Use of alternative or adjuvant pharmacologic treatment strategies in ...

International Journal of Infectious Diseases 15 (2011) e438–e448

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International Journal of Infectious Diseases journal homepage: www.elsevier.com/locate/ijid

Review

Use of alternative or adjuvant pharmacologic treatment strategies in the prevention and treatment of Clostridium difficile infection Caitlin R. Musgrave a, P. Brandon Bookstaver b,*, S. Scott Sutton b, April D. Miller b a b

South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina, USA Department of Clinical Pharmacy and Outcomes Sciences, South Carolina College of Pharmacy, University of South Carolina, 715 Sumter Street, Columbia, SC 29208, USA

A R T I C L E I N F O

S U M M A R Y

Article history: Received 3 November 2010 Received in revised form 19 March 2011 Accepted 24 March 2011

Infection with Clostridium difficile is currently the leading cause of infectious diarrhea in hospitalized patients, and recent surveillance data indicate that C. difficile has surpassed methicillin-resistant Staphylococcus aureus as the number one cause of hospital-acquired infections in some areas of the USA. In addition, concern over C. difficile has increased over the past decade due to the appearance of new hypervirulent strains. Metronidazole and vancomycin have remained the treatments of choice for initial therapy of primary infection with C. difficile for the past 25 years, but the persistence of spores leads to a recurrence of infection in an estimated 20–25% of patients. Patients who have one recurrent episode have up to a 65% chance of having additional recurrence. While the judicious use of antimicrobials in accordance with antibiotic stewardship guidelines remains the most effective method for the control of C. difficile, the high recurrence rate, increasing incidence, and changing epidemiology of C. difficile has led to an increased interest in the study of alternative strategies for the prevention and treatment of C. difficile disease. These alternative strategies attempt to eliminate C. difficile spores, replenish the normal gut flora, reduce the C. difficile toxin load in the bowel, or bolster the patient’s own immune response to the C. difficile toxins. To evaluate the available evidence on these alternative strategies, we conducted a literature search of MEDLINE (1966–March 2011) and International Pharmaceutical Abstracts (1970– March 2011). Available citations from these articles were also utilized. The aim of this review is to summarize the available evidence for alternative treatment strategies for C. difficile disease and to make recommendations for their place in therapy. ß 2011 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Corresponding Editor: Craig Lee, Ottawa, Canada. Keywords: Clostridium difficile Probiotics Polymers Immunotherapy Rifamycin Nitazoxanide Fidaxomicin

1. Introduction Clostridium difficile is a Gram-positive, anaerobic, spore-forming, cytotoxin-producing bacillus transmitted via the fecal–oral route.1 C. difficile was first linked to human disease in 1977 and has increased in incidence to become the leading cause of infectious diarrhea in hospitalized patients.2,3 The Centers for Disease Control and Prevention (CDC) estimates the annual incidence of hospitalized cases of C. difficile infection (CDI) to exceed 250 000, with a mortality rate of 1–2.5% in infected persons and an estimated cost to the health care system of over 3 billion dollars per year.1,4,5 Recent surveillance data indicate that C. difficile has surpassed methicillin-resistant Staphylococcus aureus (MRSA) as the number one cause of hospital-acquired infections in some areas of the USA.6 The increasing concern with C. difficile seen over the past decade has primarily been due to changing epidemiology. North America

* Corresponding author. Tel.: +1 803 777 4786; fax: +1 803 777 2820. E-mail address: [email protected] (P.B. Bookstaver).

has seen CDI incidence increase five-fold in the community dwelling populations. Incidence has also increased in Europe, most noticeably the UK, the Netherlands, and France.7 In addition to the increased number of cases, the severity has also increased. Between 1997 and 2005, a nearly four-fold increase in C. difficile-associated mortality was observed in Canada.8 These epidemiologic changes appear to be due in part to a new hypervirulent, epidemic strain of C. difficile, referred to as BI/ NAP1/027, which produces higher concentrations of toxins and appears more resistant to treatment.7 The heightened interest in C. difficile treatment is also related to the high risk of C. difficile infection in severely immunocompromised HIV and cancer patients, as well as the appearance of C. difficile in patients treated with short courses of antibiotics for traveler’s diarrhea or surgical prophylaxis.9,10 Therefore, the best practice in all patients—high or low risk—is the judicious use of antimicrobials for the prevention of CDI. Despite efforts to prevent CDI, changing epidemiology and high rates of recurrence of CDI demand an understanding of not only traditional treatment options for infection, but also the evidence for alternative

1201-9712/$36.00 – see front matter ß 2011 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijid.2011.03.017

C.R. Musgrave et al. / International Journal of Infectious Diseases 15 (2011) e438–e448

treatments. To evaluate the available evidence of alternative treatments, we conducted a literature search of MEDLINE (1966– March 2011) and International Pharmaceutical Abstracts (1970– March 2011) and available citations from the reviewed literature. 2. Standard treatment of Clostridium difficile infection Initial treatment of CDI involves the discontinuation of causative antimicrobial therapies.1,5 After discontinuation of inciting antibiotics, current practice guidelines from the Society for Healthcare Epidemiology of America and the Infectious Diseases Society of America (SHEA/IDSA) recommend either metronidazole or oral vancomycin as the treatments of choice.5 Oral metronidazole is recommended for initial episodes of mild-tomoderate CDI (500 mg orally three times daily for 10–14 days) and oral vancomycin (125 mg four times daily for 10–14 days) is recommended for initial treatment of severe disease.5 The European Society of Clinical Microbiology and Infectious Diseases treatment guidance document for CDI recommends teicoplanin, a glycopeptide with similar activity to vancomycin, at a dose of 100 mg twice daily as an additional oral treatment option.11 Oral bacitracin (20 000–25 000 U four times daily for 7– 10 days) and fusidic acid (250–500 mg three times daily for 7–10 days) are considered less effective than the glycopeptides and metronidazole and are therefore not recommended for use. Teicoplanin, fusidic acid, and oral bacitracin are not available in the USA.11,12 Because optimal treatment of CDI involves oral antibiotic administration, treatment of a patient without oral access can be challenging. Intravenous (IV) administration of metronidazole diffuses from the serum of inflamed colon into the lumen and undergoes hepatic recirculation, providing comparable concentrations to oral administration.1 Vancomycin can also be administered per rectum in the form of a retention enema or intracolonically.13 Combination therapy with oral vancomycin and IV metronidazole has also been suggested as initial therapy in severe disease.5 3. Alternative agents and therapies 3.1. Assessing the need for alternative/adjuvant treatment strategies Vancomycin and metronidazole have been used as effective treatments for CDI for over 25 years, but they may further disrupt and suppress the return of the healthy intestinal flora and do not reduce exposure to spores in the environment or positively alter host risk factors. For these reasons, it is estimated that 20–25% of patients who respond to initial treatment with metronidazole or vancomycin will experience recurrence of C. difficile, or reappearance of clinical symptoms, typically within 2 weeks of completed therapy.14,15 Approximately half of recurrences are due to relapse, while the other half are due to reinfection. A relapse involves the same strain of C. difficile as the original infection and occurs when C. difficile spores remain in the intestine after CDI treatment.14,15 These spores can easily proliferate and begin producing toxins again, because the normal flora of the intestine is not reestablished for approximately 3 months.16 The SHEA/IDSA guidelines recommend that a patient experiencing their first recurrence of C. difficile be treated with the same antibiotic as was used for the initial episode; however, patients who have a single recurrence have up to a 24% chance of having repeat recurrence, and risk increases up to 65% when a patient has had more than two prior episodes of CDI. Treatment with vancomycin instead of metronidazole or vice versa does not reduce this likelihood.16,17

