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Fidaxomicin: Cost Considerations for the Treatment of Clostridium difficile Infection
By Jessica C. Song, MA, PharmD, Assistant Professor, Pharmacy Practice, University of the Pacific, Stockton, CA; Pharmacy Clerkship and Coordinator, Santa Clara Valley Medical Center, is Associate Editor for Infectious Disease Alert.
Paul Hsiao, PharmD, Pharmacist Specialist, Santa Clara Valley Medical Center.
Stephanie Tran, PharmD, PGY1 Pharmacy Resident, Santa Clara Valley Medical Center.
Drs. Song, Hsiao, and Tran report no financial relationship to this field of study.
Clostridium difficile infection (CDI) is a serious medical condition associated with significant morbidity and mortality. Thirty-day mortality rates associated with CDI have been estimated to be anywhere from 6.0% to 32.5%, with higher mortality rates observed in older patients.1,2 Rates of CDI have increased worldwide over the past decade, with an estimated 500,000 cases in U.S. hospitals and nursing homes per year.3 Recent outbreaks of more aggressive CDI have been temporally associated with a hypervirulent strain of Clostridium difficile, known as North American pulsed-field gel electrophoresis type 1, restriction endonuclease analysis group B1, PCR ribotype 027 (NAP1/BI/027). This strain has been shown to exhibit greater spore-forming capabilities, heightened toxin production, and higher rates of failure with metronidazole treatment compared with other strains.4
New clinical practice guidelines for CDI were recently developed by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA).5 The working group recommended the use of oral metronidazole 500 mg three times a day for mild-to-moderate cases of CDI. Oral vancomycin 125 mg four times a day was recommended for severe cases of CDI. Complicated cases of CDI merited a higher dose of vancomycin (500 mg orally four times a day), either as monotherapy or in combination with intravenous (IV) metronidazole 500 mg every 8 hours. The same regimen that was used for the initial infection could be used for first recurrences, provided that disease severity is taken into account. Tapered and/or pulsed-dose vancomycin regimens should be considered for infections beyond the first recurrence.
At present, alternative treatment options for primary and recurrent infection in the United States are limited. Small case series and studies have featured the use of alternative agents such as rifaximin,6,7 nitazoxanide,8 and tigecycline9 in patients with recurrent infections. Fidaxomicin, an 18-membered macrocyclic antibiotic with activity against Gram-positive anaerobes and aerobes, was recently granted FDA approval for the indication of CDI, making it the second FDA-approved agent (after vancomycin) for this indication.10
Given the economic downturn in recent years, institutions have been under greater scrutiny with regard to selection of antimicrobial agents for formulary inclusion. The purpose of this review is to discuss clinical and cost considerations of drugs used for the treatment of patients with primary and recurrent CDI.
Average Wholesale Pricing and Clinical Efficacy Data
Metronidazole, the first-line agent for mild-to-moderate CDI, is available as a generic tablet, priced at $0.07 per tablet. A 10-day treatment course would cost $2.10. Because of its higher acquisition cost and the concern for selecting vancomycin-resistant bacteria in hospitals, oral vancomycin therapy is usually reserved for use in patients with severe or complicated cases of CDI. The costs of the 125 mg and 250 mg capsule formulations (Vancocin®) are $26.52 and $48.93, respectively. A 10-day treatment course would cost $1061 and $3914, respectively. At Santa Clara Valley Medical Center (San Jose, CA), prior to oral administration, vancomycin IV is diluted with 10 mL of normal saline. Since one 500 mg vial costs $2.21, the cost of a 10-day course of therapy for complicated CDI would approach $88 for hospitalized patients. With the addition of IV metronidazole (500 mg IV every 8 hours), the cost would increase by $34, assuming that the IV piggyback formulation is used for treatment.
To date, the safety and efficacy of fidaxomicin has mainly been established in patients with mild-to-moderate primary CDI.11 Louie and associates conducted a prospective, multicenter, double-blind, randomized, parallel group trial that included 629 patients with CDI.11 The rate of clinical cure in the modified intention-to-treat and per-protocol populations upon completion of treatment or at the time of discontinuing participation in the study was the primary efficacy outcome measure. Patients underwent randomization to receive oral vancomycin (125 mg four times a day) or fidaxomicin (200 mg twice daily by mouth) for 10 days. Approximately 83% of patients in the modified intention-to-treat and per-protocol populations did not have a previous CDI episode. The proportions of patients diagnosed with mild-to-moderate CDI ranged from 59% to 62% in the modified intention-to-treat and per-protocol populations. The proportions of patients displaying strain type NAP1/BI/027 ranged from 35.3% to 38.6% in the modified intention-to-treat and per-protocol populations. Clinical cure rates seen in fidaxomicin-treated patients were non-inferior to those who received vancomycin in both the modified intent-to-treat analysis (88.2% with fidaxomicin and 85.8% with vancomycin, respectively) and the per-protocol analysis (92.1% and 89.8%, respectively).
Of note, a secondary outcome measure, recurrence of CDI during the 28-day period following the end of the 10-day treatment course, was assessed in the study conducted by Louie and colleagues.11 Fidaxomicin-treated patients were less likely to experience infection recurrence than vancomycin-treated patients in both the modified intention-to-treat population (15.4% vs. 25.3%; P = 0.005) and the per-protocol population (13.3% vs. 24.0%; P = 0.004). However, recurrence rates did not differ significantly between fidaxomicin-treated patients and vancomycin-treated patients with the NAP1/BI/027 strain.
