++?

+++

++

++

++

+++

+++

Relative efficacy

++

+++

?

++

+?

++

++

++

+

Recurrence risk

Reported in vivo

Increased resistance noted

Not reported

Potential for development of high-level resistance Not reported

Not reported

Increased MICs noted in some studies

Not reported

Not reported

Resistance in clinical isolates

Nausea, vomiting, epigastric pain, anorexia

Minimal absorbed, poor taste

Not absorbed so systemic symptoms unlikely Nausea, vomiting, diarrhea

Nausea, diarrhea, abdominal pain Headaches, abdominal pain, nausea, flatulence, not absorbed

Nausea, neuropathy, abnormal taste in mouth

Abdominal pain, nausea, vomiting, anemia, neutropenia bowel obstruction and gastrointestinal hemorrhage Nausea, not absorbed so systemic symptoms unlikely

Adverse events

Not FDA approved for CDI, similar results to vancomycin. Not FDA approved for CDI; limited case reports of treatment success and failures Not FDA approved for CDI; limited efficacy secondary to resistance Not FDA approved for CDI, concern about use as a single agent

Not FDA approved for CDI, used primarily as postvancomycin

Not FDA approved for CDI, increased reports of treatment failures and slow response, less effective in severe CDI Not FDA approved

FDA approved for CDI; firstin-class oral macrocyclic antibiotic with targeted bactericidal activity against C. difficile and minimal impact on normal flora FDA approved for CDI; potential for resistance induction in other clinically important pathogens (VRE)

Comments

bid, twice daily; CDI, Clostridium difficile infection; FDA, United States Food and Drug Administration; po, per os; qid, four times daily; tid, three times daily.

500 mg po bid for 10 days

Nitazoxanide

Metronidazole

Dose

Agent

Table 1.  Available antibiotics and investigational new agents for the management of CDI. (Adapted from Cornely [2012] and Venugopal and Johnson [2012].)

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K Mullane Table 2.  Nonantibiotic alternatives and investigational new agents for the management of CDI. (Adapted from Cornely [2012] and Venugopal and Johnson [2012].) Agent

Comments

IVIG

Multisystemic side-effects profile. Most commonly renal failure. Efficacy for use in adults is inconclusive; in pediatrics, evidence favors efficacy. Infusion of feces from a healthy donor. Most evidence comes from single-center case series and case reports. A recent multicenter, long-term follow-up study has shown positive results. Multiple studies favor the use of probiotics for the prevention of CDI and antibiotic associated diarrhea (Hempil et al. 2012; Johnson et al. 2012; McFarland, 2006); however, appropriately powered studies are needed to confirm these findings. Guidelines do not recommend the routine use of probiotics given the lack of definitive evidence of effectiveness and potential risk of blood stream infection.

Fecal transplantation Probiotics

Investigational new agents Agent

Comments

Ramoplanin

Under investigation (phase III) for the treatment of CDI. Lipoglycodepsipeptide with spectrum activity similar to vancomycin but considerably more potent. Narrow spectrum, Gram-positive lipopeptide antibiotic in phase III: development status (Mascio et al. 2012; Rege et al. 2012; NTC 01597505; NTC 01598311). Hybrid oxazolidinone-quinolone antibiotic. Currently in phase II [ClinicalTrials.gov identifier: NCT01222702]. Human monoclonal antibodies against C. difficile toxins A and B. Phase III trials for prevention of CDI, recurrence (MODIFY I [ClinicalTrials.gov identifier: NCT01241552] and MODIFY II [ClinicalTrials.gov identifier: NCT01513239]). Active C. difficile toxoid vaccine. Phase II placebo-controlled for primary CDI prevention [ClinicalTrials.gov identifier: NCT00772343]. Nontoxigenic C. difficile. Phase II trial for prevention of CDI recurrence [ClinicalTrials.gov identifier: NCT01259726].