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Due to the high recurrence rate, as well as increasing incidence and fatality rate of CDI since the year 2000, there has been increased interest in the study of alternative and adjuvant strategies for the prevention and treatment of CDI.4 These strategies attempt to eliminate C. difficile spores, replenish normal gut flora, reduce C. difficile toxin load in the bowel, or bolster the patient’s own immune response to C. difficile toxins. Table 1 provides a summary of pharmacologic agents discussed in this review. 3.2. Alternative vancomycin dosing strategies Alternative dosing strategies that have been successfully used in the treatment of chronically recurring CDI are tapered dose vancomycin, which involves a gradual lowering of the vancomycin dose over time, and pulsed dose vancomycin, which involves short, intermittent courses. In addition, the use of adjunctive intracolonic vancomycin has been studied for the treatment of severe CDI. In 1985, Tedesco et al. reported a case series of 22 patients whose recurrent CDI was treated using these strategies: patients were first treated with a 6-week tapered regimen of vancomycin (125 mg every 6 h for 1 week, then 125 mg every 12 h for 1 week, then 125 mg daily for 1 week), followed by a pulsed dose regimen (125 mg every other day for 1 week, then 125 mg every 3 days for 2 weeks). No recurrences were reported after 6 months.18 In 2002, McFarland et al. reported a case series of 163 patients with recurrent CDI who were treated with various dosing regimens of vancomycin. Vancomycin tapered dosing (doses decreased stepwise from 500 mg–3 g per day down to 125–750 mg per day over approximately 21 days) resulted in a 31% recurrence rate, and pulsed dosing of vancomycin (125–500 mg as a single daily dose every 2–3 days over approximately 27 days) resulted in a 14% recurrence rate, compared to 43–54% recurrence rates with standard vancomycin 10-day regimens.17 Targeted antibiotic therapy eradicates C. difficile colonies but has no effect on spores, leading to recurrence of infection. It is hypothesized that pulsed and tapered dosing regimens allow C. difficile spores to germinate and then eliminate the cells, while also supporting re-establishment of normal flora in the intestines.17 One major concern with pulsed and tapered regimens is the development of vancomycin-resistant Enterococcus (VRE), given the protracted exposure to vancomycin.15 Though there are no randomized controlled trials evaluating these dosing regimens, 2010 SHEA/IDSA guidelines recommend for second recurrence of CDI a usual dosage of 125 mg four times daily for 10–14 days followed by 125 mg twice daily for 1 week, 125 mg once daily for 1 week, and then 125 mg every 2 or 3 days for 2 to 8 weeks.5 At this time, the use of tapered or pulsed dose vancomycin should be considered for treatment of second or later recurrences of CDI. The adjunctive intracolonic administration of vancomycin to patients with C. difficile colitis has been studied in an attempt to achieve higher concentrations of drug within the colon than may be achieved by oral administration of vancomycin or metronidazole alone.13 Intracolonic vancomycin therapy involves administration of an IV solution of vancomycin via intracolonic bolus (for example, a 2 g bolus followed by 100 mg after each watery stool in addition to 125 mg of oral vancomycin four times daily) or via rectal retention enema (for example, individual doses of 500 mg in 1 l of normal saline).19 Administration via retention enema may be a more desirable option due to the risk of perforation with the insertion of catheters into the colon for intracolonic bolus. A literature review by Apisarnthanarak et al. estimates a success rate for intracolonic vancomycin of 57–75%. Patients receiving intracolonic vancomycin in case reports or case series have not experienced recurrent disease, required surgical intervention, or

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Table 1 Summary of alternative or adjuvant treatment options for Clostridium difficile infection Agent Alternative dosing regimens of vancomycin Tapered dose

Pulsed dose Intracolonic administration

Prebiotics

Mechanism of action

Role in treatment

Cautions

125 mg every 6 h 10–14 days, then 125 mg every 12 h 7 days, then 125 mg every 24 h 7 days

Normal antibiotic therapy has no effect on spores; tapered or pulsed dosing allows spores to germinate before eliminating the cells See ‘tapered dose’

Second or greater recurrence of CDI

See ‘tapered dose’

Do not administer with cholestyramine, colestipol or other anion-exchange resins, which will bind vancomycin See ‘tapered dose’

Attempts to achieve higher concentrations of vancomycin within the colon than may be achieved by oral administration

Patients who cannot take vancomycin by mouth; adjunctive to oral treatment in severe or recurrent disease

Intracolonic bolus may lead to a risk of perforation with insertion of catheters into the colon

Studied dosages typically range from 107 to 1011 CFU per day, which are comparable doses to those found in available over-the-counter probiotic preparations Dosage levels differ based on type of prebiotic fiber; ranges from 3 g/day for short-chain fructooligosaccharides to 8 g/day for mixed short- and long-chain inulin

