Clostridium difficile Infections in Solid Organ Transplantation

Clostridium difficile infection (CDI) is a common problem encountered in solid-organ transplant (SOT) recipients and the incidence is increasing. SOT recipients have an incidence of CDI that is higher than other postoperative patients, and this group has several unique risk factors that may contribute to more severe disease. Recent publications in nontransplant patients have indicated that treatment choices should be based on the severity of the illness (1Cohen SH Gerding DN Johnson S et al.Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA).Infect Control Hosp Epidemiol. 2010; 31: 431-455Crossref PubMed Scopus (2527) Google Scholar). Although there continues to be a lack of well-designed, randomized, controlled trials to support the management decisions that must be made for SOT recipients with CDI, the available evidence is reviewed and summarized for these treatment guidelines. Clostridium difficile is a spore-forming, anaerobic, Gram-positive bacillus. It causes 6–25% of cases of antibiotic-associated diarrhea, up to 75% of antibiotic-associated colitis, and over 90% of cases of antibiotic-associated pseudomembranous colitis (1Cohen SH Gerding DN Johnson S et al.Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA).Infect Control Hosp Epidemiol. 2010; 31: 431-455Crossref PubMed Scopus (2527) Google Scholar). C. difficile causes inflammatory diarrhea and colonic mucosal injury through production of two exotoxins, toxin A and toxin B, which trigger a cytotoxic response, neutrophilic infiltrate and cytokine release (1Cohen SH Gerding DN Johnson S et al.Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA).Infect Control Hosp Epidemiol. 2010; 31: 431-455Crossref PubMed Scopus (2527) Google Scholar). The resulting inflammatory response results in the visible yellow plaques that form the characteristic pseudomembrane. This finding is less commonly seen in patients on immunosuppressive medications (2Nomura K Fujimoto Y Yamashita M et al.Absence of pseudomembranes in Clostridium difficile-associated diarrhea in patients using immunosuppression agents.Scand J Gastroenterol. 2009; 44: 74-78Crossref PubMed Scopus (60) Google Scholar). Although most strains of C. difficile produce both toxins A and B (toxigenic C. difficile), some produce only toxin B, and some do not produce any toxin. Strains that produce only toxin B can produce the same spectrum of illness as those that produce both toxins and are considered toxigenic. Strains that do not produce toxins A or B (nontoxigenic) are not capable of causing C. difficile infection (CDI). Some C. difficile strains also produce a binary toxin; however, what role this toxin plays in humans disease is not known (1Cohen SH Gerding DN Johnson S et al.Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA).Infect Control Hosp Epidemiol. 2010; 31: 431-455Crossref PubMed Scopus (2527) Google Scholar). It is also important to note that 50% or more of patients in healthcare settings colonized with toxigenic C. difficile never develop CDI (1Cohen SH Gerding DN Johnson S et al.Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA).Infect Control Hosp Epidemiol. 2010; 31: 431-455Crossref PubMed Scopus (2527) Google Scholar,3Loo VG Bourgault AM Poirier L et al.Host and pathogen factors for Clostridium difficile infection and colonization.N Engl J Med. 2011; 365: 1693-1703Crossref PubMed Scopus (636) Google Scholar,4Clabots CR Johnson S Olson MM Peterson LR Gerding DN Acquisition of Clostridium difficile by hospitalized patients: Evidence for colonized new admissions as a source of infection.J Infect Dis. 1992; 166: 561-567Crossref PubMed Scopus (381) Google Scholar). Whether this proportion differs in SOT recipients is not known. The incidence and severity of CDI have increased dramatically since the year 2000 (5Loo VG Poirier L Miller MA et al.A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality.N Engl J Med. 2005; 353: 2442-2449Crossref PubMed Scopus (1689) Google Scholar). These changes in CDI epidemiology have been associated with the emergence of the North American pulsed field gel electrophoresis type 1 (NAP1)/restriction enzyme analysis type BI/PCR-ribotype 027 (NAP1/BI/027) strain of C. difficile (5Loo VG Poirier L Miller MA et al.A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality.N Engl J Med. 2005; 353: 2442-2449Crossref PubMed Scopus (1689) Google Scholar). CDI is a more frequently encountered problem in SOT recipients than other hospitalized populations. The incidence of CDI is estimated to be 3–19% in liver recipients, 3.5–16% in kidney recipients, 1.5–7.8% in pancreas–kidney recipients, 9% in intestinal recipients, 8–15% in heart recipients and 7–31% in lung recipients (6Boutros M Al Shaibi M Chan G et al.Clostridium difficile colitis: Increasing incidence, risk factors, and outcomes in solid organ transplant recipients.Transplantation. 