CB-183,315 Cadazolid CDAI and CDBI

ACAM-CDIFF VP 20621

IVIG, intravenous immunoglobulins; CDAI, Human monoclonal antibody to C. difficile toxin A; CDBI, Human monoclonal antibody to C. difficile toxin B.

Antimicrobial spectrum and mechanism of action Fidaxomicin is a bactericidal antibiotic that has a lower minimum inhibitory concentration (MIC) in vitro against C. difficile strains, including NAP1/ B1/027, than does metronidazole or vancomycin [Hecht et  al. 2010; Goldstein et  al. 2011]. Fidaxomicin and its related compounds interfere with RNA polymerase producing a rapid suppression of RNA synthesis thereby inhibiting bacterial protein transcription followed by an inhibition of protein synthesis and, ultimately, DNA synthesis [Artsimovitch et  al. 2012; Coronelli et  al. 1975; Seddon and Sears, 2003; Sergio et  al. 1975; Srivastava et al. 2011]. Fidaxomicin acts at a site and step of RNA synthesis different than the rifamycins and no overlapping antibiotic resistance between these agents has been described to date [Sergio et  al. 1975; Srivastava et  al. 2011; Sears et al. 2008]. Fidaxomicin is more potent at suppressing clostridial RNA polymerase than against other bacterial species, thereby it displays a narrow spectrum of antimicrobial activity characterized by excellent activity against many species of

Clostridium and moderate to good activity against Gram-positive rods and cocci with modest activity against Staphylococcus spp. and enterococcus, including VRE [Beidenbach et  al. 2010]. Fidaxomicin is inactive against Gram-negative organisms and yeasts (Candida). Fidaxomicin has potential advantages over other drugs used to treat CDI and a number of properties that appear ideally suited to the treatment of CDI [Johnson, 2007]. Unlike vancomycin which is bacteriostatic, fidaxomicin is bactericidal. Fidaxomicin has lower MICs against C. difficile when compared with vancomycin and metronidazole, and it has a prolonged post-antibiotic effect of approximately 10 hours (range 9.5–12.5 hours) allowing for twice-daily dosing [Babakhani et  al. 2011]. When administered orally both fidaxomicin and vancomycin are not well absorbed from the gastrointestinal tract resulting in high fecal concentrations that exceed the MIC for C. difficile. Metronidazole is nearly completely absorbed in the proximal jejunum and is only present with fecal concentrations above the MIC for C. difficile

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Therapeutic Advances in Chronic Disease 5(2) Table 3.  Risk factors associated with recurrent Clostridium difficile infection (CDI). (Adapted from Eyre et al. [2012], Gary et al. [2008], Hebert et al. [2013], and Hu et al. [2009].) •  Altered immunity –  Advanced age –  Inadequate antitoxin antibody response –  Peripartum women – Leukopenia –  Poor underlying health condition  Chronic renal insufficiency  Chemotherapy  Concurrent bacterial infection  High Horns index (score of 3 or 4)   Emergent hospitalization/ICU stay/ prolonged hospitalization •  Disruption of colonic flora – Concomitant antimicrobial therapy, especially flouroquinolone or cephalosporin use –  Previous episode of CDI –  Metronidazole treatment •  Severity of initial CDI –  >3 unformed stools –  Hospital admission with CDI – Elevated C-reactive protein, elevated leukocyte count •  Other factors – (?) Proton pump inhibitors, H2 blockers, antacids

when feces remain unformed [Bolton and Culshaw, 1986; Johnson et al. 1992]. Fidaxomicin taken orally achieves fecal concentrations well above the MIC90 of 0.25 µg/ml for C. difficile with fecal concentrations within 24 hours of the last dose of 639–2710 µg/g for fidaxomicin and 213–1210 µg/g for OP-1118, the major metabolite of fidaxomicin. Fidaxomicin has minimal systemic

