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

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

Disclosures

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

In This Article

Clinical Efficacy

Evidence of the clinical efficacy and safety of fidaxomicin in patients with acute CDI was obtained from analyses of a Phase IIa trial and two Phase III trials conducted in both Europe and North America.[45,47,48]

Phase III Study

Louie et al.[45] conducted a randomized, open-label study of the safety and efficacy of fidaxomicin in patients with mild-to-moderately severe CDI. Adults with three or more diarrheal stools (defined as liquid or unformed) per day or six or more diarrheal stools in a 36-hour period and a positive result for C. difficile toxin by enzyme immunoassay or cell cytotoxicity assay who had been treated with metronidazole or vancomycin for less than 24 hours were eligible for enrollment. Only patients with a primary episode or first relapse of CDI were considered for enrollment. Patients with more than 12 diarrheal bowel movements per day, vomiting, ileus, severe abdominal tenderness, a white blood cell (WBC) count of >30 × 109 cells/L, toxic megacolon, or concern about life-threatening CDI were excluded, as were patients who were not expected to survive the duration of the study period, who experienced more than one relapse or recurrence within three months, who required concurrent antibiotic therapy, or who were diagnosed with Crohn's disease or ulcerative colitis. Forty-eight patients were randomized to receive 50 mg (n = 16), 100 mg (n = 16), or 200 mg (n = 16) of oral fidaxomicin twice daily for 10 days and were monitored for six weeks after treatment for CDI relapse or recurrence.

The primary outcome variables were clinical cure or failure, time to resolution of diarrhea, and total relief of CDI symptoms. Clinical cure was defined as the patient requiring no additional therapy for CDI and resolution of diarrhea (conversion of three or more liquid or unformed stools per day to no more than two semiformed or formed stools per day) and abdominal pain during the 10-day treatment period. Clinical failure was defined as the need for additional therapy during the 10-day study period. The time to resolution of diarrhea was defined as the number of days from treatment initiation to the day of resolution of diarrhea (one or two formed stools [defined as not watery or loose] within a 24-hour period) and lasting up to day 10. Total relief of CDI symptoms was defined as no more than three bowel movements per day (whether solid, semiformed, or liquid) without any signs or symptoms of CDI (e.g., fever ≥ 37.7 °C, abdominal pain, elevated WBC count) by day 10. CDI recurrence, a secondary outcome variable, was regarded as three or more unformed stools (loose or watery) and a positive stool result for C. difficile toxin A or B within six weeks after treatment completion.

Although 48 patients were randomized to receive fidaxomicin, the clinical outcomes were evaluable for only 14, 15, and 16 patients in the 100−, 200−, and 400-mg/day groups, respectively. Clinical cure rates in the 100-, 200-, and 400-mg/day groups were 71%, 80%, and 94%, respectively, on day 10. There was no significant difference in the time to resolution of diarrhea among groups, with a mean ± S.D. time to resolution of diarrhea of 6.3 ± 3.7, 4.8 ± 3.6, and 3.6 ± 2.0 days in the 100−, 200−, and 400-mg/day groups, respectively. The rates of clinical failure were similar among treatment groups (8.3% [n = 1], 0%, and 6.3% [n = 1] in the 100-, 200-, and 400-mg/day groups, respectively). Total relief of CDI symptoms was dose related and occurred more frequently in the 400-mg/day group (13 of 15 [87%]) compared with 38% (6 of 16) and 50% (8 of 16) in the 100− and 200-mg/day groups, respectively.

Two patients experienced CDI recurrence (1 patient each in the 100− and 400-mg/day groups). Typing and susceptibility results of bacterial isolates from stool samples revealed that 42% of patients had the epidemic NAP1/BI/027 strain of C. difficile. Fidaxomicin appeared to be well tolerated, as no adverse effects relating to the drug were reported in this trial. Because the 400-mg/day dose was associated with the highest cure rate, this dose was used in Phase III clinical trials.