Inhibit the growth of C. difficile via production of antimicrobials and acids to decrease the pH of the intestine; protect the endothelium; have positive immunologic effects Non-digestible oligosaccharides; dietary fibers that improve intestinal microflora

Prevention of CDI or as an adjunct to treatment in otherwise healthy patients

Immunocompromised HIV or cancer patients are at an increased risk for translocation of the organism, leading to bacteremia or fungemia

See ‘probiotics’

See ‘probiotics’

Patient preparation: Vancomycin 250 mg PO every 8 h 4 days; omeprazole 20 mg 2 doses; (+/ ) polyethylene glycol Stool sample preparation: Blend 30 g stool sample and 50–70 ml sterile normal saline for 2–4 min, filter twice with coffee filter Administration: Via rectal retention enema, colonoscope, or nasogastric, nasoduodenal, or nasojejunal

Replacement of the healthy intestinal flora will suppress the growth of C. difficile

Treatment of third or greater recurrence of CDI

Ensure donors are screened for contagious infectious agents before performing transplant

Dosing is based on the specific strain of nontoxigenic C. difficile administered (i.e., 106 CFU)

Compete with toxigenic strains for nutrients and adherence in the bowel

If developed, may be useful for prevention of recurrence of CDI

May be ineffective if nontoxigenic strain is susceptible to the antibiotic used for treatment of CDI

Given until patient produces profuse, clear liquid stools: 17 g of powder mixed in 8 oz of clear liquid administered every 10 min until 2 l are consumed

May reduce the bacterial, toxin, and spore load from the intestines by producing a rapid intestinal transit time and diluting intestinal bacteria

For adjunctive use prior to fecal transplantation or in patients who have experienced multiple recurrences of CDI

Will cause an increase in abdominal bloating, cramping, diarrhea, flatulence and nausea

Cholestyramine: 4 g three to four times a day 1–2 weeks Colestipol: 10 g four times a day 5 days or 5 g twice a day 1–2 weeks Tolevamer 3 to 6 g daily (not available)

Exchange a chloride ion for C. difficile toxin to form a non-absorbable complex with the toxin in the intestinal tract A toxin-binding polymer developed to bind C. difficile toxins in the intestinal tract

For refractory cases of CDI, or in patients for whom a negative toxin assay is necessary for discharge

Due to binding of vancomycin and potential binding of metronidazole, do not administer within 2–3 h of either antibiotic Development of tolevamer has been halted secondary to negative results in phase III clinical studies

125 mg every other day 7 days, then 125 mg every 3 days x 14 days Intracolonic 2 g bolus, then 100 mg after each watery stool. Rectal retention enema: 500 mg in 1 l of normal saline per dose

Fecal transplantation

Colonization with nontoxigenic C. difficile

Whole bowel irrigation Polyethylene glycol

Toxin binding adsorbents Ion-exchange resins

Non-antibiotic polymer

If developed, non-antibiotic polymers would be useful as an adjunctive agent to standard therapies


Probiotics and prebiotics Probiotics (lactobacilli, bifidobacteria, Saccharomyces boulardii)

Dosing

Table 1 (Continued ) Agent

Dosing

Mechanism of action

Role in treatment

Cautions

1 or 6 mg/kg in mice

Orally administered beta-lactamase enzyme would maintain colonization resistance of the intestinal flora by inactivating any parenterally administered beta-lactam given to treat an infection outside the GI tract

Human models may prove this to be a potential prevention strategy in patients who are at high risk for the development of CDI

Must not be used with orally administered antibiotics, and will only be effective for prevention of C. difficile caused by beta-lactam antibiotics; not yet tested in humans

150–400 mg/kg for 1–6 doses

Attempt to increase low serum antibody levels of C. difficile toxin A, which can predispose patients to CDI Neutralize the toxins and boost the ability of the immune system to respond to infection

For patients who have failed other therapies or in patients in whom surgery is being considered For patients with severe or recurrent CDI in combination with metronidazole or vancomycin

Passive immunization by increasing circulating antibody levels against C. difficile toxins and reducing rate of recurrence

Upon development, may be useful for CDI prevention in high-risk individuals

Further clinical studies are needed before recommendations can be made regarding its use Further development and clinical evaluation of monoclonal antibodies is necessary before they are routinely used Older adults who would benefit most from vaccination may have suboptimal response

An over-the-counter product with in vitro antibacterial activity against C. difficile at concentrations achievable within the GI tract A rifamycin antibiotic with high in vitro activity against C. difficile

No current in vivo evidence to support use as an adjunctive option in the prevention or treatment of C. difficile

General ADEs include darkening of the tongue or tinnitus; avoid use of salicylates in pediatric patients

Not recommended for use

Non-significant increase in mortality in single study; concern for drug–drug interactions and development of resistance Further clinical studies necessary to confirm efficacy; caution recommended due to the chance for increased MICs of isolates during treatment; general ADEs include peripheral edema, dizziness, fatigue, ascites and nausea Further studies are needed to confirm efficacy and compare to current treatment strategies; general ADEs are mild

Oral beta-lactamases

Immunotherapy Intravenous immunoglobulin

Intravenous infusion of 10 mg/kg of each monoclonal antibody

Vaccination with inactivated toxoids A and B

Alternative antimicrobials Bismuth subsalicylate

100 mg of bismuth subsalicylate added to 10 ml of fluid to produce a soluble bismuth product

Rifampin

300–600 mg every 12 h in combination with vancomycin treatment

Rifaximin (Xifaxan1)

400–800 mg daily doses 2 weeks

Nitazoxanide

500 mg every 12 h

Tigecycline

100 mg IV daily 1 dose, 50 mg IV every 12 h

Linezolid

600 mg IV/PO every 12 h (standard dosing, specific dosing for CDI unknown)

Unapproved antimicrobials Ramoplanin

in

2–3

divided

200 or 400 mg administered twice daily for 10 days

A rifamycin antibiotic with high in vitro activity against C. difficile; neither absorbed by the GI tract nor inactivated by gastric juices; exerts its action entirely within the intestinal lumen