absorption with plasma concentrations within a Tmax window (1–5 hours) of 0.3–197 ng/ml for fidaxomicin and 0.29–871 ng/ml for OP-1118, even in patients with severe CDI [Sears et  al. 2009]. 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]. Clinical and bacteriological cure in patients with CDI is therefore achieved with minimal effects on the composition of the microbiome, thus allowing for a more rapid restoration of the commensal microflora, thereby reducing the risk of C. difficile colonization, re-infection, and proliferation [Louie et al. 2012]. In a recent study, treatment of CDI with fidaxomicin was less likely to promote acquisition of VRE and candida species when compared with vancomycin, a potential benefit in relationship to infection control implications [Nerandzic et  al. 2012]. Fidaxomicin blocks gene transcription, halting bacterial sporulation and suppressing toxin production [Babakhani et  al. 2012, 2013]. Reappearance of toxin in fecal filtrates was observed in 28% of vancomycin-treated patients samples (29 of 94), compared with 14% of fidaxomicin-treated patient samples (13 of 91; p = 0.03) [Louie et al. 2012]. In a recent study, the effects of fidaxomicin, its major metabolite (OP1118), vancomycin, and metronidazole on the expression of toxin genes and toxin proteins in four strains of C. difficile, including two hypervirulent NAP-1 isolates were compared [Babakhani

Figure 1.  Structure of fidaxomicin.

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K Mullane Table 4.  Minimum inhibitory concentration (MIC) data [Optimer Pharmaceuticals, Inc., 2011].

BI group (N = 283) All strains (N = 792)

Fidaxomicin MIC90

Vancomycin MIC90

Metronidazole MIC90

0.5 0.25

2.0 2.0

2.0 1.0

et  al. 2012, 2013]. Subinhibitory levels of fidaxomicin and OP-1118, but not vancomycin or metronidazole, suppressed both sporulation and toxin production (≥60%) in C. difficile through at least 1 week of culture. Suppression of toxin production may contribute to the improved sustained clinical response observed with fidaxomicin when compared with vancomycin. Inhibition of sporulation may well have an impact on the rate of recurrences seen in patients treated with fidaxomicin in comparison with vancomycin and a reduction of the shedding of spores has the potential benefit of decreasing transmission of C. difficile in hospital and long-term care settings; however, further studies are needed to determine this impact of fidaxomicin on C. difficile transmission. Efficacy studies and comparative analysis In two large concurrently run double-blind randomized noninferiority trials (OPT 101.1.C.003 and OPT 101.1.C.004), fidaxomicin was compared with vancomycin in the treatment of new onset or first recurrence of CDI [Louie et  al. 2011; Cornely et  al. 2012a]. Patients received either fidaxomicin (200 mg twice daily) or vancomycin (125 mg four times daily) orally for a 10-day course of treatment. The primary endpoint of noninferior clinical cure (resolution of CDI symptoms and no need for further therapy at the end of therapy) between the two treatment arms was met in both the modified intention-totreat (mITT) analysis and the per-protocol analysis in both studies. Analysis of the secondary endpoints of CDI recurrence and global cure (clinical cure and no recurrence of disease at 28 days after completion of study drug therapy) in both studies showed that significantly fewer patients in the fidaxomicin group than in the vancomycin group had recurrence of CDI. Consequently, in both studies, those subjects treated with fidaxomicin had a statistically significant improved rate of global cure. In both studies, the numbers of subjects enrolled who were infected with NAP1/BI/027 strains were small, but the rates of cure and global cure in the perprotocol analysis were numerically similar in those treated with vancomycin than in those