2012; 93: 1051-1057Crossref PubMed Scopus (99) Google Scholar,7Riddle DJ Dubberke ER Clostridium difficile infection in solid organ transplant recipients.Curr Opin Organ Transplant. 2008; 13: 592-600Crossref PubMed Scopus (75) Google Scholar). This is higher than that seen in other hospitalized patient populations, where the incidence is typically <1% (8Zerey M Paton BL Lincourt AE Gersin KS Kercher KW Heniford BT The burden of Clostridium difficile in surgical patients in the United States.Surg Infect. 2007; 8: 557-566Crossref PubMed Scopus (139) Google Scholar,9Dubberke ER Butler AM Yokoe DS et al.Multicenter study of Clostridium difficile infection rates from 2000 to 2006.Infect Control Hosp Epidemiol. 2010; 31: 1030-1037Crossref PubMed Scopus (82) Google Scholar). Fulminant colitis develops in up to 8% of immunocompetent patients and 13% of SOT recipients with CDI (10Dallal RM Harbrecht BG Boujoukas AJ et al.Fulminant Clostridium difficile: An underappreciated and increasing cause of death and complications.Ann Surg. 2002; 235: 363-372Crossref PubMed Scopus (523) Google Scholar). The incidence of CDI in SOT recipients is highest within the first 3 months after the procedure, probably because of more frequent antimicrobial exposure, intense immunosuppression and increased exposure to the healthcare setting (6Boutros M Al Shaibi M Chan G et al.Clostridium difficile colitis: Increasing incidence, risk factors, and outcomes in solid organ transplant recipients.Transplantation. 2012; 93: 1051-1057Crossref PubMed Scopus (99) Google Scholar,10Dallal RM Harbrecht BG Boujoukas AJ et al.Fulminant Clostridium difficile: An underappreciated and increasing cause of death and complications.Ann Surg. 2002; 235: 363-372Crossref PubMed Scopus (523) Google Scholar). Late-onset CDI occurs months to years after the transplant and is usually associated with either antimicrobial exposure or intensified immunosuppression to treat graft rejection (10Dallal RM Harbrecht BG Boujoukas AJ et al.Fulminant Clostridium difficile: An underappreciated and increasing cause of death and complications.Ann Surg. 2002; 235: 363-372Crossref PubMed Scopus (523) Google Scholar). It is not known how the NAP1/BI/027 strain has impacted the incidence and severity of CDI in SOT recipients relative to the general hospital population. Antimicrobial exposure is the most important risk factor for development of CDI (7Riddle DJ Dubberke ER Clostridium difficile infection in solid organ transplant recipients.Curr Opin Organ Transplant. 2008; 13: 592-600Crossref PubMed Scopus (75) Google Scholar). Any antimicrobial agent may predispose to CDI, but clindamycin, ampicillin, cephalosporins and fluoroquinolones are most frequently implicated (1Cohen SH Gerding DN Johnson S et al.Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA).Infect Control Hosp Epidemiol. 2010; 31: 431-455Crossref PubMed Scopus (2527) Google Scholar). The use of multiple antimicrobial agents and extended treatment courses have also been identified as risk factors (1Cohen SH Gerding DN Johnson S et al.Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA).Infect Control Hosp Epidemiol. 2010; 31: 431-455Crossref PubMed Scopus (2527) Google Scholar). Antimicrobial agent administration has been associated with CDI in nearly all immunocompetent inpatients with CDI. However, some studies have found only 80% of transplant recipients who develop CDI have recent antimicrobial exposures (11Bignardi GE Risk factors for Clostridium difficile infection.J Hosp Infect. 1998; 40: 1-15Abstract Full Text PDF PubMed Scopus (533) Google Scholar). The reduced relationship with antimicrobial exposure in SOT recipients may be secondary to alterations in the normal flora and impaired immunity due to immunosuppressive medications, severe pretransplant illness and surgical intervention. Immune system dysfunction may also be an important factor in the development of CDI in SOT recipients. The importance of the humoral immune response is demonstrated by a fourfold greater incidence of symptomatic disease in patients who are newly infected and lack preexisting immunity (12Shim JK Johnson S Samore MH Bliss DZ Gerding DN Primary symptomless colonisation by Clostridium difficile and decreased risk of subsequent diarrhoea.Lancet. 