PharmacoEconomics DOI 10.1007/s40273-014-0161-y

REVIEW ARTICLE

A Review of the Economics of Treating Clostridium difficile Infection Kari A. Mergenhagen • Amy L. Wojciechowski Joseph A. Paladino

•

Ó Springer International Publishing Switzerland (outside the USA) 2014

Abstract Clostridium difficile infection (CDI) is a costly result of antibiotic use, responsible for an estimated 14,000 deaths annually in the USA according to the Centers for Disease Control and Prevention. Annual costs attributable to CDI are in excess of $US1 billion. This review summarizes appropriate utilization of prevention and treatment methods for CDI that have the potential to reduce the economic and humanistic costs of the disease. Some cost-effective strategies to prevent CDI include screening and isolation of hospital admissions based on C. difficile carriage to reduce transmission in the inpatient setting, and probiotics, which are potentially efficacious in preventing CDI in the appropriate patient population. The most extensively studied agents for treatment of CDI are metronidazole, vancomycin, and fidaxomicin. Most economic comparisons between metronidazole and vancomycin favor vancomycin, especially with the emergence of metronidazole-resistant C. difficile strains. Metronidazole can only be recommended for mild disease. Moderate to severe CDI should be treated with vancomycin, preferably the compounded oral solution, which provides the most cost-effective therapeutic option.

K. A. Mergenhagen
A. L. Wojciechowski (&) Veterans Affairs Western New York Healthcare System, 3495 Bailey Avenue, Buffalo, NY 14215, USA e-mail: [email protected] K. A. Mergenhagen e-mail: [email protected] J. A. Paladino University at Buffalo School of Pharmacy and Pharmaceutical Sciences, 213 Kapoor Hall, Buffalo, NY 14214, USA e-mail: [email protected] J. A. Paladino CPL Associates, LLC, Buffalo, NY 14226, USA

Fidaxomicin offers a clinically effective and potentially cost-effective alternative for treating moderate CDI in patients who do not have the NAP1/BI/027 strain of C. difficile. Probiotics and fecal microbiota transplant have variable efficacy and the US FDA does not currently regulate the content; the potential economic advantages of these treatment modalities are currently unknown.

Key Points for Decision Makers Metronidazole is the most cost-effective treatment for mild Clostridium difficile infection (CDI). Vancomycin, especially the oral compounded solution, is cost effective for moderate to severe CDI. Fidaxomicin may be considered in patients with moderate CDI in those who have C. difficile strains other than NAP1/BI/027. The cost effectiveness of unregulated products, such as probiotics and fecal microbiota transplant, are currently unknown and therefore cannot be recommended for widespread implementation at this time.

1 Introduction Clostridium difficile infection (CDI) has become an increasingly problematic adverse event associated with the systemic use of antibiotics. C. difficile is a gram-positive, spore-producing anaerobe that is transmitted via the fecal– oral route. It produces toxins A and B and a binary toxin that are the cause of colitis symptoms during CDI [1]. The

K. A. Mergenhagen et al.

US Centers for Disease Control and Prevention recently increased the threat level to urgent in their 2013 publication on antibiotic resistance, meaning that C. difficile poses an ‘‘immediate public health threat’’ [2]. CDI causes an estimated 250,000 infections and 14,000 deaths annually, representing a 400 % increase in mortality between 2000 and 2007 in the USA. Attributable costs in this country due to CDI are in excess of $US1 billion per year. Colonization with C. difficile is present in up to 3 % of healthy adults, but this number increases to 20–40 % in hospitalized patients and up to 70 % in patients chronically residing in a healthcare environment such as long-term care facilities (LTCFs) [3, 4]. Nearly half of all CDI cases occur in patients aged \65 years, but over 90 % of deaths occur in patients aged [65 years [2]. Severity of CDI can range from mild, self-limited diarrhea to fulminant pseudomembranous colitis and toxic megacolon, requiring urgent total colectomy. The cost associated with the hospitalization and management of patients with CDI places a significant burden on healthcare resources. The economics of the treatment of CDI is the focus of this review.

2 Literature Review A literature search was performed using Embase via Elsevier (1974–2013) and MEDLINE via Ovid (1946–2013) for randomized controlled trials, observational studies, systematic reviews, and meta-analyses. Keywords used were Clostridium difficile, pseudomembranous colitis, treatment, transmission, epidemiology, economic, and cost effectiveness. The search was limited to English-language publications. Articles were selected for inclusion based on their relevance to the topic of economics of treating C. difficile infection. References from the bibliographies of the selected articles were also evaluated for inclusion in this review.