treated with fidaxomicin. The numbers of individuals with NAP1/BI/027 strain type CDI enrolled in these trials were so small as to preclude an adequately powered sample of subjects for statistical analysis evaluating possible differences in outcome of therapy with fidaxomicin versus vancomycin in these subjects. Therefore, no definitive statements can be made regarding the significance of treatment outcomes in those subjects infected with the NAP1/BI/027 strain of C. difficile at this time. There was no difference in the MIC90 for the NAP1/BI/027 strains compared with non-NAP1/BI/027 strains of C. difficile in those subjects enrolled in the registry trials (see Table 4). A post hoc exploratory intention-to-treat (ITT) time-to-event meta-analysis of the combined data from these two trials was performed, to allow increased power with a total of 1164 subjects, using fixed-effects meta-analysis and Cox regression models [Crook et  al. 2012]. There was no evidence found of heterogeneity in the primary and secondary outcomes in either the mITT or per-protocol populations (p > 0.3). Overall, the results of this analysis demonstrated noninferiority of fidaxomicin when compared with vancomycin for clinical cure and superiority of fidaxomicin over vancomycin in the reduction of recurrence and global cure (p < 0.0001). When compared with vancomycin, treatment with fidaxomicin was associated with an overall 40% reduction in persistent diarrhea, recurrence, or death through the 40-day study period (p < 0.001). When comparing the fidaxomicin-treated with the vancomycin-treated subjects there was no evidence to show that the significant differences in relapse and global cure were altered according to disease severity, prior history of CDI, previous antibiotic therapy for CDI, inpatient/outpatient status, age, baseline albumin, or creatinine levels. In the combined dataset, the number of NAP1/BI/027 CDI cases remained underpowered to definitively conclude whether or not fidaxomicin had a beneficial effect over vancomycin for treating CDI due to NAP1/BII/027 strains [Crook et al. 2012].

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Therapeutic Advances in Chronic Disease 5(2) In the post hoc subgroup analysis of combined data sets from studies OPT 101.1.C.003 and OPT 101.1.C.004, outcomes of populations at high risk for recurrent CDI including older patients, patients requiring concomitant antibiotic therapy, patients with severe renal impartment, cancer patients, and those with recurrent CDI were evaluated. Analysis of subgroups from the combined data from studies OPT 101.1.C.003 and OPT 101.1.C.004 explored these high-risk populations. Overall, use of fidaxomicin in patients with conditions associated with a high risk for recurrence had significantly improved outcomes. In the post hoc subgroup analysis evaluating the geriatric population, individuals over the age of 65 showed similar clinical cure rates between the fidaxomicin and vancomycin treatment groups; however, fidaxomicin treatment was associated with a 60% lower risk of recurrence than vancomycin after adjusting for age, concomitant antibiotics, and C. difficile strain [Louie et al. 2013]. In the subjects that required concomitant antibiotic therapy for concurrent infections randomized to fidaxomicin, the cure rate was 90.0% compared with 79.4% (p = 0.04) in the vancomycin treatment groups [Mullane et  al. 2011]. In those treated with concomitant antibiotics, fidaxomicin therapy was associated with 12.3% less recurrences compared with vancomycin therapy (p = 0.048). In subjects with chronic kidney disease (CKD), CDI cures declined and recurrences increased with progressively declining creatinine clearance [Mullane et al. 2013; Crook et al. 2012]. Cure rates were similar for normal (91%) and mild CKD (92%), but fell to 80% for moderate and 75% for severe CKD (p < 0.001). Recurrence rates were 16%, 20%, 27%, and 24% for normal, mild, moderate, and severe CKD (p = 0.009). Fidaxomicin was associated with significantly lower odds of recurrence (odds ratio [OR] = 0.46, 95% confidence interval [CI] 0.32–0.66) and superior sustained response (OR = 1.85, 95% CI 1.39–2.47) than vancomycin. In the patients with severe CKD recurrence occurred in 15% of fidaxomicin-treated subjects compared with 35% of those randomized to vancomycin. Odds of recurrence were 54% lower and odds of sustained response were 85% greater with fidaxomicin relative to vancomycin. In those patients enrolled into the studies who carried a diagnosis of cancer, CDI cure was more likely in those randomized to fidaxomicin than in subjects who were treated