Phase III Trials

Two randomized, double-blind, Phase III trials with identical protocols comparing the safety and efficacy of fidaxomicin with vancomycin for the treatment of acute CDI have been conducted.[47,48] Louie et al.[48] recently reported the results of a prospective, multicenter, double-blind, randomized, parallel-group trial. A total of 629 patients were enrolled from 52 sites within the United States and from 15 sites in Canada. Patients age 16 years or older with a diagnosis of CDI were eligible for enrollment. CDI was defined as the presence of diarrhea (more than three unformed bowel movements in the 24 hours before randomization) and a positive test result for C. difficile toxin A or B or both 48 hours before randomization. Patients were still eligible for enrollment if they had received up to four doses of either vancomycin or metronidazole in the 24 hours before randomization. Subjects with life-threatening or fulminant CDI, toxic megacolon, more than one occurrence of CDI within the three months before randomization, ulcerative colitis or Crohn's disease, or prior exposure to fidaxomicin were excluded. Patients were randomized to either oral fidaxomicin 200 mg twice daily or oral vancomycin 125 mg four times daily for 10 days.

The primary endpoint was clinical cure, defined as three or fewer unformed stools for two consecutive days maintained for the duration of therapy, with no further need for CDI therapy as of the second day after treatment completion (Table 3). Patients who had obtained clinical cure were followed for four weeks to assess secondary endpoints (recurrent CDI and global cure). Recurrent CDI was defined as more than three diarrheal stools in 24 hours within four weeks after treatment completion, a positive stool test result for toxin A or B or both, and the need for additional CDI treatment. Global cure was defined as resolution of CDI without recurrence.

Baseline demographics and characteristics were similar among the treatment groups, with a mean ± S.D. age of 60.3 ± 16.9 and 62.9 ± 16.9 years, respectively. The majority of patients (59.4%) were hospitalized at the time of study enrollment. Fewer than 20% of patients had a previous episode of CDI (16.7% and 17.5% of patients in the fidaxomicin and vancomycin groups, respectively). Isolation of the NAP1/BI/027 strain was comparable between the fidaxomicin (37.5%) and vancomycin (38.6%) groups.

Analysis of the clinical cure rate found no significant difference between the fidaxomicin and vancomycin groups using the modified intent-to-treat (mITT) (88.7% versus 85.8%) and per-protocol (92.1% versus 89.8%) analyses. An analysis of the rate of clinical cure among subgroups (i.e., age, hospital status, previous episode of CDI, treatment for current episode of CDI in previous 24 hours, severity of disease, strain type, lack of response to metronidazole before study, and concomitant systemic antimicrobial therapy) found no significant difference between the vancomycin and fidaxomicin groups in the mITT and per-protocol populations. An association between fidaxomicin and lower rates of recurrence was found in the mITT and per-protocol populations when the analysis was performed among the subgroups. The rate of recurrence was similar among patients with the NAP1/BI/027 strain in both the fidaxomicin and vancomycin groups (24.4% versus 23.6% in the per-protocol group, p = 0.93; 27.1% versus 20.9% in the mITT group, p = 0.42). However, the rate of recurrence was significantly lower among patients with other C. difficile strains in the fidaxomicin group (7.8% in the per-protocol group and 10.3% in the mITT group) compared with patients in the vancomycin group (25.5% in the per-protocol group and 28.1% in the mITT group) (p < 0.001 for both comparisons). There was no significant difference between the vancomycin and fidaxomicin groups in global cure in the mITT analysis (64.1% versus 74.6%, p = 0.006) or in the per-protocol analysis (67.1% versus 77.7%, p = 0.006).

Crook et al.[47] recently reported results similar to those of Louie et al.[48] A total of 100 clinical sites (39 in Europe, 30 in the United States, and 31 in Canada) participated in the trial. Adult patients were eligible for trial inclusion if they had a positive result from a stool toxin test and acute CDI symptoms. Patients were given fidaxomicin (200 mg twice daily) or vancomycin (125 mg four times daily) orally for 10 days. Of the 535 patients who received treatment, 509 were evaluable for the mITT analysis, 451 for the per-protocol analysis, and 524 for the safety analyses. The primary endpoint was clinical cure (i.e., the resolution of symptoms and no further need for CDI therapy). Secondary endpoints were CDI recurrence (diarrhea and positive result of a stool toxin test within four weeks after treatment) and global cure (clinical cure with no recurrence).

Fidaxomicin and vancomycin were associated with similar clinical cure rates (91.7% and 90.6%, respectively, in the per-protocol analysis). As did Louie et al.,[48] Crook et al.[47] reported that treatment with fidaxomicin resulted in fewer recurrences of CDI caused by the non-NAP/BI/027 strain than did treatment with vancomycin (12.8% versus 25.3%, respectively, in the per-protocol analysis, p = 0.002).

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