A 10-day course of fidaxomicin (200 mg twice daily by mouth) costs $2,800, since one 200 mg tablet costs $140. The use of fidaxomicin in patients with two or more recurrences of CDI has not been established, and this drug has not been compared to other drug regimens such as oral/IV metronidazole or to tapered and/or pulsed-dose vancomycin.
Rifaximin, a non-systemic, rifamycin-derived antibiotic, exerts its in vitro bactericidal activity against Clostridium difficile through inhibiting bacterial RNA synthesis.6 In addition to case reports of its success in the treatment of patients with recurrent CDI, four small studies (n = 6-25) of patients with CDI treated with rifaximin support its clinical use.7 Tannous et al reported a case of a patient with recurrent CDI who had previously received: 1) two 14-day courses of metronidazole 500 mg three times daily by mouth; 2) a 2-week course of vancomycin 125 mg four times daily by mouth; and 3) tapered oral vancomycin: 125 mg four times daily for 1 week, 125 mg three times daily for 1 week, 125 mg once daily for 1 week, 125 mg every other day for 1 week, then 125 mg every third day for 1 week.6 The patient received rifaximin 400 mg three times daily for 28 days and showed sustained response to therapy (no further episodes of diarrhea) within 6 months after completion of therapy. A single 200 mg tablet costs $9.13, so a 4-week course of rifaximin 1200 mg/day would cost $1,534.
Patrick-Basu and associates evaluated the efficacy of a 2-week course of rifaximin 400 mg three times daily in 25 patients with mild-to-moderate CDI unresponsive to metronidazole therapy.7 Twenty-two of the 25 recruited patients completed the 2-week treatment. At the end of treatment, 16 of the 22 patients (73%) had stool samples negative for Clostridium difficile. This response to therapy was sustained for at least 56 days post-treatment. Other smaller studies (n = 6-8) showed response rates (defined as being symptom-free or achieving complete resolution of diarrhea) ranging from 67% to 88%, with follow-up times of 54-780 days.7 Rifaximin dosing featured in the smaller studies included 400-800 mg daily for 14 days ($256-$511), and 400 mg three times daily for 14 days, followed by 200 mg three times daily for 14 days ($1,150).
Musher et al evaluated the efficacy of a 10-day course of nitazoxanide 500 mg twice daily by mouth in 35 patients with CDI recalcitrant to standard therapies (metronidazole or vancomycin).8 Nitazoxanide, a nitrothiazolide, blocks anaerobic metabolism, and has been shown to inhibit Clostridium difficile (in vitro studies). Twenty-eight patients had previously received a minimum of 14 days of metronidazole 500 mg three times daily and 7 patients had at least two recurrences despite receiving appropriate therapy (two courses of metronidazole or vancomycin). Twenty-six of the 35 patients (74%) responded to nitazoxanide, but recurrences occurred in 7 of the 26 patients within a mean of 12.1 (range 7-24) days. Three of the 9 patients who initially failed nitazoxanide therapy and 1 patient with recurrent CDI responded to a second course of nitazoxanide. Since one nitazoxanide tablet costs $20.60, the cost of a 10-day treatment course is $412.
Tigecycline, an analog of minocycline, has demonstrated activity against Clostridium difficile in numerous in vitro studies.9 Larson and associates recently reviewed 7 cases of patients with CDI who received this broad spectrum antibiotic as monotherapy or in combination with other drugs.9 Six of the 7 patients received tigecycline after failing to respond to treatment with metronidazole, vancomycin, or to the combination of metronidazole and vancomycin. Three patients received tigecycline alone and the other patients received it in combination with other agents such as vancomycin, metronidazole, and/or IVIG. Treatment duration ranged from 14 to 24 days for patients who received tigecycline monotherapy. One patient with septic shock and acute respiratory distress syndrome received a 7-day course of tigecycline as primary therapy, followed by a 4-week course of oral vancomycin. Six of the 7 patients achieved treatment success with tigecycline that was sustained for at least 3 months. One patient discontinued tigecycline therapy because of worsening hepatic function and eventually died of multiple organ failure and refractory septic shock. A single 50 mg IV tigecycline vial costs $65.53, so a 2-week course of tigecyline 50 mg IV given twice a day would cost $1,835.
CDI has been a major cause of hospital infections for the past few decades, with increasing rates noted over the past decade. Moreover, CDI has become more problematic in recent years, given the emergence of hypervirulent strains that are well-adapted to health care settings. At present, vancomycin and fidaxomicin are FDA-approved for use in the treatment of patients with CDI. Metronidazole, because of its low cost, is the first-line therapeutic option for patients with mild-to-moderate CDI. However, recurrence rates associated with metronidazole and vancomycin treatment regimens, the current standards of care, have been increasing over the past decade. Some alternative therapeutic strategies have demonstrated encouraging results in the treatment of CDI, but these agents are considerably more expensive than metronidazole. Providers should consider the acquisition costs of treatment options and the potential for reducing the frequency of recurrences, along with the development of complicated disease when selecting appropriate agents for treating patients with CDI.