3 Epidemiology C. difficile has been recognized since 1978 as a causative pathogen in many cases of antibiotic-associated diarrhea and colitis [1, 5]. Early cases of CDI were associated with clindamycin; however, since then, most other antibiotics have also been implicated in causing the disease [5]. The antibiotics most strongly associated with CDI include clindamycin, third-generation cephalosporins, and fluoroquinolones [6]. Several CDI outbreaks have been linked to previously unrecognized and emerging strains of C. difficile [7–10]. The clindamycin-resistant ‘J strain’ was associated with large outbreaks in the USA in the early 1990s [11]. More

recently over the past decade, fluoroquinolone use has been associated with an increase in a new strain known as NAP1/BI/027 [12]. This strain appears to be more virulent than others, causing more severe CDI symptoms, likely related to increased toxin production. A major outbreak in Quebec, Canada, was associated with the NAP1/BI/027 strain and was implicated in causing severe disease with higher rates of treatment failure, leading to significant rates of toxic megacolon, urgent colectomy, and death [12–14]. The two biggest risk factors for CDI are antibiotic use and hospitalization [3]. Traditionally, C. difficile was thought to spread from patient to patient in the hospital setting through contact with contaminated surfaces, or through carriage on healthcare workers’ hands, clothing, or stethoscopes [3, 15]. The non-vegetative spore form of C. difficile is highly resistant to alcohol-based hand sanitizers and thus is easily spread between patients if this method of hand-sanitization is used exclusively [16]. A prospective study from Canada found that the time to infection was double that of the colonization rate for C. difficile; for example, by day 7 of admission, 2.5 % of hospitalized patients were colonized with C. difficile, and 2.5 % of hospitalized patients had developed clinical CDI by day 14 [17]. A recent whole-genome sequencing study has challenged the traditional model of C. difficile transmission, finding that only 38 % of CDI cases had close hospital contact with another patient, and 36 % had no hospital or community contact with another patient. This study found that only 35 % of cases were genetically related to at least one prior case (defined as two or fewer single-nucleotide variants), indicating that, in a majority of cases, C. difficile is not transmitted from one patient with active CDI to the next [18]. The genetic diversity of the C. difficile seen in this study between infected patients suggests that perhaps the best way to prevent infection is to reduce each patient’s susceptibility to it, by decreasing overall antibiotic use. For example, CDI rates fell in England after the utilization of fluoroquinolones and cephalosporins decreased [18]. Other risk factors associated with CDI include advanced age, immunosuppression, gastric acid suppression, enteral tube feeding, and gastrointestinal surgery [19–23]. A recent large, prospective study found that older age and use of antibiotics and proton-pump inhibitors were significantly associated with infection. Predictors of colonization with C. difficile included hospitalization in the prior 2 months and use of chemotherapy, proton-pump inhibitors, and H2 blockers. Antibodies to toxin B were also associated with colonization [17]. Although primarily associated with nosocomial transmission, community-associated CDI has been increasingly recognized as an important source of morbidity. A recent study of community-associated CDI from 2009 to 2011 showed that 35.9 % of patients had not received antibiotics and 18.0 % had no outpatient

Treating Clostridium difficile Infection

healthcare system exposure in the previous 12 weeks, emphasizing the importance of other risk factors in the development of CDI [24].

4 Economic Impact The economic burden of CDI has been explored in several recent publications. The direct financial costs attributed to CDI include those associated with hospitalization, drug treatment, and follow-up care. The attributable cost per case of CDI in year 2008 values has been estimated to range between $US3,197 and $US11,868 [25–28]. Overall costs from these calculations estimate the total annual cost of CDI in the USA to be between $US1 billion and $US3.6 billion. These amounts are based on hospital admissions for CDI and/or increases in duration of hospitalization for patients already hospitalized. These estimates are conservative, as the reported amounts do not sufficiently reflect the full costs, including outpatient care and repeat hospitalizations [29]. The European Society of Clinical Microbiology and Infectious Diseases estimated that, in 2006, the direct cost to the EU was €3 billion per year [30]. Assuming a 3 % per year inflation rate, the cost in 2013 would be €3.7 billion per year [31]. The estimated cost per case of CDI varies significantly between different counties in Europe. Additional hospitalization costs attributed to CDI in Italian hospitals from 2009 to 2012 of €13,958 per case were estimated in one study [32]. The estimated cost in per CDIrelated hospitalization in Ireland was €2,860 in the year 2000 [33]. In Germany in 2006, CDI accounted for an additional €7,147 per hospitalization [33]. The economic considerations are different for patients residing in LTCFs or in the community who do not require hospitalization for their CDI. Dubberke et al. [34] provided

an analysis of CDI costs for LTCFs. There is often an increased need, after an episode of CDI, for additional care that can not be provided in the patient’s home, which can lead to short-term stays in skilled nursing facilities, generating an estimated $141 million annually in additional healthcare costs [34]. In addition to the direct costs of caring for patients with CDI, indirect costs include productivity losses for the patient and caregiver during the acute illness and the productivity loss related to shortened lifespan due to death from CDI. McGlone et al. [35] modeled different scenarios and found that societal costs, which took into account productivity losses, were around 40 % higher than the direct costs alone, emphasizing the need to take these costs into account when considering the overall impact of CDI. Quality of life is undoubtedly impacted for patients who have CDI. Interestingly, in a health-related quality-of-life survey by Shupo et al. [36], 54 % of participants rated moderate diarrhea associated with CDI as ‘worse than death’. It is difficult to directly measure the economic impact of reduced quality of life associated with CDI; however, both the acute and the long-term burden of CDI will have a significant impact on quality of life for patients.