with vancomycin (p = 0.041), recurrence was less likely (p = 0.025), and sustained response rate was significantly higher (p = 0.03) [Cornely et al. 2013]. Finally, in those subjects enrolled into the trial with first recurrence of CDI, within 28 days recurrence occurred in 35.5% of subjects in the vancomycin group compared with 19.7% of those who were treated with fidaxomicin (p = 0.045) [Cornely et al. 2012b]. Safety and tolerability Both fidaxomicin and vancomycin are poorly absorbed and therefore serum levels are low [Shue et al. 2008; Sears et al. 2012]. High doses of fidaxomicin were administered to dogs (approximately 1 g/kg/day) in nonclinical studies, with no toxicities reported [Optimer Pharmaceuticals, Inc., 2011]. Metronidazole, however, is nearly completely absorbed in the normal gut and in those with diarrhea associated with CDI, intracolonic levels have been found to be similar when the drug is administered either by the oral or intravenous route [Bolton and Culshaw, 1986]. In a small randomized trial comparing metronidazole with vancomycin in the treatment of CDI, the only adverse events reported were one case of nausea and emesis in each treatment arm [Zar et al. 2007]. Metronidazole has been reported to cause nausea, diarrhea, and dysgeusia commonly. At high doses it can cause bone marrow suppression, neuropathy, and central nervous system toxicity. In the phase III clinical trials, the safety profile of fidaxomicin was comparable with oral vancomycin with no differences in the rates of serious adverse events or death [Louie et al. 2011; Cornely et al. 2012a]. Patients receiving fidaxomicin and vancomycin have been reported to have anemia and leukopenia at nearly identical rates; however, no specific bone marrow toxicity has been observed with fidaxomicin in nonclinical studies. The incidence of infection resulting in death was similar between fidaxomicin (2%) and vancomycin (1.9%) in those subjects who developed leukopenia. Fidaxomicin is FDA category B for pregnancy as animal reproduction studies have failed to demonstrate any risk to the fetus; however, there are no adequate and well-controlled studies in pregnant women [Optimer Pharmaceuticals, Inc., 2011]. The available evidence is inadequate for determining infant risk when used during breast-

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K Mullane feeding and caution is advised when administering fidaxomicin to a nursing mother. Based on online reviews, the patient satisfaction ratings are very favorable with rapid resolution of symptoms and frequency of diarrhea even after failed attempts of therapy with vancomycin and metronidazole [Miller et  al. 2009; Optimer Pharmaceuticals, Inc., 2011]. Guidelines for use of fidaxomicin in the management of CDI While fidaxomicin has proven superior in efficacy to vancomycin this superiority comes at a steep cost. In the United States, the healthcare payment systems for inpatient and outpatient care currently work independently [Bouza, 2012]. Because there is a significant disconnect in payment for costs associated with hospital care and costs associated with post-hospitalization care of patients, the consideration of the true overall costs of managing a patient with CDI is difficult to assess. Most inpatient facilities are concerned with budgetary constraints associated with the specific patient admission diagnosis at the time of acquisition of CDI and not for the possibility of readmissions associated with treatment relapses and further the overall consequences of these relapses to the healthcare system. Acquisition costs for treatments should be considered in the context of the wider economic impact of managing CDI. Prolongation of hospital stay carries the greatest cost burden in the management of these patients; however, isolation precautions, environmental decontamination, cohort isolation, and outbreak evaluations all increase the cost of managing this patient population. Significant proportions of patients who suffer from CDI relapses are managed in extended care facilities or as outpatients and these costs are usually not included in the cost of management evaluations for this infection. Patients who require hospitalization for relapsed CDI may not return to the hospital from which they were discharged but be admitted to another facility. Based upon 2009 United States Healthcare Cost Utilization Project data, the risk of readmission following a hospital admission with CDI, in any diagnostic field, is 12.8% at 30 days and 17.2% at 90 days after discharge with an associated hospital cost per stay of US$17,700 [Steiner et  al. 2012] (see Tables 5 and 6). This data follows patients from discharge to rehospitalization without regard to the facility to which patients are