1998; 351: 633-636Abstract Full Text Full Text PDF PubMed Scopus (305) Google Scholar). A brisk humoral response to C. difficile toxins after infection reduces the likelihood of symptomatic disease (13Kyne L Warny M Qamar A Kelly CP Asymptomatic carriage of Clostridium difficile and serum levels of IgG antibody against toxin A.N Engl J Med. 2000; 342: 390-397Crossref PubMed Scopus (782) Google Scholar). The hypogammaglobulinemia commonly associated with lung, heart and liver transplants may result in a poor immune response and increase the incidence of CDI by fivefold in some patient subsets (14Munoz P Giannella M Alcala L et al.Clostridium difficile associated diarrhea in heart transplant recipients: Is hypogammaglobulinemia the answer?.J Heart Lung Transplant. 2007; 26: 907-914Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar). The use of medications that suppress gastric acid, such as proton pump inhibitors and H2 receptor antagonists, is common in SOT recipients and may also serve as a significant risk factor for the development of CDI. The acidic environment of the stomach is usually fatal to vegetative forms of C. difficile and may prevent germination of the spore form of the organism. Proton-pump inhibitors (PPIs) may also cause disturbances in the gastrointestinal flora that can allow C. difficile to more easily colonize the bowel. However, whether gastric acid suppression plays a causative role in CDI pathogenesis or is a marker for patients at risk for CDI remains unresolved (1Cohen SH Gerding DN Johnson S et al.Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA).Infect Control Hosp Epidemiol. 2010; 31: 431-455Crossref PubMed Scopus (2527) Google Scholar). Other risk factors commonly cited in the literature include age greater than 65 years old, severe underlying disease, uremia, gastrointestinal surgery, presence of a nasogastric or endotracheal tube and prolonged hospitalization (15Dubberke ER Reske KA Yan Y Olsen MA McDonald LC Fraser VJ Clostridium difficile-associated disease in a setting of endemicity: Identification of novel risk factors.Clin Infect Dis. 2007; 45: 1543-1549Crossref PubMed Scopus (223) Google Scholar). SOT recipients frequently have a combination of these risk factors. Of note, infants under the age of 1 are generally not thought to be at risk for CDI; however, asymptomatic carriage of C. difficile in this population is common (12Shim JK Johnson S Samore MH Bliss DZ Gerding DN Primary symptomless colonisation by Clostridium difficile and decreased risk of subsequent diarrhoea.Lancet. 1998; 351: 633-636Abstract Full Text Full Text PDF PubMed Scopus (305) Google Scholar). In this population, detection of C. difficile or its toxins should not be assumed to be the cause of diarrhea until alternate causes of diarrhea are ruled out.-Antimicrobial exposure, advanced age, immune system dysfunction or immunosuppression and gastric acid suppression are important risk factors for CDI (II-2). CDI is diagnosed by confirming the presence of toxigenic C. difficile in the stool of a symptomatic patient. Recent evidence suggests that clinical information is critical when it comes to interpreting C. difficile test results, especially if more sensitive assays such as nucleic acid amplification tests (NAAT) are used (16Dubberke ER Han Z Bobo L et al.Impact of clinical symptoms on interpretation of diagnostic assays for Clostridium difficile infections.J Clin Microbiol. 2011; 49: 2887-2893Crossref PubMed Scopus (158) Google Scholar). While SOT patients may have an atypical presentation, their transplant status should not affect diagnostic assays. The laboratory gold standard for C. difficile toxin detection in stool is the cytotoxicity cell assay, and the gold standard for detecting toxin producing C. difficile is toxigenic culture. Cytotoxicity cell assays detect biologically active toxin in stool. However cytotoxicity cell assays have fallen out of favor because it is relatively labor intensive and the delay of at least 24 h before interpretation (1Cohen SH Gerding DN Johnson S et al.Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA).Infect Control Hosp Epidemiol. 