5 Treatment Options Given the substantial direct and indirect costs associated with CDI, it is important to evaluate ways to decrease the economic burden of the disease. Preventative measures such as effective hand hygiene and decreasing the unnecessary use of broad-spectrum antibiotics are strategies that can reduce the incidence and costs associated with CDI [37–39]. The remainder of this paper focuses on the various available treatments to evaluate whether any offer an economic advantage over the others. Table 1 provides an

Table 1 Comparison of Clostridium difficile infection treatments Drug cost per treatment coursea

Cost per hospitalization

References

$18–25b

$16,953

[48, 66]

Vancomycin (Vancocin )

$1,400–1,950c

$14,718

Vancomycin (generic)

$480–672c

[66]

Vancomycin compounded oral solution

$23.64–33.09c

[66]

Drug Metronidazole Ò

d

[48, 66]

Fidaxomicin

$3,550

Rifaximin

$900–3,450e

[66]

Fecal transplant

$500–1,500

[68]

a

Prices based on average wholesale price

b

500 mg three times daily for 10–14 days

c

125 mg four times daily for 10–14 days

d

200 mg twice daily for 10 days

e

400 mg two to three times daily for 14–36 days

$31,539

[65, 66]

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overview of costs associated with some of the currently available treatments for CDI. 5.1 Metronidazole and Vancomycin The most common treatments for CDI, and those recommended as first line by current guidelines, are oral metronidazole and oral vancomycin [40, 41]. Although metronidazole is not officially approved by the US FDA for the treatment of CDI, it is commonly used as first-line therapy and is recommended in the Infectious Diseases Society of America (IDSA), the European Society of Clinical Microbiology and Infectious Diseases, and the American College of Gastroenterology guidelines for mild to moderate infections [40–42]. Metronidazole is chosen over vancomycin because of its low price and due to the concern for the selection of vancomycin-resistant bacteria associated with vancomycin use, although clinically both vancomycin and metronidazole have been associated with the persistent overgrowth of vancomycin-resistant enterococci when used to treat CDI [43]. Vancomycin has shown superior efficacy for moderate–severe CDI, and as such is considered the firstline choice for the more severe infections [40]. A recent meta-analysis indicates that the mean treatment failure in metronidazole patients was higher than those treated with vancomycin (22.4 vs. 14.2 %; p = 0.002) [44]. The pharmacokinetics of these antibiotics differ, which may account for the increased risk of failures with metronidazole [45]. Oral vancomycin has minimal systemic absorption, so concentrations remain high throughout the gut during therapy. Intestinal concentrations of metronidazole decline as the stool becomes more formed and colonic inflammation improves, possibly decreasing the effective concentration at the site of action against C. difficile [46]. Many studies have compared efficacy between metronidazole and vancomycin but few have examined the costs associated with these two drugs [44, 45, 47–49]. Several studies have directly evaluated the cost difference between metronidazole and vancomycin for the treatment of CDI [48–51]. Unfortunately, some of these studies are only available in abstract form. A meta-analysis by the Canadian Agency for Drugs and Technology is also reviewed. Based on drug cost alone, metronidazole is less expensive, with costs of only several dollars compared with upwards of $1,000 for a typical 10- to 14-day treatment course of oral vancomycin capsules [52, 53]. Studies by Lahue et al. [48] and Al-Eidan et al. [49] evaluate the expenditures, from an institutional perspective, and results of treatment with vancomycin compared with metronidazole, while Thomas et al. [50] provide a cost comparison between the two drugs. The severity of disease was unknown in the study by Lahue et al. [48], although 10.4 % of patients using metronidazole and 30.7 % of

