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1st Department of Internal Medicine, Clinical Trials Centre Cologne (ZKS Köln, BMBF 01KN1106), Center for Integrated Oncology CIO Köln Bonn, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and German Centre for Infection Research, University of Cologne, Cologne, Germany
Until recently, treatment of Clostridium difficile infection (CDI) was mainly limited to oral metronidazole and vancomycin, neither of which is optimal. Up to 25% of patients with CDI experience recurrence of infection within 30 days following treatment with these agents, while c. 45-65% of these patients experience further (and sometimes multiple) recurrences. Recurrent CDI represents a major treatment challenge for which new therapeutic options are sorely needed. Fidaxomicin is a first-in-class, oral macrocyclic antibiotic with targeted bactericidal activity against C. difficile and minimal effect on the constituents of the normal colonic microflora. This microflora-sparing activity allows for more rapid restoration of the normal colonic microflora in patients with CDI. In two separate, but almost identical, phase 3 clinical trials in which patients with CDI were treated with either fidaxomicin or vancomycin, fidaxomicin demonstrated superior clinical outcomes in comparison with the current best available treatment. While non-inferiority was demonstrated with respect to rates of clinical cure at end of treatment, significantly fewer fidaxomicin-treated patients experienced disease recurrence, which translated into clinically significant improvements in sustained clinical cure. Subsequent sub-population analyses suggest that these benefits extend to older patients, patients with severe CDI, renally impaired patients and patients with a prior episode of CDI. For CDI patients receiving concomitant antibiotics, fidaxomicin achieved significantly better rates of clinical cure and sustained clinical cure than vancomycin recipients. Fidaxomicin has a safety profile similar to oral vancomycin and appears generally well tolerated. Fidaxomicin represents an important addition to current treatment options for CDI.
In patients with Clostridium difficile infection (CDI), the aim of treatment is to achieve rapid resolution of symptoms together with restoration of the normal colonic microflora and normalization of bowel function. Cessation of the antibacterial therapy associated with the onset of CDI is usually the first step and may be effective in a minority of patients [
]. However, this approach is feasible for only a small number of patients with very mild disease who do not need to continue taking antibiotic therapy for a concurrent systemic infection. In addition, because it is difficult to predict which patients will clear the infection spontaneously following cessation of antibiotic therapy, and because delays to treatment may result in clinical deterioration, most patients with CDI need specific antibacterial therapy to treat C. difficile.
Although there have been attempts to develop non-antibacterial therapies for CDI, none has yet demonstrated superior clinical effectiveness [
]. Today, we are still essentially dependent on two antibiotics (metronidazole and vancomycin) for the treatment of CDI. However, there are shortcomings with both agents and, consequently, a need exists for new, more effective CDI therapies that will not only treat an initial episode of the disease but, more importantly, reduce the risk of recurrence.
Of the new and emerging treatment options for the management of CDI, several of which are listed in Table 1 from reviews on the topic [
In use for more than 30 years, oral metronidazole and oral vancomycin continue to underpin the treatment of CDI. Both antibiotics show similar rates of clinical cure in patients with initial or recurrent mild-to-moderate CDI, while higher cure rates have been reported with vancomycin in patients with initial or recurrent severe CDI [
]. Current guidelines from the European Society for Clinical Microbiology and Infectious Diseases (ESCMID) reflect these differences, with oral metronidazole being recommended for patients with non-severe CDI and oral vancomycin for severe CDI [