2010; 31: 431-455Crossref PubMed Scopus (2527) Google Scholar). Toxigenic culture involves anaerobic culture of C. difficile followed by testing isolates for toxin production. It is rarely used for clinical diagnosis due to slow turnaround time and costs. However it is an important tool for epidemiological studies. According to a 2008 College of American Pathologists survey, 45% of institutions in the United States currently use commercially available ELISAs for C. difficile toxin detection (17Schmidt ML Gilligan PH Clostridium difficile testing algorithms: What is practical and feasible?.Anaerobe. 2009; 15: 270-273Crossref PubMed Scopus (55) Google Scholar). These assays provide a rapid turnaround of results and are relatively inexpensive. ELISAs are generally only 60–90% sensitive compared with cytotoxicity assays, though newer assays continue to improve detection rates (18Mohan SS McDermott BP Parchuri S Cunha BA Lack of value of repeat stool testing for Clostridium difficile toxin.Am J Med. 2006; 119: 356-358Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar) and may provide better specificity (16Dubberke ER Han Z Bobo L et al.Impact of clinical symptoms on interpretation of diagnostic assays for Clostridium difficile infections.J Clin Microbiol. 2011; 49: 2887-2893Crossref PubMed Scopus (158) Google Scholar). Even with the relatively low sensitivity, the negative predictive value of a negative toxin ELISA is greater than 95%, and repeat testing increases the likelihood of a false positive result. Therefore additional diagnostic and treatment decisions after an initial negative toxin assay should be based on the clinical suspicion of CDI rather than automatically repeating the test (1Cohen SH Gerding DN Johnson S et al.Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA).Infect Control Hosp Epidemiol. 2010; 31: 431-455Crossref PubMed Scopus (2527) Google Scholar). It is important to note some ELISAs only detect toxin A. These assays will miss strains that produce only toxin B. While ELISA may still be a common diagnostic modality for CDI, more hospitals are converting to a two-step algorithm that utilizes new molecular methods (17Schmidt ML Gilligan PH Clostridium difficile testing algorithms: What is practical and feasible?.Anaerobe. 2009; 15: 270-273Crossref PubMed Scopus (55) Google Scholar). Screening stool for the presence of glutamate dehydrogenase (GDH), a common cell wall protein produced by both toxigenic and nontoxigenic C. difficile, is the foundation for many of the new protocols. Testing for the presence of GDH allows for rapid and cost-effective screening; however, as GDH does not differentiate toxigenic strains from nontoxigenic strains, subsequent toxin testing is required for those stool specimens that are GDH positive (1Cohen SH Gerding DN Johnson S et al.Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA).Infect Control Hosp Epidemiol. 2010; 31: 431-455Crossref PubMed Scopus (2527) Google Scholar). The presence of toxigenic C. difficile in GDH positive specimens has been evaluated by several different assays. In addition to the previously mentioned ELISA and cytotoxicity cell assays, NAAT have been evaluated both as a stand-alone test as well as to confirm the presence of toxigenic C. difficile in GDH positive specimens (19Chapin KC Dickenson RA Wu F Andrea SB Comparison of five assays for detection of Clostridium difficile toxin.J Mol Diagn. 2011; 13: 395-400Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar). While the sensitivity of using NAAT testing alone for detecting C. difficile in stool approaches 93–100% (20Kvach EJ Ferguson D Riska PF Landry ML Comparison of BD geneOhm Cdiff real-time PCR assay with a two-step algorithm and a toxin A/B enzyme-linked immunosorbent assay for diagnosis of toxigenic Clostridium difficile infection.J Clin Microbiol. 2010; 48: 109-114Crossref PubMed Scopus (118) Google Scholar,21Sloan LM Duresko BJ Gustafson DR Rosenblatt JE Comparison of real-time PCR for detection of the tcdC gene with four toxin immunoassays and culture in diagnosis of Clostridium difficile infection.J Clin Microbiol. 2008; 46: 1996-2001Crossref PubMed Scopus (182) Google Scholar), the positive predictive value can be as low as 63% for the diagnosis of CDI, and it is the most costly method of diagnosis (16Dubberke ER Han Z Bobo L et al.Impact of clinical symptoms on interpretation of diagnostic assays for Clostridium difficile infections.J Clin Microbiol. 