patients prescribed vancomycin had a prior admission for CDI [47]. This study had a large population, with 3,420 patients receiving vancomycin and 28,905 patients receiving metronidazole. Severity of illness was only roughly assessed in the smaller study of 87 patients by AlEidan et al. [48]; 42.5 % of patients had fever and 52.9 % had leukocytosis, defined as a total white blood cell count of C12 9 109 cells/l. Severity of illness was not defined in the study by Thomas et al. [50]. Lahue et al. [48] found a significantly longer length of stay (12.8 vs. 11.5 days, p \ 0.0001) and a higher proportion of patients in the intensive care unit (ICU) (23.2 vs. 17.7 %, p \ 0.0001) in the metronidazole group. The rate of in-hospital mortality was higher in the metronidazole group (7.9 vs. 6.8 %, p \ 0.02). The total costs of CDI treatment were higher in the vancomycin-treated patients for drug costs alone. However, when the total pharmacy costs for patients with CDI were compared, metronidazole and vancomycin were similar (pharmacy cost: $2,439 vs. 2,494). The higher pharmacy costs may be attributed to a longer ICU stay in the metronidazole group (23.2 vs. 17.7 days) and overall longer length of stay in the metronidazole group (12.8 vs. 11.5 days, p \ 0.0001). The longer length of stay and time in the ICU likely also explain the higher hospitalization costs found in the metronidazole group ($16,953 vs. 14,718; p \ 0.0001) [48]. Thomas et al. [50] reported that the average cost of treatment in the vancomycin group was $910 and in the metronidazole group was $561. These costs were evaluated in a model using a resistance rate of 20 % to metronidazole. While this study accounts for resistance, it does not address the pharmacokinetic properties of the drugs (discussed above), which may account for the lower treatment success rates seen with metronidazole. In the study by Al-Eidan et al. [48], the mean length of stay was 17 days, and overall mortality was 10 %. The duration of treatment, length of stay, and mortality did not differ between those patients who were treated with metronidazole compared with those treated with vancomycin. This study was conducted in Ireland, and the average cost of CDI treatment was significantly higher in the vancomycin group [49]. Notably, these studies evaluating the economic impact of CDI were performed before the hyper-virulent NAP1/ BI/027 strain of C. difficile became more prevalent. It is plausible that vancomycin, which is more effective for severe disease [40], may prove to have a greater economic advantage over metronidazole in settings where the NAP1/ BI/027 strain is more prevalent; however, economic data are lacking. This economic advantage of vancomycin may be especially apparent in institutions where the compounded intravenous form of vancomycin is used orally as opposed to capsules, which are more expensive.

Treating Clostridium difficile Infection

A meta-analysis from Canada utilized existing efficacy studies to determine a base-case average for treatment with metronidazole compared with vancomycin [51]. The basecase average assumed that both metronidazole and vancomycin were given as capsules. The estimated cost associated with metronidazole use was $36,018 and with vancomycin was $36,250, with an incremental cost of $232 in favor of metronidazole. Total costs from this analysis include direct costs to the publically funded health system (hospital costs, physician payments, diagnostic tests) and direct costs to patients (out-of-pocket copayments). In the sensitivity analysis, it was assumed that each patient was given the generic intravenous formulation of vancomycin orally, and the study population included both NAP1/BI/ 027 and non-NAP1/BI/027 strains of C. difficile [51]. Based on a study by Zar et al. [54], the average cost of treatment with metronidazole would be $33,476 assuming an effectiveness of 0.76, with an average cost for vancomycin treatment of $33,054 assuming an effectiveness of 0.97. Based on these data, the incremental cost-effectiveness ratio (ICER) for vancomycin (generic, compounded intravenous formulation) compared with metronidazole is $135 per clinical cure in a non-NAP1/BI/027 population [51]. A sensitivity analysis assessing a more difficult to treat NAP1/BI/027 population found the average cost for metronidazole to be $36,147, with an effectiveness of 0.42, and the average cost for vancomycin to be $36,445, with an estimated effectiveness of 0.609. In this NAP1/BI/027 population, the ICER for vancomycin (generic, compounded intravenous formulation) compared with metronidazole rises to $1,584 per clinical cure due to the higher failure rates associated with the drugs [51]. When a sensitivity analysis was performed assuming that the complication rates are related to treatment failure, the average cost per patient treated with metronidazole rose to $36,464, and the average costs per patient treated with vancomycin dropped to $33,465, leading to a total incremental cost of vancomycin of $-1,999. The cost benefit of vancomycin in this analysis is largely attributable to the decreased length of stay (1.15 days) in patients treated with vancomycin [51]. The studies included in the above analysis were small and one was published only in abstract form. It is also unclear if neurotoxicity due to excessive use of metronidazole was added into the sensitivity model accounting for complication rates. Though considerable knowledge gaps exist in the comparison of the economics of metronidazole and vancomycin for CDI, the preponderance of data concurs with current IDSA guidelines, which suggest that the most economic treatment for mild disease should be metronidazole. For more severe or recurrent CDI, vancomycin may be a better clinical and economic alternative to metronidazole. The generic intravenous formulation of vancomycin can be