]. For patients who experience second and subsequent recurrences of CDI (i.e. a third episode and beyond), ESCMID recommends treatment with vancomycin for a severe first recurrence with the option of using tapered or pulsed (intermittent) dosing regimens. The aim of tapered or pulsed therapy is to eradicate any vegetative C. difficile cells that have germinated from spores since the last antibiotic exposure [
]. Despite these varied treatment regimens, significant numbers of patients experience recurrent CDI, including multiple recurrences, following treatment with either metronidazole or vancomycin. In fact, ESCMID has identified recurrent CDI as the biggest treatment challenge we face today in managing patients with CDI [
Shortcomings of Current Antibacterial Therapy for CDI
Failure to prevent CDI from recurring following successful treatment of an initial episode is common with both metronidazole and vancomycin. Up to 25% of CDI patients experience recurrent CDI within 30 days following treatment with these antibiotics [
]. At the same time, there has been growing concern about the declining efficacy of metronidazole. A review of studies published between 1966 and 2005 showed that rates of treatment failure increased dramatically from about 3% before 2000 to an average of 18% (range 16–38%) from 2000 onwards [
]. It is possible that reduced susceptibility and the poor pharmacokinetic properties of oral metronidazole, which result in very low intracolonic drug levels, may together account for rising rates of treatment failures [
]. In this hospital-based, cohort study, mortality within 30 days of the start of treatment was significantly higher in the intravenous metronidazole arm compared with patients on oral metronidazole or oral vancomycin (38.1% vs. 7.4% and 9.5%, respectively, p <0.001) [
]). However, fusidic acid is considered less effective than oral metronidazole or vancomycin, while concerns have been raised about the development of resistance to rifaximin among strains of C. difficile [
]. Recent data suggest that resistance to rifaximin, an antibiotic commonly used in some European hospitals for CDI, may be as high as 26% for isolates of the hypervirulent 027 ribotype of C. difficile [
Recurrent CDI can be due to either a relapse of the original infection or to re-infection with a different strain of CDI. Certain patients appear to be at increased risk of recurrent CDI, including those who are immunocompromised [
], those who are renally impaired (Bauer et al., 2011, 21st European Congress of Clinical Microbiology and Infectious Diseases (ECCMID)/27th International Congress of Chemotherapy (ICC), Abstract LB2771) and those aged 65 years and older [
Current antibiotics for CDI have several limitations, chief of which is unacceptably high rates of disease recurrence. New treatments that significantly reduce recurrence rates would represent an important therapeutic advance for patients with CDI.
Fidaxomicin as a New Treatment Option for CDI
Among antibiotics in development for CDI, fidaxomicin has attracted particular interest. The first member of a new class of antibiotics called macrocycles, fidaxomicin has a number of properties that appear ideally suited to the treatment of CDI. Unlike current antibiotics used for CDI, fidaxomicin displays targeted bactericidal activity against C. difficile [
]. This microflora-sparing activity may allow for more rapid restoration of the commensal microflora in the colon of patients with CDI and may reduce the risk of further colonization and overgrowth with C. difficile [
]. This means it has potential to maintain antibacterial activity to a certain degree even when the concentration has fallen below the minimum inhibitory concentration. This could be beneficial in CDI, a disease in which rapid intestinal transit due to diarrhoea may hasten faecal drug elimination.
Fidaxomicin inhibits RNA polymerase activity of Gram-positive bacteria at a very early stage of transcription [
]. Because it blocks gene transcription it has potential to inhibit the expression of genes responsible for sporulation and toxin production. Studies have shown that fidaxomicin (and its active metabolite) inhibits C. difficile sporulation, in contrast to vancomycin, metronidazole and rifaximin, which have no inhibitory effect on the sporulation process (Gomez et al., Interscience Conference on Antimicrobial Agents and Chemotherapy, 2011, Abstract CI-632). Fidaxomicin also inhibits C. difficile toxin production (Sims et al., Interscience Conference on Antimicrobial Agents and Chemotherapy, 2011, Abstract CI-634).