2011; 49: 2887-2893Crossref PubMed Scopus (158) Google Scholar). The low positive predictive value is due to detection of C. difficile in asymptomatic carriers. Regardless of what assay or algorithm an individual hospital uses, caution should be employed for only testing patients for whom there is a clinical concern for CDI. In cases where the presentation of CDI is atypical or the presence of ileus results in a lack of diarrhea, clinicians will need to rely on physical examination and laboratory findings. Fever, abdominal pain and abdominal distension are typically present in severe colitis, even in the absence of diarrhea (1Cohen SH Gerding DN Johnson S et al.Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA).Infect Control Hosp Epidemiol. 2010; 31: 431-455Crossref PubMed Scopus (2527) Google Scholar). Striking bandemia and a leukemoid reaction can be seen in SOT recipients with CDI. CT scan findings suggestive of severe colitis include significant bowel wall edema and ascites. These exam and laboratory findings usually precede organ dysfunction. A high index of suspicion for CDI is necessary in SOT patients with these otherwise unexplained exam and laboratory findings.-Providers should be familiar with the C. difficile diagnostic modalities available at their institution and customize their clinical evaluations accordingly (III).-Testing of stool for C. difficile and/or its toxins should only be performed in symptomatic patients who have stool that is not formed (II-2). If the initial ELISA test is negative, testing should be repeated only if there is a high index of suspicion for CDI and if test results will alter clinical management (II-2). Immediate repeat toxin testing is not indicated for cytotoxic tissue assays, GDH based algorithms and NAAT (II-2).-Test of cure assays (i.e. testing stool for the presence of C diff toxin at the completion of therapy) should be avoided (III).-Otherwise unexplained fever, abdominal pain and leukocytosis in a patient with ileus should prompt the clinician to consider CDI despite a lack of diarrhea (II-2). The presence of formed bowel movements indicates CDI is unlikely the cause of these symptoms (II-2). Severity of CDI can be divided into three categories: mild-to-moderate, severe and severe with complications (1Cohen SH Gerding DN Johnson S et al.Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA).Infect Control Hosp Epidemiol. 2010; 31: 431-455Crossref PubMed Scopus (2527) Google Scholar). Of note, there are no validated methods to objectively categorize patients as such. Mild-to-moderate CDI is typically patients with diarrhea and possibly also with mild abdominal pain and minimal systemic symptoms. Severe CDI includes abdominal pain, leukocytosis and fever or other systemic symptoms along with profuse diarrhea. Advanced age and patients with hypoalbuminemia are at increased risk for severe disease (1Cohen SH Gerding DN Johnson S et al.Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA).Infect Control Hosp Epidemiol. 2010; 31: 431-455Crossref PubMed Scopus (2527) Google Scholar). Severe disease with complications includes the symptoms of severe disease accompanied by life-threatening conditions such as paralytic ileus, toxic megacolon, refractory hypotension and/or multi-organ failure secondary to CDI. The disease severity may rapidly progress so clinicians should frequently reassess and adjust therapy accordingly. The first intervention that should occur in any patient with CDI is cessation of the inciting antimicrobial agent whenever possible. Removing antimicrobial pressure on the normal flora was curative in roughly 15–25% of immunocompetent patients prior to the NAP1/BI/027 epidemic (1Cohen SH Gerding DN Johnson S et al.Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA).Infect Control Hosp Epidemiol. 2010; 31: 431-455Crossref PubMed Scopus (2527) Google Scholar). If antimicrobial agents must be continued in order to treat another ongoing bacterial infection, clinicians may consider changing to a more narrow-spectrum regimen or an alternate antimicrobial agent with less association with CDI. Previously published guidelines support basing the initial antibiotic choice on the severity of CDI (1Cohen SH Gerding DN Johnson S et al.Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA).Infect Control Hosp Epidemiol. 