used orally in this situation with an incremental cost of $346 per clinical cure to achieve the benefits of decreased complication rates and reduced hospitalization costs [51]. 5.2 Fidaxomicin The US FDA approved a macrocyclic antibiotic, fidaxomicin, in 2011 for the treatment of CDI. Studies have shown similar rates of clinical cure when compared with vancomycin, but fidaxomicin may have the advantage of decreasing rates of relapse after treatment. However, this reduced rate of recurrence has not been conclusively demonstrated in the hyper-virulent NAP1/BI/027 strain of C. difficile [55, 56]. The high cost of fidaxomicin, especially when compared with the compounded oral solution of vancomycin, has led to reluctance to prescribe fidaxomicin for many patients with CDI. There have been two major cost-effectiveness studies comparing fidaxomicin and vancomycin published to date. A third-party payer perspective study by Bartsch et al. [57] found the ICER for fidaxomicin to be greater than $43.7 million per qualityadjusted life-year (QALY) compared with the severitystratified use of metronidazole or vancomycin. However, this study had several major methodological flaws. The authors used the assumption that the hyper-virulent NAP1/ BI/027 strain accounts for half of the circulating strains of C. difficile, while most published evidence suggests the rate is closer to 20–30 %. The authors also assumed that the second course of CDI treatment was curative, which is often not the case in clinical practice [58–62]. These flawed assumptions may have made fidaxomicin appear less economically viable. A more robust cost-effectiveness study, also from a third-party payer perspective, published by Stranges et al. [63] provided a cost-analysis model that accounted for up to three treatment failures, with patients continued in the model until either cure with non-recurrence was achieved or the patient was committed to surgical intervention. The model was based on a clinical cure rate of 81.4 % for fidaxomicin and 78.1 % for vancomycin [55]. Recurrence rates for hospitalized patients were 17.6 % of patients receiving fidaxomicin and 27.4 % receiving vancomycin [55]. The model was consistent with the medications recommended in the treatment guidelines, with initial choice of metronidazole or vancomycin based on disease severity, and second or later recurrences treated with a vancomycin taper course [40–42]. The wholesale acquisition price for a 10-day treatment course of fidaxomicin used in this study was $2,800. This analysis found the ICER with fidaxomicin compared with vancomycin for the treatment of CDI in the USA was $67,576 per QALY. The authors concluded that, overall, fidaxomicin is a cost-effective option for CDI treatment when using an elevated threshold of $100,000

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per QALY [63]. However, fidaxomicin was not found to be cost effective for CDI caused by the NAP1/BI/027 strain or for institutions that compound vancomycin oral solution, where vancomycin dominated fidaxomicin [63]. In patients with severe disease, the ICER was not cost effective at $352,994. However, in mild–moderate CDI, fidaxomicin was found to be cost effective, with an ICER of $32,020 [63]. A comparison of metronidazole, vancomycin, and fidaxomicin found that fidaxomicin was cost effective only if the willingness-to-pay threshold was greater than $22,000 per clinical cure, while vancomycin was the most cost effective for willingness-to-pay threshold of less than $22,000. Metronidazole was not cost effective when compared with either vancomycin or fidaxomicin [64]. Another study of vancomycin versus fidaxomicin from a hospital perspective found that hospitals would pay an additional $31,539 for each episode of CDI treated with fidaxomicin rather than vancomycin. Fidaxomicin only showed a financial advantage in sensitivity analyses if it had higher rates of clinical cure, which has not been shown in most clinical trials, or a lower price [65]. Fidaxomicin appears to be cost effective in non-severe cases of CDI, caused by strains other than NAP1/BI/027, especially when the non-compounded, brand name formulation of vancomycin capsule is used (VancocinÒ). There are no available cost-effectiveness analyses of generic vancomycin capsules, which are now available at an average wholesale price of $12 per 125-mg capsule, bringing the cost of a 10-day treatment course down to less than $500 [66]. The cost effectiveness is driven primarily by reduced hospitalization costs and lower rates of recurrence compared with vancomycin. Fidaxomicin would become less cost effective with smaller differences in recurrence and clinical cure rates. 5.3 Fecal Transplant Fecal microbiota transplant (FMT), also called fecal bacteriotherapy, consists of a liquid suspension of stool from a healthy donor delivered into the CDI patient’s upper gastrointestinal tract via a nasoduodenal catheter or via the colon through a colonoscope or an enema catheter [67, 68]. The UK National Institute for Health and Care Excellence (NICE) recently released a guidance that supports the use of FMT for patients with recurrent CDI who have failed to respond to other treatments [69]. A newer method of delivery is a capsule prepared with freshly passed feces encapsulated in three layers of gelatin to form a capsule that stays intact until reaching the small intestine [70]. Efficacy of FMT is due to the introduction of protective bacteria into the colon, which suppresses the growth of C. difficile and helps restore the microbiologic balance of the