Although there is debate surrounding the relative importance of metronidazole and vancomycin in promoting acquisition of vancomycin-resistant enterococci (VRE) [
], antibiotics with reduced likelihood of promoting VRE may be beneficial. Compared with vancomycin, fidaxomicin demonstrated a significantly lower risk of acquisition of VRE among CDI patients with negative VRE stool samples at enrolment in the phase 3 registration trials [
The antibacterial properties of fidaxomicin are complemented by pharmacokinetic properties that are suited to treatment of an infection localized to the gut. These include very low systemic absorption following oral administration and correspondingly high intracolonic concentrations and an attendant low risk of systemic adverse effects [
]. In two separate, but almost identical, randomized, double-blind trials, in which patients with confirmed CDI received either 200 mg oral fidaxomicin twice daily or 125 mg oral vancomycin four times daily for 10 days, rates of clinical cure in both the modified intent-to-treat (mITT) and per protocol (PP) populations were similar at end of therapy in both treatment arms (Fig. 1). Time to resolution of diarrhoea was also similar in both treatment arms. The trials thus met the primary efficacy endpoint of non-inferiority to vancomycin in clinical cure at end of treatment in both analysis populations. However, fidaxomicin achieved significantly lower rates of recurrence of CDI (no recurrence within 30 days of cessation of therapy) compared with vancomycin. In the mITT and PP populations of the North American trial (study 003), the reduction in recurrence achieved with fidaxomicin compared with vancomycin was 9.9% (p 0.005) and 10.7% (p 0.004), respectively [
]. This led to significantly higher rates of sustained clinical cure, defined as clinical cure without recurrence of diarrhoea during the 30-day follow-up period, in the fidaxomicin vs. the vancomycin treatment arms (Fig. 2). Across the two trials, 75.5% and 78.6% of fidaxomicin-treated patients in the mITT and PP populations, respectively, achieved a sustained clinical cure compared with 63.8% and 66.4% of vancomycin recipients, respectively [
]. Based on an intent-to-treat (ITT) analysis of pooled data, the post-hoc, exploratory time-to-event investigation showed that in comparison with oral vancomycin, treatment with fidaxomicin was associated with an overall 40% reduction in persistent diarrhoea, recurrence of CDI or death during the 40-day follow-up period (p <0.0001) [
]. Thus, as the authors of this study concluded, fidaxomicin has the potential to greatly improve outcome in patients with CDI of mild-to-moderate severity.
Fidaxomicin: Efficacy in Patients at Increased Risk of CDI Recurrence
Within the CDI population, certain patients are at increased risk of recurrence. To this end, separate, prespecified efficacy analyses were carried out on key subgroups within the population of patients enrolled in the fidaxomicin phase 3 registration trials. These subgroups included older patients, those with severe CDI, patients infected with the hypervirulent 027 strain of C. difficile, patients receiving concomitant antibiotic therapy, patients who had experienced a prior episode of CDI and patients with renal impairment. Table 2 summarizes rates of CDI recurrence by treatment arm and subgroup in the North American trial (study 003) [
Among the older cohort of patients enrolled in the two trials, almost a third of whom were aged 75 years or older, rates of clinical cure were similar between treatment arms. However, and consistent with the results for the whole study population, significantly lower rates of recurrence and superior rates of sustained clinical cure were seen in the fidaxomicin treatment arm in the older age groups. Similar results were seen with respect to the subgroup of patients with severe CDI, broadly defined in relation to current ESCMID severity criteria [
]. Again, treatment with fidaxomicin provided comparable efficacy to vancomycin but with the added benefit of a lower risk of disease recurrence and a corresponding, superior sustained clinical response [
Across the two trials, approximately one-third of patients were infected with the hypervirulent 027 strain of C. difficile, with most cases arising in North America rather than in Europe where prevalence of the 027 ribotype appears lower. A comparison of outcomes based on pooled data from the two treatment arms showed no significant difference in clinical cure rates, suggesting that fidaxomicin is as effective as vancomycin in these more difficult-to-treat patients. There was no significant difference in recurrence rates between treatments in patients with infections due to the hypervirulent 027 strain of C. difficile; however, in the non-027 group recurrence rates were significantly lower in fidaxomicin-treated patients compared with vancomycin recipients (8.4% vs. 25.3%, respectively; p <0.001) [
]. Of the 128 patients from the two trials who were evaluable for a second recurrence (third episode), 22 vancomycin-treated patients (35.5%) experienced a further recurrence within 30 days compared with 13 (19.7%) of those treated with fidaxomicin (p 0.045).