readmitted. In this patient population, CDI surpassed septicemia, congestive heart failure, pneumonia, and urinary tract infections as the principal diagnosis associated with 30- and 90-day readmissions. In a systematic review of healthcare costs associated with caring for patients with primary and recurrent CDI, the 13 studies that met inclusion criteria for this analysis showed that the total cost for treating primary CDI ranged from US$9822 to US$13,854 compared with control costs of US$6950–9008 [Ghantoji et  al. 2010]. These costs escalated if individuals had significant comorbidities. In a similar European analysis of 39 publications and 30 abstracts, the incremental increase in cost of managing patients with CDI varied between £4577 (approximately US$7049) in Ireland and £8843 (approx US$13,777) in Germany, after standardization to 2010 prices [Wiegand et al. 2012]. The consideration of value of the drug compared with agents already available must be evaluated by the value this drug brings in reduced rates of recurrent CDI especially when associated with hospital readmissions. The question of whether or not fidaxomicin is cost effective has been evaluated in two cost analysis studies [Stranges et  al. 2013; Sclar et al. 2012]. In comparison with oral vancomycin, including when using extemporaneously compounded oral vancomycin solution from intravenous formulations and using Average Warehouse Price (AWP) drug costs, by probabilistic Monte Carlo sensitivity analysis fidaxomicin was found to be cost effective in terms of recurrences and clinical cure rates based upon a 9.8% difference in recurrences as reported in the two major pivotal trials [Louie et  al. 2011; Cornely et al. 2012a]. In a secondary analysis, it was also found to be cost effective specifically in individuals receiving concomitant antimicrobials and in those with mild to moderate CDI [Stranges et al. 2013]. Because the major advantage of fidaxomicin is a reduction of the risk of CDI recurrence, cost effective use of this agent would entail targeting its use to that population at highest risk of relapse. Retrospective and prospective analyses as well as computer-based analyses have delineated readily obtainable factors for predicting a high risk of CDI relapse [Mauskopf et al. 1998; Pepin et  al. 2005; Hu et  al. 2009; Garey et  al. 2008; Eyre et  al. 2012; Hebert et  al. 2013; Lavergne et  al. 2013; McGlone et  al. 2012]. These factors include: age >65 years; severity of underlying disease state based upon scoring

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Therapeutic Advances in Chronic Disease 5(2) Table 5.  Readmission following hospital stays associated with Clostridium difficile infection (CDI) and cost per stay, 2009.

Number of index stays with CDI (January to November)   Percentage readmitted within 30 days    With CDI as the principal diagnosis    With CDI in any diagnosis field*    With any diagnosis** Number of index stays with CDI (January to September)   Percentage readmitted within 90 days    With CDI as the principal diagnosis    With CDI in any diagnosis field*    With any diagnosis**

N (Percentage readmitted)

Cost per stay (US$)

280,700

26,900   11,800 17,700 16,200 26,800   11,500 17,700 15,800

4.8% 12.8% 29.1% 233,800 6.8% 17.2% 44.8%

Source: Weighted national estimates from a readmission analysis file derived from the Healthcare Cost and Utilization Project (HCUP) State Inpatient Databases (SID), 2009, and Agency for Healthcare Research and Quality (AQHR) [Elixhauser et al. 2012]. * CDI is the principal diagnosis or a secondary diagnosis in the readmission, i.e. all-listed CDI. ** All-cause readmission.