colon [71]. It was first used in China in the fourth century to treat diarrhea [72]. Challenges to this form of treatment are many, including lack of a uniform treatment protocol, variable composition of fecal matter between donors, and the risk of disease transmission. A publication by Brandt [73] provides a comprehensive overview of how to administer FMT. Generally 50 g of stool are suspended in 250 ml of diluent. A volume of \200 ml is associated with a lower rate of clinical resolution of 80 % and a relapse of rate of 6 %. A volume of [500 ml is associated with a 97.3 % clinical resolution rate and a relapse rate of 4.7 %. Additionally, loperamide may be used to help patients retain the transplanted stool. A small trial published by van Nood et al. [74] examined 43 patients with recurrent CDI enrolled between 2008 and 2010 in Amsterdam. Patients were randomly assigned to receive donor feces (17 patients) or vancomycin (13 patients) or vancomycin and bowel lavage (13 patients). Feces were obtained via a donor pool, which was screened every 4 months. Patients were followed for 10 weeks as a test of cure. Of the patients in the FMT group, 81 % were cured after the first infusion of feces. The three patients who had continued CDI received a second infusion of feces at 14, 50, and 53 days from a different donor. Two of the three patients responded, providing an overall cure rate of 94 %. Of the patients receiving vancomycin alone, a surprisingly low number of 31 % were cured, compared with more typical initial cure rates of 70–97 % [54, 55]. In the bowel lavage and vancomycin group, only 23 % had no symptoms at 10 weeks [74]. FMT has been shown to be effective for treating CDI, with overall mean cure rates of 91 % [75]. The cure rates in a case series of 70 patients showed that FMT remained effective (89 %) at 12 weeks post-transplant, even in the presence of the NAP1/BI/027 strain of C. difficile [76]. A survey-based study published in 2012 of 77 patients in five medical centers across the USA found that the primary cure rate was 91 % after a follow-up period of 3–68 months [77]. These patients were followed for 3 years after their transplant; diarrhea recurred in 22 of the 77 patients (29 %). Seven of these patients had diarrhea that was selflimiting and was not attributed to CDI. Seven of the patients were considered treatment failures as they had recurrence of CDI within 90 days. The remaining eight patients developed CDI [90 days after transplant [77]. Extensive long-term outcome data on FMT are still lacking. While clinically effective, FMT is not without risk, and has not yet been approved for use by the US FDA. Extensive screening of fecal donors is necessary to prevent transmission of diseases. Assays performed include blood tests and stool pathogen examinations, the costs of which are significant. Sample costs of recommended screening

Treating Clostridium difficile Infection

tests in $US are listed below based on an article from Avery and Hasan [78]. Blood tests prior to stool transplant include complete blood count with differential, complete metabolic profile, human immunodeficiency virus types 1 and 2 ($28.84), hepatitis A virus immunoglobulin (Ig)-M and total antibody ($43.28), hepatitis B surface antigen ($29.25), hepatitis B core antibodies ($35.01), hepatitis B surface antibody ($36.36), hepatitis C virus antibody ($35.09), cytomegalovirus, Epstein-barr virus, Treponema pallidum rapid plasma antigen ($15.91), and Treponema IgG/IgM ($33.99). The donor stool must be screened for the presence of C. difficile toxin B by polymerase chain reaction ($101.48), Giardia antigen ($33.95), Cryptosporidium antigen ($33.95), acid-fast stain for Cyclospora, Isospora, and Cryptosporidium ($80.73), protozoa (trophozoites and cysts), helminthes, trematodes, and tapeworms [68]. Donor stool should also be tested for enteric pathogens including Shigella, Salmonella, Campylobacter, and Shiga-like toxin ($109.13). If the donor stool is to be administered by nasogastric tube, Helicobacter pylori fecal antigen should also be assayed ($45.00). Risk of disease transmission and intolerance with FMT may be mitigated by using a stool donor who is closely related to the recipient [79, 80]. The cost of fecal transplant is varied based on the setting of the transplant. Fecal transplant via a rectal retention enema can be safely performed on an outpatient basis. However, fecal transplantation via colonoscopy or nasogastric tube is most frequently performed in a hospital setting, increasing the costs associated with FMT [68]. The sum of the aforementioned cost for testing the donor of the feces for the listed tests is estimated to be $659. This number does not include the passage of the nasogastric tube or rectal tube, physician time, time for preparation of the stool, and sterilization of the instruments. The Institute of Health Economics in Alberta, Canada, estimates the costs of this therapy ranges from $CAN500 to $CAN1,500 [68]. Economic or cost data for FMT using fecal capsules are not yet available. There are limited published data on long-term outcomes with FMT and on economic comparisons with other treatment modalities. Further information will be needed to determine whether FMT can offer a costeffective solution for treating CDI. 5.4 Rifaximin Rifaximin is a non-absorbable oral antibiotic that has been used as an adjunct to oral vancomycin for the treatment of CDI. Several small studies have suggested that vancomycin followed by a rifaximin ‘chaser’ can decrease CDI recurrence compared with vancomycin treatment alone [81–84]. The efficacy of rifaximin in these studies ranged from 79 to 87 %. The dosing of rifaximin was varied, most commonly

400 mg two-to-three times a day for 14–36 days. The average wholesale price of rifaximin is $16.04 per 200-mg capsule, making a course of treatment an estimated $900 to $3,450, which would be added to the cost of the vancomycin treatment that typically precedes rifaximin [66]. C. difficile resistance to rifaximin has been described [85]. Resistance testing is not commonly performed in the microbiology laboratory, as the Clinical Laboratory Standards Institute method of anaerobic agar dilution is time consuming [86]. Italian isolates of C. difficile show 18.8 % resistance, while Canadian isolates show 2.1 % resistance [86]. A single-center trial based in the USA concluded that rifaximin would not be effective in the study institution because the rifampin resistance was 36.8 % overall, with as much as 81.5 % resistance in a clone of NAP1/BI/027 C. difficile [87]. Patients who were previously exposed to rifamycins were more likely to harbor rifaximin-resistant C. difficile (relative risk [RR] 2.4, 95 % confidence interval [CI] 1.8–3.3), suggesting that resistance rates are likely to increase as use of rifaximin increases [87]. The high drug cost, the need to use other CDI treatments prior to rifaximin, and the increasing rates of resistance, suggest that rifaximin is unlikely to be an economically viable option for treating most CDI patients.