For patients with refractory or recurrent CDI

A nitrothiazolide which blocks anaerobic metabolism of eukaryocytes and inhibits C. difficile in vitro at low concentrations A glycylcycline antibiotic found to be highly active in vitro against some C. difficile strains; reaches fecal concentrations high enough to reduce intestinal microflora without inducing C. difficile or cytotoxin production An oxazolidinone which is highly active in vitro against some C. difficile strains and has a high percentage excreted unchanged in the stool

For initial treatment of severe C. difficile or for recurrent, refractory disease

An antimicrobial compound that inhibits cell wall synthesis by acting at the level of lipid intermediate formation against C. difficile

For initial treatment of other Grampositive infections in patients who may be at high risk for development of CDI

Further clinical studies are necessary to determine the true therapeutic role; general ADEs are GI complaints

Despite promising in vitro activity, in vivo results are not conclusive enough to recommend use at this time

Further clinical studies are necessary to determine the true therapeutic role; ADEs include diarrhea

May offer an alternative for the initial treatment of CDI upon approval

Further clinical studies are necessary to determine the true therapeutic role; general ADEs include GI complaints


Monoclonal antibodies against C. difficile

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Further clinical studies are necessary to determine the true therapeutic role; general ADEs may include GI complaints, general disorders (fever, chills, and fatigue), and development of infection (urinary tract infection, pneumonia)

experienced complications in the 6 weeks post-therapy.13 Intracolonic vancomycin may be a useful treatment option not only in those patients who cannot take vancomycin orally, but also as an adjunctive treatment to standard therapy in patients with severe or recurrent disease. 3.3. Probiotics

ADEs, adverse drug effects; CDI, Clostridium difficile infection; CFU, colony-forming units; GI, gastrointestinal; IV, intravenous; MICs, minimum inhibitory concentration; PO, by mouth.

Cautions

May offer an alternative for initial treatment of mild-to-moderate CDI upon approval A narrow spectrum antibiotic which selectively eradicates C. difficile without disturbing the normal intestinal flora

Mechanism of action Dosing

200 mg every 12 h Fidaxomicin

Agent

Table 1 (Continued )


Role in treatment

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The use of probiotics for the prevention and treatment of CDI has been an area of growing interest over the past decade. Probiotics have multiple mechanisms of action against pathogenic C. difficile. Some probiotics (specifically lactobacilli and bifidobacteria) have been shown to cause a phenomenon known as ‘colonization resistance’, in which the growth of C. difficile is inhibited via production of antimicrobials and acids to decrease the pH of the intestine. Probiotics also protect the epithelium as a result of increased mucin production in the colon, and can cause an increased absorption of water via chloride channels to reduce diarrhea. Probiotics also have immunologic effects, decreasing inflammation or increasing expression of immunoglobulins against C. difficile toxin A. Some probiotics (specifically Saccharomyces boulardii) have been shown to prevent the C. difficile toxins A and B from binding in the intestine.20 Probiotics are dosed based on colony-forming units (CFU), and studied dosages typically range from 107 to 1011 CFU per day. These dosages are comparable to those found in over-the-counter probiotics such as Culturelle1 (Lactobacillus rhamnosus GG), Align1 (Bifidobacterium infantis), or Florastor1 (S. boulardii). Some products may list the dosage in terms of milligrams (Align1, 4 mg; Florastor, 250 mg), but this is typically listed along with the number of CFU contained in the product. Probiotics have been shown to be safe in most patient populations, and cause few drug interactions.20,21 There have been reports of serious adverse events, including bacteremia or fungemia acquired by translocation of the organism from the gastrointestinal tract to other areas of the body.22 Severely immunocompromised HIV or cancer patients are at highest risk for translocation due to depletion of CD4 cells in the gut or direct toxic effects of chemotherapy agents, respectively.9,10 Use of probiotics in this patient population should be done with caution. Another concern with the use of probiotics is the lack of standardization, regulation, and quality control of these overthe-counter supplements.23,24 In 2006, a meta-analysis reported that the probiotics S. boulardii, L. rhamnosus GG, and mixtures of probiotics were useful in the prevention of CDI, significantly reducing development of the disease. The meta-analysis also found S. boulardii to be effective for the treatment and prevention of CDI. When used as adjuvant therapy for secondary prophylaxis against CDI, S. boulardii significantly decreased the rate of relapse. L. rhamnosus GG and Lactobacillus plantarum 299 v were not found to produce statistically significant reductions in the rate of relapse.25 Trials of probiotics as prophylaxis against CDI in hospitalized patients have shown that combinations of probiotics may be more effective. The combination of Lactobacillus acidophilus, Bifidobacterium bifidum, and Lactobacillus bulgaricus significantly decreased the rate of occurrence of CDI, while a combination of Lactobacillus casei DN-114 001, L. bulgaricus, and Streptococcus thermophilus has been shown to prevent reoccurrence and significantly decrease the rate of occurrence of CDI.26 In 2008, a Cochrane Review reported studies suggesting a benefit in the treatment of recurrent infection, but did not recommend the use of probiotics for treatment or prevention of initial CDI.27 The use of ‘designer probiotics’ in CDI has also been explored. Lactococcus lactis and Lactobacillus salivarius produce bacteriocins,