Table 6.  Top 10 principal diagnoses for readmissions following a Clostridium difficile infection (CDI) index stay, 2009. Principal diagnosis*

30-day readmissions

90-day readmissions

 

Readmission with CDI as any diagnosis

 

Percentage of total

Clostridium difficile (ICD-9 008.45) Septicemia (except in labor) Congestive heart failure Complication of device, implant or graft Pneumonia Urinary tract infections Respiratory failure; insufficiency; arrest Aspiration pneumonitis; food/vomitus Complications of surgical procedures or medical care Acute and unspecified renal failure Fluid and electrolyte disorders Percentage of all readmissions attributable to the top 10 principal diagnoses

37.6

16.5

39.3

15.1

13.7

12.1

13.9

11.8

 4.0  3.4

 4.9  4.2

 3.6  3.2

 5.0  4.2

 2.8  2.0  1.7

 3.6  3.1  2.2

 2.7  2.1  1.5

 3.9  3.3  2.0

 1.7

–

 1.7

–

 1.6

 2.6

 1.6

 2.6

 1.6

 2.3

 1.7

 2.2

–

 2.6

–

 2.4

70.7

54.1

71.3

52.5

All-cause readmission following a stay with CDI

Readmission with CDI as any diagnosis

All-cause readmission following a stay with CDI

Percentage of total

Source: Weighted national estimates from a readmissions analysis file derived from the Healthcare Cost and Utilization project (HCUP), State Inpatient Databases (SID), 2009, and Agency for Healthcare Research and Quality (AHQR) [Elixhauser et al. 2012]. * Except for Clostridium difficile, all diagnoses are categorized using the Clinical Classification Software (CCS).

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K Mullane using the Horn’s index or evaluating markers of poor underlying illness such as renal failure; presence of a hypervirulent C. difficile strain; prolonged hospital exposure, concomitant need of antibiotic therapy especially fluoroquinolones or cephalosporins; metronidazole use in treatment of CDI; concomitant proton pump inhibitor or antacid; and a high white cell count or very low lymphocyte count (see Table 3). Serum antitoxin A IgG has as well been identified as a marker for relapsed disease; however, it is not a routinely available laboratory assessment. Subjects having two or more of these factors have been shown to be at high risk of relapse [Hu et  al. 2009]. Targeting fidaxomicin by selection of patients at high risk for relapse for use of the drug over metronidazole or vancomycin in conjunction with addressing those factors placing the patient at risk for relapse that can be altered may well prove the most reasonable approach to rational use of this agent. Prospective studies validating predictive models to identify patients at high risk for recurrence and modifying those risk factors that may be altered along with judicious use of therapeutic measures for managing CDI need to be conducted, not only to improve patient outcomes from CDI, but also to evaluate the true cost of treating this infection.

Funding This research received no specific grant from any funding agency in the public, commercial, or notfor-profit sectors.

Conclusion Fidaxomicin represents an important development in the treatment of CDI with significant advantages over the other currently available antimicrobial agents. These advantages include lower rates of CDI recurrence, twice-daily dosing, and minimal side effects. That fidaxomicin has been shown to be superior to vancomycin in preventing recurrent CDI may be due to its narrow spectrum of activity allowing the gut to repopulate a normal microbiome, as well as the inhibition of C. difficile sporulation and of clostridial toxin production. Inhibition of sporulation by fidaxomicin may reduce transmission of the infection to others by reducing shedding or spores and resultant environmental contamination. Fidaxomicin should be considered as first-line therapy for the management of CDI in patients with multiple factors cited in the literature that would place them at high risk for relapse and recurrent CDI especially in those populations that have been identified as having improved outcomes with fidaxomicin use: those receiving concomitant antibiotics, those with renal dysfunction, older individuals, and in those with malignancies.

Avbersek, J., Janezic, S., Pate, M., Rupnik, M., Zidaric, V., Logar, K. et al. (2009) Diversity of Clostridium difficile in pigs and other animals in Slovenia. Anaerobe 15: 252–255.

Conflict of interest statement Kathleen Mullane is on advisory boards for Optimer Pharmaceuticals and Merck and is involved in clinical trials for Actelion Pharmaceuticals, Astellas Pharma, Chimerix, Merck, Novartis, Optimer Pharmaceuticals, and ViroPharma.

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