6 Prevention Strategies 6.1 Probiotics Probiotics are live bacteria, generally unable to incite infection, that colonize the lower gastrointestinal tract of humans [88]. They are low-cost agents available over the counter and regulated as dietary supplements rather than as drugs. The efficacy of probiotics in the prevention of C. difficile has been controversial in the literature. Two of the most commonly used probiotic bacteria include Lactobacillus and Bifidobacteria. Saccharomyces boulardii is a yeast that is also often used as a probiotic agent. A recent Cochrane Review and meta-analysis of 23 randomized controlled trials found that there was moderate evidence that probiotics are safe and effective for the prevention of C. difficile [89]. The incidence of CDI was 2.0 % in the probiotic group compared with a CDI rate of 5.5 % in the placebo or no-treatment group (RR 0.36, 95 % CI 0.26–0.51). However, a recent randomized, double-blind placebocontrolled trial did not detect a benefit of probiotics for CDI prevention. In this trial, 1,493 patients over the age of 65 years who were being prescribed one or more antibiotics were given a multi-strain preparation of Lactobacillus and Bifidobacteria, with a total of 6 9 1010 organisms daily for 21 days compared with 1,488 patients who received

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matched placebo. The study found no impact on the rate of CDI or antibiotic-associated diarrhea [90]. The study population was somewhat divergent from typical patient populations seen in North America in that CDI after antibiotic use was rare (*1 % of patients), and the antibiotic regimens were quite narrow in spectrum (only 0.7 % received a third-generation cephalosporin, 2.2 % received a carbapenem, and very few were prescribed clindamycin). It may not be appropriate to generalize these results to groups of patients typically prescribed more broad-spectrum antibiotics, which often lead to higher rates of CDI. In another randomized, double-blind placebo-controlled trial, Saccharomyces boulardii was demonstrated to decrease recurrent CDI. Patients who were randomized to S. boulardii 1 g per day for 4 weeks had a significantly lower RR of CDI recurrence (RR 0.43, 95 % CI 0.20–0.97). Notably, immune-compromised patients were excluded from this trial. In general, probiotics are very well tolerated, with the most prevalent adverse effects being nausea, fever, cramping, flatulence, and taste disturbance [89]. Probiotics, especially Lactobacillus and Saccharomyces, have been noted to cause serious adverse outcomes in immune-compromised patients, those with severe disease, and neonates [91–95]. Bacteremia is a rare potential adverse effect of probiotics, which when combined with severe underlying illness, can have a mortality prediction of up to 48 % at 1 year [96]. Due to their status as dietary supplements rather than drugs, there are no specific laws requiring manufacturing consistencies with probiotics [92]. Thus with these products, the specific bacterial or fungal strain, as well as quantity per dose, can vary significantly between lots and among different manufacturers. The average wholesale price of S. boulardii is $0.75 per 250-mg capsule, making the daily cost $1.50 [66]. Prices and dosing are more varied for Lactobacillus, but generally the cost remains under a dollar per day [66]. Currently, the IDSA does not advocate the use of probiotics for the prevention of CDI, based on the lack of conclusive efficacy evidence and the possibility of harm in certain patient populations [40]. The use of these agents may represent an economically viable option for prevention of recurrent CDI in individual patients where the conventional options have failed, provided their immune status is adequate. More information on efficacy is needed before these agents can be recommended for widespread use.