toxins that can inhibit the growth of C. difficile. Gastric acidity negatively affects the stability of the bacteriocin produced by Lactococcus lactis, so the genes required for production of this bacteriocin have been cloned and expressed in L. salivarius to prevent degradation during digestion. Other ‘designer probiotics’ have been engineered to contain receptors to the C. difficile toxin. These receptors bind the toxin, preventing it from causing damage and allowing it to be safely eliminated. Trials of these recombinant probiotics in animal models are ongoing, but they have not yet been tested in human subjects.28,29 Probiotics are not recommended in the 2010 SHEA/IDSA treatment guidelines.5 There are numerous clinical trials underway assessing the efficacy of these agents, and the results of these studies will help determine the future use of probiotics in CDI. At this time, the use of probiotics could be considered for the prevention of CDI or as adjunctive treatment in otherwise healthy patients, considering the risk of translocation and secondary infection in severely immunocompromised patients. 3.4. Bacteriotherapy by way of fecal transplantation When treatment with antibiotics fails to clear CDI due to lack of restoration of healthy intestinal flora, replacement of the gastrointestinal contents with healthy fecal material could be considered the ‘ultimate probiotic’.30 Patients considered for stool transplantation typically have a laboratory-confirmed diagnosis of C. difficile colitis with two or more documented relapses after initial antimicrobial treatment. Preferred stool donors are typically individuals who have intimate contact with the patient in an attempt to reinstate gastrointestinal microbiota similar to the patient’s original flora. Donors must be screened for infectious agents, including serologic testing for hepatitis A, B, and C; HIV-1 and HIV-2; syphilis; and stool cultures for enteric bacterial pathogens, ova, and parasites.31,32 The stool transplant recipient is often treated with 4 days of vancomycin (250 mg every 8 h) to reduce the C. difficile load, as well as two doses of omeprazole (20 mg) to decrease gastric acid production and create a receptive environment for the new bacteria to colonize. Some colonic preparation regimens also include administration of polyethylene glycol in an attempt to eliminate C. difficile organisms and spores before administration of transplanted stool. Preparation of the donor stool sample before transplantation typically involves obtaining the sample, adding sterile normal saline and homogenizing in a blender, and filtering the suspension with a paper coffee filter.31,32 The prepared stool sample may be instilled into the lower or upper end of the gastrointestinal tract. To date, most reported cases have received fecal transplantation through the rectum via retention enema or colonoscope, although instillation into the upper gastrointestinal tract via a nasogastric, nasoduodenal, or nasojejunal tube appears to have a low risk of complications, requires a small volume of stool, and may require only one treatment.31,32 The use of fecal transplantation has been documented in the literature since 1958, and though treatment guidelines still do not recommend fecal transplantation due to insufficient evidence, the available evidence of fecal bacteriotherapy for recurrent CDI is promising, with some studies reporting over 90% success rates.5,33 Particular interest and success with this treatment option has been seen in Canada, where the new hypervirulent, epidemic strain of C. difficile has led to a three-fold increase in mortality since the early 1990 s; and success rates have led to increased interest in the USA as well.8 A recently published retrospective case series reported a response rate of 100% in 12 patients with recurrent CDI treated with transplantation of donor stool via colonoscopy.34

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While fecal transplantation appears to be extremely successful and well tolerated assuming accurate and extensive screening of donors, the procedure does lack a certain aesthetic appeal, which could result in a patient’s unwillingness to accept treatment. However, after recurrent bouts of C. difficile-associated disease, most patients appear receptive to the procedure.31 In the willing patient who has experienced multiple episodes of CDI refractory to current therapies, fecal transplantation could be used as an alternative treatment strategy. 3.5. Colonization with nontoxigenic Clostridium difficile Pathogenic strains of C. difficile produce toxin A, toxin B, and binary toxin. Nontoxigenic strains of C. difficile, which lack the genes to produce toxins and do not appear to cause human disease, have been found in studies of asymptomatic patients.35 It is assumed that nontoxigenic strains compete with toxigenic strains for nutrients and adherence in the bowel, thus preventing infection or recurrence of infection. In 1987, Seal et al. reported that oral administration of nontoxigenic strains of C. difficile led to remission of infection in two patients.36 A 1998 study by Kyne et al. suggested that patients who had been asymptomatically colonized with C. difficile developed enough serum IgG antibody response to toxin A to prevent clinical symptoms.37 Nontoxigenic colonization of both hamsters and pigs has been successful in preventing subsequent colonization with a toxigenic strain of C. difficile upon challenge.35,38 Dosages of nontoxigenic C. difficile are typically based on the specific strain administered (e.g., 1 106 spores/day).35 Due to the promising results in animal models, a phase I clinical trial for nontoxigenic C. difficile (NTCD) is underway to determine the safety and tolerability of oral NTCD in healthy adults.39 3.6. Whole bowel irrigation Polyethylene glycol is often used prior to fecal transplantation in hopes of reducing bacterial and toxin load, as well as providing a suitable environment for transplantation of healthy fecal matter. In 1996, Liacouras and Piccoli reported the success of whole bowel irrigation with polyethylene glycol as adjuvant therapy in two pediatric patients with refractory C. difficile disease.40 In these patients, the polyethylene glycol was given until the patient produced profuse, clear liquid stools (which typically requires a dosing regimen of 17 g of powder in 8 ounces of clear liquid given every 10 min until 2 l are consumed). The polyethylene glycol was followed by a 3-week course of oral vancomycin plus Lactobacillus; therefore, it is difficult to determine if the whole bowel irrigation was essential to therapeutic success. However, the authors suggest that whole bowel irrigation clears active C. difficile organisms, toxins, and spores from the intestine. The possible mechanism of action of polyethylene glycol in C. difficile is unknown, but theories include that polyethylene glycol results in rapid intestinal transit time and dilution of intestinal bacteria.41 It does not appear that polyethylene glycol has any antibacterial effect.41 It is important to keep in mind that polyethylene glycol will cause abdominal bloating, cramping, and diarrhea. There is not extensive evidence in the literature for the use or success of whole bowel irrigation; therefore, at this time whole bowel irrigation should be reserved for adjuvant use prior to fecal transplantation or in patients who have experienced multiple recurrences of CDI. 3.7. Toxin-binding adsorbents 3.7.1. Ion-exchange resins Cholestyramine and colestipol have been studied for use in CDI due to their ability to exchange chloride ions for C. difficile toxin to form a non-absorbable complex with the toxin in the intestine.42