2010; 31: 431-455Crossref PubMed Scopus (2527) Google Scholar) (Figure 1). Oral metronidazole is recommended for mild-to-moderate disease in both the general population and SOT recipients. Metronidazole undergoes biliary excretion and crosses the inflamed colonic mucosa so it also reaches adequate levels in the feces when given intravenously. This route of administration has not been rigorously studied, but is supported by several case series (22Johnson S Peterson LR Gerding DN Intravenous metronidazole and Clostridium difficile-associated diarrhea or colitis.J Infect Dis. 1989; 160: 1087-1088Crossref PubMed Scopus (10) Google Scholar). There has also been a long-held concern that the use of oral vancomycin will increase the incidence of vancomycin-resistant enterococci, but recent studies have not substantiated this effect (23Sethi AK Al Nassir WN Nerandzic MM Donskey CJ Skin and environmental contamination with vancomycin-resistant Enterococci in patients receiving oral metronidazole or oral vancomycin treatment for Clostridium difficile-associated disease.Infect Control Hosp Epidemiol. 2009; 30: 13-17Crossref PubMed Scopus (53) Google Scholar). A major disadvantage of metronidazole use in SOT recipients is an interaction with medications such as tacrolimus or sirolimus, so that levels of tacrolimus should be monitored during treatment. Readers are referred to the corresponding guidelines on interactions between antiinfective agents and immunosuppressants published in this supplement for further comment. Oral vancomycin is the preferred therapy for severe CDI. Several studies demonstrated improved response rates with vancomycin compared to metronidazole in severe disease. Two randomized studies found that 85–97% of patients with severe CDI were cured with vancomycin therapy, but only 65–76% of patients were cured with oral metronidazole (24Scheinfeld N Biggers K Tolevamer, an orally administered, toxin-binding polymer for Clostridium difficile-associated diarrhea.Curr Opin Investig Drugs. 2008; 9: 913-924Google Scholar,25Zar FA Bakkanagari SR Moorthi KM Davis MB A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity.Clin Infect Dis. 2007; 45: 302-307Crossref PubMed Scopus (1031) Google Scholar). These same studies continue to show no significant difference between the two antimicrobial agents in mild-to-moderate disease (24Scheinfeld N Biggers K Tolevamer, an orally administered, toxin-binding polymer for Clostridium difficile-associated diarrhea.Curr Opin Investig Drugs. 2008; 9: 913-924Google Scholar,25Zar FA Bakkanagari SR Moorthi KM Davis MB A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity.Clin Infect Dis. 2007; 45: 302-307Crossref PubMed Scopus (1031) Google Scholar). Vancomycin typically is administered at 125 mg four times daily in adults because higher doses have increased cost and side effects without improved efficacy (26Fekety R Silva J Kauffman C Buggy B Deery HG Treatment of antibiotic-associated Clostridium difficile colitis with oral vancomycin: Comparison of two dosage regimens.Am J Med. 1989; 86: 15-19Abstract Full Text PDF PubMed Scopus (236) Google Scholar). This regimen achieves stool vancomycin concentrations that are hundreds of times greater than the minimum inhibitory concentration (MIC) of C. difficile (27Hecht DW Galang MA Sambol SP Osmolski JR Johnson S Gerding DN In vitro activities of 15 antimicrobial agents against 110 toxigenic Clostridium difficile clinical isolates collected from 1983 to 2004.Antimicrob Agents Chemother. 2007; 51: 2716-2719Crossref PubMed Scopus (210) Google Scholar). The usual dose of oral vancomycin for children is 40 mg/kg daily given in three or four divided doses. Many pharmacies now constitute oral vancomycin solution from IV vancomycin with marked cost savings yet no obvious impact in clinical outcomes. In contrast to metronidazole, vancomycin does not reach adequate levels in the feces when given intravenously and should never be administered intravenously to treat CDI. In 2011, fidaxomicin was FDA approved for the treatment of CDI (28Cornely OA Crook DW Esposito R et al.Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: A double-blind, non-inferiority, randomised controlled trial.Lancet Infect Dis. 2012; 12: 281-289Abstract Full Text Full Text PDF PubMed Scopus (596) Google Scholar,29Louie TJ Miller MA Mullane KM et al.Fidaxomicin versus vancomycin for Clostridium difficile infection.N Engl J Med. 2011; 364: 422-431Crossref PubMed Scopus (1240) Google Scholar). Fidaxomicin is a macrocycline (in the United States it is designated as a macrolid; in Europe as a macrocycle) antibiotic with minimal systemic absorption, high colonic concentrations and limited impact on normal gut flora. It has been evaluated in patients with no or 1 prior episode of CDI. Data reveal similar clinical response, but decreased rates of recurrent infection, as compared with vancomycin 125 mg orally every 6 h (28Cornely OA Crook DW Esposito R et al.Fidaxomicin versus vancomycin for infection with Clostridium dif