healthcare costs. Several studies have investigated the screening of hospitalized patients for presence of C. difficile on admission, with subsequent isolation and/or treatment of patients who test positive. A peri-rectal surveillance test, which uses pre-amplified C. difficileselective medium followed by toxin detection via polymerase chain reaction, is an effective way to determine carriers of toxin-producing C. difficile with a turnaround time of 1.25–3.25 days [97]. A simulation study used this test to determine the economic value of screening hospital admissions for C. difficile colonization [98]. Patients were screened with a peri-rectal swab, and those who were positive were placed on contact precautions (gloves and gowns for each patient contact). Testing took 1.25–3.25 h; during which colonized patients could potentially transmit C. difficile to other patients. In this simulation, the patients who became colonized with C. difficile could develop CDI or remain asymptomatically colonized. Patients with mild to moderate CDI were treated with oral metronidazole. Patients with severe CDI could undergo surgery and receive oral vancomycin and intravenous metronidazole, or, if they were not treated with surgery, a 14-day course of oral vancomycin was prescribed. Recurrences were also built into the model. The cost savings to a hospital depends on the baseline colonization rate. In this study, a 10.3 % colonization rate on admission [99] would yield cost savings of $16,071 per year, assuming a 75 % compliance rate and 1,000 annual admissions [98]. Assuming the same colonization rate and a compliance rate of only 25 %, the costs savings is reduced to $10,256. The analyzed costs included universal screening and isolation for C. difficile carriers. Another study evaluated the efficacy of treating asymptomatic carriers with 10 days of either oral metronidazole or oral vancomycin. Metronidazole was ineffective, leading to the non-detection of C. difficile in only three of ten patients, compared with two of ten patients treated with placebo. Oral vancomycin was more effective in temporarily eradicating C. difficile, with nine of ten patients becoming non-detectable at the conclusion of treatment. However, 2 months later, those patients had a significantly higher rate of C. difficile carriage [100]. Thus, the treatment of asymptomatic C. difficile carriers as a method to reduce the economic burden of CDI cannot be recommended at this time.

7 Discussion 6.2 Screening Methods to prevent C. difficile transmission are of great economic importance, as reduced transmissions lead to decreased disease burden and consequently decreased

CDI is an important disease, with significant economic implications for the healthcare system and for society in general. The increasing severity of disease seen recently with the emergence of the hyper-virulent NAP1/BI/027

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strain of C. difficile is especially concerning and has the potential to lead to an even greater economic burden. Additionally, the increased rate of treatment failure has led to the increased use of higher-cost medications for the treatment of CDI. Appropriate utilization of prevention and treatment methods for CDI has the potential to reduce the economic and humanistic costs of the disease. Screening and isolation of hospital admissions based on C. difficile carriage may offer a cost-effective strategy for reducing transmission in the inpatient setting. In contrast, treatment of asymptomatic carriers does not appear to be a viable strategy for C. difficile eradication as a method to decrease transmission. Prevention of CDI through the use of probiotics has the potential to provide an inexpensive method for reducing CDI burden if utilized in the appropriate patient population. Individuals at high risk of CDI who are not immune-compromised are likely to realize the most potential benefit from the use of probiotics during antibiotic treatment. The most extensively studied agents for treatment of CDI are metronidazole, vancomycin, and fidaxomicin. Most economic comparisons between metronidazole and vancomycin favor vancomycin, especially with the increasing rate of treatment failure with metronidazole. Fidaxomicin offers a clinically effective option for treating CDI; however, the high price and variable cost effectiveness has prevented its wide acceptance into medical practice. The clinical efficacy of vancomycin, along with the availability of low-cost compounded oral solutions and generically available capsules, has allowed vancomycin to emerge as an economically superior option for CDI treatment. Fidaxomicin may be cost effective over vancomycin in non-severe CDI where there is a low incidence of the NAP1/BI/027 strain of C. difficile. Other CDI treatments, including rifaximin and FMT, require further clinical and economic study before they can be routinely recommended. Due to the high cost of rifaximin, the need for prior treatment with vancomycin, and the emergence of resistance, it is unlikely to become a commonly used medication for CDI. FMT appears to be a promising alternative, with excellent cure rates in clinical trials. Further studies comparing FMT with more traditional treatment options are needed to fully evaluate the potential economic advantages this treatment modality may be able to offer.

8 Conclusion Overall, we recommend using metronidazole for mild CDI only. Moderate to severe CDI should be treated with vancomycin, preferably the compounded oral solution as the most cost-effective option. If the facility has the capability

to test for the NAP1/BI/027 strain of CDI, then fidaxomicin may be an option for those patients who do not have the NAP1/BI/027 strain. Fidaxomicin may also be a costeffective alternative in the treatment of patients with moderate disease. Rifaximin is not an effective treatment due to increasing resistance and more established treatment options. Probiotics and fecal transplants have variable efficacy and the US FDA does not currently regulate the content. More studies are needed on both probiotics and fecal transplant before they can be recommended on an institutional level. Acknowledgments This manuscript is the result of work supported in part by resources and the use of facilities at the Veterans Affairs Western New York Healthcare System. The contents of this manuscript are not intended to represent the views of the Department of Veterans Affairs or the US Government. Kari Mergenhagen has no relevant conflicts of interest to disclose. Amy Wojciechowski has no relevant conflicts of interest to disclose. Joseph Paladino has no relevant conflicts of interest to disclose. Kari Mergenhagen and Amy Wojciechowski performed the initial literature search, wrote and prepared the manuscript for submission, and responded to reviewer comments and requests for revisions. Joseph Paladino contributed to the conceptualization and design of the review article and helped with editing and revisions of the manuscript. Senior author, Joseph Paladino, serves as the overall guarantor of the content of this manuscript.

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