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Cholestyramine was first used for pseudomembranous colitis in the late 1970 s, even prior to identification of C. difficile as the causative pathogen.43 One early study showed successful binding of C. difficile toxin by both agents in vitro and also demonstrated efficacy of cholestyramine at delaying death in hamster models.44 Colestipol was studied in a randomized controlled trial of 38 patients at a dose of 10 g four times daily for 5 days, but was shown to be no better than placebo with an initial cure rate of 25%.45 Further studies of colestipol administered in conjunction with vancomycin were inconclusive. Subsequently, case studies reporting success of extended course cholestyramine in patients with recurrent or relapsing C. difficile colitis were published.46–48 While ion-exchange resins are generally safe, with the major side effect being constipation, a potential contraindication to their use in CDI is their binding of oral vancomycin. Ion-exchange resins reduce fecal concentrations of vancomycin up to 80%.42,44,49 SHEA/ IDSA guidelines indicate that this interaction is a contraindication to the use of ion-exchange resins, but some researchers support their use when separated by 2–3 h from the vancomycin doses.1,5 There have been conflicting reports of whether metronidazole is bound by cholestyramine. In vitro studies have failed to show an interaction, but other studies have demonstrated an approximate 20% reduction in metronidazole bioavailability.49 Without conclusive data, the administration of ion-binding resins and metronidazole should be separated by at least 2 h.50 Despite binding of vancomycin and potentially metronidazole, ion-exchange resins have a mild adverse effect potential and are inexpensive, making them attractive adjunctive treatment options to standard therapy for CDI. Current suggestions for the use of ionexchange resins include colestipol 5 g every 12 h or cholestyramine 4 g three to four times daily for 1 to 2 weeks, in conjunction with metronidazole or vancomycin, administered at least 2 h after the oral antibiotic dose.1,5 Toxin-binding capacity of these agents is a known commodity, but the risk of binding orally administered therapies often precludes their routine use as an adjunctive therapy. A potentially novel use of these agents may be in patients requiring a negative toxin to be eligible for discharge. 3.7.2. Non-antibiotic polymer Tolevamer is a toxin-binding polymer developed to bind C. difficile toxins in the intestinal tract at doses of 3–6 g daily.42 Tolevamer offers inherent advantages over standard therapies as it has no antibiotic properties, does not further suppress or harm normal gut flora, and would not result in the development of resistant strains.51 As opposed to ion-exchange resins, tolevamer does not appear to bind metronidazole or vancomycin. Initial studies resulted in severe hypokalemia, prompting product reformulation to a potassium sodium salt (ExodifTM) by Genzyme, which was found to be safe and effective in phase I trials.52 Early phase II studies of tolevamer reported similar outcomes compared to standard therapy in mild-to-moderate CDI, as well as a trend towards lower recurrence rates. These results were confounded by high dropout rates in the tolevamer groups ranging from 23% to 50%. Phase III trials of tolevamer published in 2009 reported that tolevamer was not successful in reducing the duration or magnitude of C. difficile toxin activity, and at this time further development of tolevamer has been terminated.42,53 If development of non-antibiotic polymers does resume, they would most likely serve an adjunctive role to standard therapies for C. difficile treatment. 3.8. Oral beta-lactamases Exposure to antibiotics remains the most important risk factor for the development of CDI. In many cases, the inciting antibiotic is being used to treat a source of infection that lies outside of the

gastrointestinal tract; therefore, there is no need for antimicrobial activity within the intestines. It has been hypothesized that administration of an oral beta-lactamase in conjunction with a parenterally administered beta-lactam antibiotic could be a useful strategy for prevention of development of CDI. Theoretically, betalactam antibiotics reaching the intestine during parenteral administration would be inactivated by the orally administered beta-lactamase, thus preventing destruction of normal gastric flora and subsequent colonization with C. difficile. Stiefel et al. have demonstrated that administration of a proteolysis-resistant betalactamase could degrade beta-lactam antibiotics—thus maintaining the colonization resistance of intestinal flora—within the small intestine in animal models.54,55 Human models may prove the use of oral beta-lactamase enzymes to be a potential preventative strategy in patients at high risk for development of CDI requiring parenteral beta-lactam therapy. 3.9. Immunotherapy Immunotherapy has become an area of increasing interest with the emergence of hypervirulent strains of C. difficile. Immunotherapy for CDI involves administration of antibodies against clostridial toxins via transfer of active immunity with intravenous immunoglobulins (IVIG) or through monoclonal antibody therapy. 3.9.1. Immunoglobulins IVIG have been studied in C. difficile disease in an attempt to increase low serum antibody levels to C. difficile toxin A, as these low levels have been shown to predispose patients to the development of CDI.37 Though the true mechanism of IVIG entering the colon and binding C. difficile toxins is not understood, it is thought that immunoglobulins may be able to cross the colonic membrane due to the inflammation caused by C. difficile toxin.56IVIG was first used for C. difficile colitis in 1991 by Leung et al. in the treatment of pediatric patients, all of whom achieved a full resolution of symptoms.57 Unfortunately, since then, studies on the use of immunoglobulins for C. difficile have been limited. A systematic review of the literature in 2009 by O’Horo et al.58 revealed only four retrospective studies and five case reports on the use of IVIG for the treatment of C. difficile infection, as well as one study using oral immunoglobulin. Only one study was controlled, which failed to show a benefit of IVIG compared to standard treatment in severe CDI.58 A retrospective review of 21 patients with C. difficile colitis conducted by Abougergi et al. in 2010 found that not all patients benefited from treatment with IVIG. Only nine patients survived their illness and were discharged from the hospital, while 12 patients died during hospitalization.59 Doses of IVIG range from 150 to 400 mg per kg per dose.60 Often, only one dose of IVIG is necessary, but repeat doses have been documented in patients who experience further recurrence of C. difficile.57–59 The available literature does indicate a possible benefit with IVIG in severe CDI and it may be considered in refractory and recurrent CDI, given the relatively low immune response common among patient with recurrent infections. Drug-induced aseptic meningitis should be considered as a possible adverse event from IVIG therapy. IVIG may be a useful adjunctive treatment option in those who have failed initial therapies or in seriously ill patients in whom surgery is being considered. 3.9.2. Monoclonal antibodies Monoclonal antibodies targeted against C. difficile toxins have been developed in an attempt to neutralize toxins and enhance the immune response. A randomized, double-blind, placebo-controlled study of 200 patients found that the addition of 10 mg per kg of two monoclonal antibodies against C. difficile toxins A and