Clostridium difficile infection typically occurs in hospitalized patients who have been treated with broad-spectrum antibiotics and yet for many of these patients discontinuing antibiotic therapy is not an option. In the phase 3 trials, 275 (27.5%) patients in total received concomitant antibacterial therapy for other infections during the 10-day course of treatment for CDI or in the 30-day follow-up period. In patients receiving concomitant antibacterial therapy, rates of clinical cure based on pooled data were significantly higher in patients treated with fidaxomicin compared with vancomycin recipients (90.0% vs. 79.4%, respectively; p 0.04) and rates of recurrence based on pooled data were significantly lower (16.9% vs. 29.2%, respectively; p 0.048) [
]. In the phase 3 trials, 57% of patients had abnormal renal function at baseline, of which almost a third had moderate-to-severe renal impairment. Consistent with results for the study population as a whole, rates of clinical cure were similar in the two treatment arms for each level of renal impairment, albeit lower in patients with severe renal impairment. Treatment with fidaxomicin was, however, superior in reducing the risk of CDI recurrence at all levels of renal function (p <0.05). In patients with normal renal function there was an absolute 10% difference in recurrence rates between fidaxomicin and vancomycin (11% vs. 21%, respectively) but this increased to 21% in patients with severe renal impairment (15% vs. 35%, respectively; Mullane et al., Annual Congress of the Infectious Diseases Society of America, 2011, Abstract), suggesting that fidaxomicin may be of particular benefit in this vulnerable patient subgroup.
Although a broad spectrum of CDI patients were enrolled in the fidaxomicin clinical trial programme, thus reflecting many patients seen in routine clinical practice, patients with CDI concurrent with inflammatory bowel disease or those with life-threatening or fulminant CDI (including toxic mega-colon) were not eligible for inclusion in the trials [9, supplement to 30]. Patients with extremely severe CDI may have paralytic ileus and there is no consensus on how best to treat such cases [
]. As an orally administered antibiotic, fidaxomicin is not suitable for CDI patients who need parenteral therapy. In addition, only adult patients were enrolled in the phase 3 trials of fidaxomicin and data are not therefore available on the use of fidaxomicin in paediatric patients, while only limited data are available to date on its use in immunosuppressed patients.
Safety and Tolerability Profiles of Metronidazole, Vancomycin and Fidaxomicin
With respect to the safety and tolerability of antibiotics used in the treatment of CDI, oral vancomycin is considered to have an improved side-effect profile compared with metronidazole, which derives from differences in their pharmacokinetics [
]. Oral vancomycin is not absorbed and serum levels are correspondingly very low. Oral metronidazole is almost completely absorbed even in the presence of diarrhoea and is completely absorbed in the normal gut [
] and is similar to oral vancomycin in this respect. Thus, it would be expected to have a generally similar tolerability profile and this is borne out in practice. In its phase 3 clinical trials, rates of treatment-emergent adverse events (TEAEs), study drug-related TEAEs, serious TEAEs and all-cause mortality were generally similar for fidaxomicin and vancomycin (Table 3).
TABLE 3.Frequency of treatment-emergent adverse events in patients treated with fidaxomicin or vancomycin in the phase 3 trials (pooled data)
Investigational Approaches for CDI and Recurrent CDI
Fidaxomicin represents an important addition to current treatment options for CDI and should help in the management of patients at increased risk of recurrent disease. Among other approaches being investigated with potential to address current treatment gaps two non-antibiotic therapies are of interest: faecal microbiota transplantation (FMT) and immunotherapy with specific anti-toxin antibodies to C. difficile. Both are designed to enhance host protection against CDI, the first by restoring colonization resistance and the second by supplementing deficiencies in the patient's adaptive immune response to C. difficile.
Most evidence for the benefit of FMT, in which donor faeces from a healthy individual are transplanted into the colon of a CDI patient, as a treatment for multiple-recurrent CDI has come from single-centre case series and case studies and is based on small numbers of patients [
]. However, a recent report from a multicentre, long-term follow-up study in a much larger number of patients (n = 77) who received FMT for refractory CDI has also shown encouraging results, with 74% of patients experiencing a resolution of diarrhoea within 3 days of treatment [
]. Given practical considerations related to material preparation and administration of donor faeces, as well as aesthetic concerns and potential risks of transmitting pathogens, for the time being FMT is likely to remain a reserve therapy for patients who experience multiple recurrences and for whom other treatments have failed.