B to a standard antibiotic agent (vancomycin and metronidazole) significantly reduced recurrence of CDI compared to those who received only standard therapy (7% vs. 25%, respectively).61 A phase II randomized, double-blind, placebo-controlled trial evaluating C. difficile anti-toxin A serum antibody was conducted to determine the correlation between C. difficile anti-toxin A serum antibodies and protection against symptomatic CDI as well as disease recurrence. The study found no significant difference in the rate of recurrence between the two groups, although time to recurrence was shorter in the antibody group. The study did find that recurrence of CDI was associated with lower concentrations of antibodies against anti-toxin A and B, as well as with resistant strains of C. difficile.62 Merck has entered a licensing agreement for this monoclonal antibody combination (CDA-1 and CDB-1, also known as MDX-066/MDX-1388 or MBL-CDA1/MBL-CDB1) and will continue the development.63 Though not yet commercially available, monoclonal antibody preparations against C. difficile toxins may be useful in patients with severe or recurrent CDI in combination with metronidazole or vancomycin. 3.9.3. Vaccination Passive and active immunization with a C. difficile toxoid vaccine are being tested in a phase II, randomized, secondary prevention trial. The vaccination contains inactivated toxoids A and B and is immunogenic and well-tolerated in healthy volunteers.64 Patients who would seemingly benefit the most from vaccination are older adults who may have a suboptimal immune response to vaccination. Sanofi-Aventis is currently conducting a study comparing the rate of CDI development in groups receiving ACAM-CDIFFTM vaccine versus placebo: the first stage of the study is designed to test four different formulations of the vaccine (low-dose or high-dose with or without adjuvant), while the second stage will determine the optimal vaccination schedule. DNA vaccines to C. difficile toxins have also been developed and have been found to produce high titer antibodies and protect mice from death; however, these vaccines have not yet been studied in humans.65 Results of human trials will help determine the place in therapy for this promising vaccination strategy. 3.10. Alternative antimicrobials 3.10.1. Bismuth subsalicylate Bismuth subsalicylate, the active ingredient in Pepto-Bismol1 (Procter & Gamble, Cincinnati, OH, USA), is known to have antibacterial activity at concentrations that are achievable within the gastrointestinal tract. Studies of the in vitro activity of bismuth subsalicylate have shown sensitivity of C. difficile to this widely available over-the-counter product. In 1990, Cornick et al. published a study demonstrating in vitro activity of bismuth subsalicylate against C. difficile, and Gorbach et al. determined that bismuth subsalicylate did not have adverse effects on normal fecal flora.66,67 Chang et al. found that bismuth subsalicylate was useful in the treatment of C. difficile in hamsters.68 A 2004 study by Mahony et al. further demonstrated the in vitro activity of bismuth subsalicylate (100 mg dissolved in 10 ml of various fluids) against C. difficile.69 General adverse effects of bismuth subsalicylate are mild and may include darkening of the tongue and stool or tinnitus. Clinical investigation of bismuth subsalicylate may be worth pursuing, as this product may be an option as an adjunct in the treatment of C. difficile or as a secondary prophylaxis during gut flora restoration following antibiotic therapy. 3.10.2. Rifamycin antibiotics Agents from the rifamycin class of antibiotics, including rifampin and rifaximin (Xifaxan1, Salix Pharmaceuticals, Morrisville, NC,

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USA), have been studied as potential agents for recurrent CDI due to their potent in vitro activity.70 In 2008, Garey et al. reviewed the literature relating to rifamycin antibiotics for use in CDI and found that while there is extensive evidence that members of this class of antibiotics have in vitro activity against C. difficile, there were only six published clinical reports investigating their use clinically.70 The evidence for rifampin included a case study indicating resolution of fever and diarrhea after administration, as well as a case series of seven patients who normalized within 3 days of rifampin initiation, with the most common dosage regimens of rifampin for C. difficile being 300–600 mg every 12 h in combination with vancomycin treatment.71,72 A prospective, single-blinded study comparing metronidazole to metronidazole plus rifampin for first episodes of CDI found no clinical benefit in the rifampin group, and rifampin treatment was associated with a non-significant increase in mortality.73 There is also a great concern with significant drug– drug interactions and the development of rifampin resistance.70 Of the rifamycins, rifaximin is the most appealing for use in the treatment of CDI. The agent is neither absorbed by the gastrointestinal tract nor inactivated by gastric juices, and it exerts its action entirely within the intestinal lumen.74 While C. difficile strains have been shown to develop resistance to rifaximin when only low concentrations of the antibiotic are present, the incidence is far lower than would be expected with rifampin, and it is thought that the drug may retain efficacy against isolates with higher minimum inhibitory concentration (MIC) values due to high concentrations achieved in the feces.70,74Published clinical evidence of rifaximin use includes three case series, a prospective pilot study, and one randomized controlled trial. Johnson et al. reported no recurrence of CDI in seven of eight women administered rifaximin following their last treatment with vancomycin, a method termed a rifaximin ‘chaser’; the one patient who exhibited recurrence responded to a second treatment course of rifaximin, though rifaximin-resistant C. difficile was isolated from this patient after her second treatment course.75 Garey et al. reported success of a rifaximin taper in symptomatic, hospitalized patients.76 More recently, a series of three liver transplant patients with recurrent diarrhea experienced resolution of symptoms within 36–48 h of initiation of rifaximin after failure of both metronidazole and vancomycin.77 Basu et al. also reported eradication of CDI in 64% of an intent-to-treat population of 25 patients who received rifaximin after failure of metronidazole therapy.78 The most common dosages of rifaximin range from 400 to 800 mg daily in two to three divided doses for 2 weeks; though some studies report extended durations of up to 28 days. Adverse reactions of rifaximin may include peripheral edema, dizziness and fatigue, ascites, and nausea, though it is generally well tolerated.75– 78

The use of rifaximin as a ‘chaser’ following standard antibiotic treatment is a potential treatment option in patients with refractory or recurrent CDI. 3.10.3. Nitazoxanide Nitazoxanide is an older agent that is effective in the treatment of parasitic gastrointestinal infections such as cryptosporidiosis, particularly in immunocompromised patients.79 Nitazoxanide blocks anaerobic metabolism of eukaryotes and has been found to inhibit C. difficile in vitro and at low concentrations, including strains resistant to metronidazole.80,81 In a hamster model, nitazoxanide was found to have MICs and minimum bactericidal concentrations (MBCs) against 15 toxigenic strains of C. difficile that were comparable to those of vancomycin or metronidazole.82 Musher et al. conducted a prospective, randomized, double-blind study to compare nitazoxanide (500 mg twice daily for 7 or 10 days) to metronidazole in hospitalized patients and found nitazoxanide and metronidazole to have comparable efficacies.

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In addition, the nitazoxanide group demonstrated a high response rate in patients who failed metronidazole therapy.83 Most recently, Musher et al. conducted a prospective, randomized controlled trial comparing 10-day therapy with vancomycin or nitazoxanide, and the two were found to have similar end-of-therapy response rates (87%, 20 of 23 vs. 94%, 17 of 18, respectively).84 The adverse effect profile of nitazoxanide appears to be mild, mainly including headache and gastrointestinal complaints. While further studies of nitazoxanide will be needed, this agent appears safe and effective as an option for recurrent or refractory disease. This also offers an additional option in select patients for initial treatment of CDI. 3.10.4. Tigecycline Tigecycline, approved for the treatment of skin and skin structure infections as well as community-acquired pneumonia, has emerging data supporting its use in CDI. Tigecycline is associated with a low risk of CDI, and recent in vitro studies, primarily in Europe, have revealed that among multidrug-resistant isolates of Clostridium, all were susceptible to tigecycline.85 Tigecycline has also been found to reach fecal concentrations high enough to reduce intestinal microflora without inducing C. difficile cytotoxin production. There have been no prospective clinical trials of tigecycline for the treatment of CDI; however, a case series did report successful outcomes with no recurrences of CDI in a group of patients in whom tigecycline was used for salvage therapy.86 One published case report discussed the success of tigecycline for the treatment of CDI refractory to metronidazole and vancomycin, while another published case reported failure of tigecycline in combination with vancomycin and metronidazole in a patient with severe CDI.87,88 Standard dosing of tigecycline is a 100 mg loading dose followed by 50 mg intravenously every 12 h, with the most common adverse effects being nausea and vomiting.86,89 While tigecycline has not been extensively studied in vivo for the treatment of CDI, it may be a promising treatment option in patients with refractory, recurrent CDI resistant to standard treatment options. Tigecycline should also be considered a lowrisk antibiotic for causing CDI. 3.10.5. Linezolid Linezolid, a member of the oxazolidinone class of antibiotics, was found to have in vitro activity against C. difficile.90,91 Approximately 12–23% of linezolid is excreted unchanged in the stool and a limited impact on normal gut flora was noted in a single study.91,92 A single case report indicated failure of IV linezolid in CDI, and Zabel and Worm reported a case of linezolid contributing to fatal C. difficile colitis.93,94 No specific dosing regimen of linezolid for C. difficile can be recommended at this time, as studies have mainly been in vitro; the typical dosing range of linezolid is 600 mg every 12 h. In addition, diarrhea can be a substantial adverse effect of linezolid.93 At this time, the inconclusive data surrounding linezolid prevent recommendation as an option for the treatment of C. difficile disease. Linezolid may be considered a low-risk antibiotic for contributing to CDI.

hamster models.96 A phase II trial of ramoplanin has revealed equivalence to vancomycin for the treatment of C. difficile colitis at doses of 200 or 400 mg administered twice daily for 10 days.96 Adverse effects of ramoplanin were also found to be comparable to vancomycin and most commonly included gastrointestinal complaints.96 Though ramoplanin is currently not approved by the FDA, it may be a promising emerging treatment alternative to vancomycin for initial treatment of CDI. 3.11.2. Fidaxomicin Fidaxomicin is a novel, narrow-spectrum macrocyclic antibiotic agent that has shown selective in vitro activity against C. difficile. Fidaxomicin differs from vancomycin and metronidazole in that it exhibits little to no activity against the normal gastrointestinal flora, eliminating C. difficile while allowing recovery of the protective normal flora.97 Fidaxomicin appears to achieve high concentrations in the feces compared to low concentrations in the plasma, preferential in the treatment of CDI. Preliminary clinical trials indicate that fidaxomicin may be an effective option for the treatment of mild-to-moderate CDI, comparable to vancomycin and resulting in fewer recurrences.98,99 Currently, two phase III clinical trials of fidaxomicin indicate that among 1105 patients with CDI, those treated with fidaxomicin experienced similar cure rates to those patients treated with vancomycin, and the fidaxomicin group experienced 47% fewer recurrences. Among 128 patients with recurrent CDI, 35.5% receiving vancomycin experienced yet another recurrence as opposed to only 19.7% in the fidaxomicin group. Fidaxomicin has also shown efficacy against the hypervirulent BI/NAP1/027 strain of C. difficile.100,101 The adverse effect profile of fidaxomicin may include gastrointestinal complaints, generalized symptoms including fever, chills, and fatigue; however, adverse effects in clinical trials have been comparable to vancomycin.101,102 The manufacturer recently reported a New Drug Application was accepted by the FDA with a goal date for priority review of May 31, 2011.103 Fidaxomicin appears to be an effective and safe alternative to standard therapy for the treatment of CDI, while also reducing the rate of relapse. 4. Conclusions The incidence and hospitalizations due to C. difficile infection and disease have grown at an alarming rate since C. difficile was first linked to human disease in 1977, due in part to the increased use of broad-spectrum antibiotics. Patients who develop an initial C. difficile infection and are treated with metronidazole or vancomycin often enter remission only to develop recurrent infections that become increasingly difficult to treat with further antibiotic therapy due to suppression of normal gut flora. While judicious use of antibiotics and implementation of proper infection control procedures will hopefully reduce the incidence of C. difficile-associated disease, there are promising alternative and adjunctive therapies for the prevention and treatment of C. difficile on the horizon. Acknowledgements

3.11. Antimicrobials under development for the treatment of C. difficile disease 3.11.1. Ramoplanin Ramoplanin is an antimicrobial compound with in vitro activity against C. difficile and is currently under investigation for treatment of enterococcal infections and CDI.95,96 Ramoplanin inhibits cell wall synthesis by acting at the level of lipid intermediate formation against C. difficile and was found to be as effective as vancomycin in

We would like to acknowledge Nadia M. BouFawaz, PharmD candidate, Jana M. Coleman, PharmD candidate, and Tiffany D. Howell, PharmD candidate for their editorial input and gracious assistance in completing this comprehensive review. Conflict of interest: PBB receives research funding from Cubist Pharmaceuticals, Pfizer Inc., Merck & Co. Inc., Astellas Pharma US; is a member of the consultant advisory board for Ortho-McNeil Pharmaceuticals; is a member of the speaker’s bureau for Merck &


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