Failure to mount an effective immunoglobulin (Ig)G-mediated antibody response to C. difficile toxins differentiates patients with CDI from those asymptomatically colonized with C. difficile [
]. Passive immunotherapy, in which patients receive an infusion of antibodies specific to C. difficile toxins, aims to aid patients who have failed to increase their adaptive immune response to C. difficile toxins. Although data are still limited, a phase 2 trial of infused human monoclonal antibodies against C. difficile toxins A and B suggests they may have protective efficacy and help reduce the frequency of recurrence when given as an adjunct to conventional antibiotic therapy [
]. In a trial involving 200 patients with CDI, a substantial reduction in recurrence was observed in patients who received neutralizing anti-toxin monoclonal antibody therapy in addition to metronidazole or vancomycin compared with those who received conventional antibiotic therapy alone (7% vs. 25%, respectively; p <0.001) [
FMT and passive immunotherapy are still investigational therapies and common to both is a need for large-scale randomized controlled trials to comprehensively evaluate their efficacy and safety. Following successful completion of the phase 2 trial of passive immunotherapy (NCT00350298) [
], patients are now being recruited for phase 3 trials (MODIFY I [NCT01241552]; MODIFY II [NCT01513239]), which are designed to investigate whether passive immunotherapy in addition to standard of care antibiotic therapy will decrease CDI recurrence.
How will New Treatments Alleviate the Burden of CDI?
Although most patients with CDI respond to an initial 10-day course of either oral metronidazole or vancomycin, when used again for recurrent CDI these treatments tend to fail repeatedly because they do not help restore normal colonization resistance [
]. In fact, prolonged use of antibiotics to treat recurrent CDI probably contributes to continued disturbance of the normal colonic microflora and further delays the re-establishment of colonization resistance [
At present there is uncertainty about how best to treat patients with recurrent CDI and especially those who experience multiple recurrences. Data presented here suggest that by reducing the risk of recurrence following either a first episode or first recurrence (second episode), use of fidaxomicin may help address this problem and improve outcomes in patients with CDI in comparison with vancomycin. Reducing the risk of CDI recurrence has the potential to be of benefit not only to patients in terms of reduced morbidity and mortality, with concomitant improvements in quality of life, but also to the healthcare system by eliminating the costs of treating additional episodes of CDI and the need for prolonged patient isolation, as well as reducing the risk of person-to-person transmission.
In current treatment guidelines for CDI, choice of first-line therapy is governed by disease severity, which ESCMID defines as an episode of CDI accompanied by one or more signs of severe colitis [
]. These include fever, rigors, haemodynamic instability, marked leucocytosis, elevated serum creatinine or lactate, pseudomembranous colitis, intestinal distension, colonic wall thickening, pericolonic fat stranding and ascites not attributable to any other cause [
]. With the approval of new antibiotics, such as fidaxomicin, and other non-antibiotic treatments on the horizon, future guidelines will likely give equal emphasis to reducing the risk of CDI recurrence in treatment decisions, especially in those subgroups that are at greatest risk of experiencing recurrence.
The author wishes to thank Elements Communications Ltd (Westerham, UK) for medical writing assistance, funded by Astellas Pharma Europe Ltd (Staines, UK).
The development of the content and the printing of this supplement has been funded by Astellas Pharma Europe Ltd. This supplement was created in collaboration with the faculty from the Astellas-sponsored symposium at the 2012 ECCMID Congress.
Oliver A Cornely is supported by the German Federal Ministry of Research and Education (BMBF grant 01KN1106). Oliver A Cornely has received grant/research support from Actelion, Astellas, Basilea, Bayer, BioCryst, Celgene, F2G, Genzyme, Gilead, Merck/Schering, Miltenyi, Optimer, Pfizer, Quintiles and ViroPharma. Oliver A Cornely has worked as a consultant for Astellas, Basilea, F2G, Gilead, Merck/Schering, Optimer, Pfizer and Sanofi Pasteur and has participated in speakers' bureaux for Astellas, Gilead, Merck/Schering and Pfizer.
The case for vancomycin as the preferred drug for treatment of Clostridium difficile infection.