Inflammatory Bowel Diseases:
Clostridium difficile Infection in the Inflammatory Bowel Disease Patient
Berg, Adam M. MD‡; Kelly, Ciarán P. MD†; Farraye, Francis A. MD, MSc*,‡
*Section of Gastroenterology, Boston Medical Center, Boston, Massachusetts
†Gastroenterology Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
‡Boston University School of Medicine, Boston, Massachusetts.
Reprints: Adam Berg, MD, Section of Gastroenterology, Boston Medical Center, 85 East Concord St., Suite 7720, Boston, MA 02118-2338 (e-mail: email@example.com).
Received March 05, 2012
Accepted March 06, 2012
Abstract: Clostridium difficile infection (CDI) has been increasing in frequency and severity in patients with inflammatory bowel disease (IBD). Population based and single center studies have shown worse clinical outcomes in concomitant CDI and IBD, with several reporting longer length of hospital stay, higher colectomy rates and increased mortality. Clinically, CDI may be difficult to distinguish from an IBD flare and may range from an asymptomatic carrier state to severe life threatening colitis. The traditional risk factors for CDI have included hospitalization, antibiotic use, older age and severe co-morbid disease but IBD patients have several distinct characteristics including younger age, community acquisition, lack of antibiotic exposure, colonic IBD and steroid use. CDI can occur in the small bowel and specifically in ulcerative colitis patients who have had a colectomy and an ileal pouch anal anastomosis. PCR based assays and combination Elisa algorithms have improved the sensitivity and specificity of testing, though in IBD patients have raised clinical questions about how to best manage diarrhea in the setting of possible C. difficile colonization. Treatment modalities for CDI have not been examined in randomized clinical trials in the IBD population. Newer antibiotics, immunotherapy and fecal microbiota transplantation may alter current treatment strategies. This review will focus on the unique epidemiology of CDI in IBD patients, detail clinical disease states, and provide updated diagnostic strategies, prevention and treatment options.
Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is characterized by chronic inflammation of the gastrointestinal tract. There is epidemiologic evidence that in patients with IBD, Clostridium difficile infection (CDI) occurs more frequently than in the general population and that these rates have been increasing over the past several decades.1,2 Advancements in our understanding of the epidemiology, immunology, and pathogenesis of CDI have not altered the increasing incidence. Compounding this issue is that asymptomatic colonization by C. difficile has been reported more frequently in the IBD population compared to the general population.3 Clinically, there is a variable host response to CDI in patients with IBD ranging from an asymptomatic carrier state to severe life-threatening colitis, colectomy, and death.2,4,5
Clostridium difficile is a Gram-positive anaerobic spore-forming bacterium that produces toxins and can lead to a clinically significant diarrhea. This can be difficult to treat and is associated with significant morbidity and mortality. The traditional risk factors for CDI have included hospitalization, antibiotic use, age, and severe comorbid disease but IBD patients have several distinct characteristics including younger age, community acquisition, lack of antibiotic exposure, IBD subtype, and steroid use.6,7 The emergence of a hypervirulent strain, characterized by high-level fluoroquinolone resistance, may be playing a role in the changing epidemiology of the disease.8 Immunological factors influence the variable host response. Specifically, high serum antibody titers against C. difficile toxins may decrease the severity of infection and could offer useful, prognostic data in determining if an exposed individual develops active infection or becomes an asymptomatic carrier.9
Diagnostic tests have been limited in the past by low sensitivity and/or specificity, slow test turnaround time, and inability to test for specific strains, but newer assays have emerged that allow for improved test performance. As the outcomes and comorbidities associated with CDI can be grave, prevention strategies including effective antimicrobial stewardship, hygiene, prophylaxis with probiotics, and vaccination have been proposed.10 Treatment regimens have been predominately studied in the non-IBD population and are based on disease severity dictating antibiotic regimens, although, in the IBD population, treatment with vancomycin as the first-line agent has been discussed by some experts.2,11 Newer antibiotics and alternative treatments have also emerged, although few studies have been conducted in the IBD population.
In this review article of CDI, we will focus on the epidemiology of CDI in IBD patients, detail clinical disease states, and provide updated diagnostic strategies, prevention, and treatment options. We will also discuss IBD-specific risk factors and complications. References were obtained by searching the Medline database from 1970 to January 2012 using the search terms: Clostridium difficile, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, CDI, IBD, antibiotic associated diarrhea, colitis, history, treatment, prevention, prophylaxis, epidemiology, immune, antibody. In addition, articles were also identified by cross-referencing studies mentioned and cited in the articles found through the initial search.
Clostridium difficile is the major pathogen responsible for antibiotic-associated colitis.12,13 There is an increased incidence and severity of CDI in the general population of North America and Europe; however, the exact epidemiology has been hindered by a lack of global reporting or surveillance programs and variable laboratory diagnostic methods.14 In the U.S., reporting is not mandatory; however, temporal trends showed a doubling of CDI in the general population based on discharge diagnoses from 1996–2003.15 The Centers for Disease Control reports increased rates of C. difficile based on hospital discharge diagnoses from 1996 to 2009, with rates for hospitalized persons aged ≥65 years increasing over 200%.16 In Quebec, Canada, a retrospective study of all cases of CDI over a 13-year period (1991–2003) reported an increase in incidence from 35 to 156 cases per 100,000.17 The cause of this outbreak is now known as NAP1/B1/027, which has since caused outbreaks throughout North America, England, continental Europe, and in parts of Asia.18
In IBD patients the incidence of CDI is also increasing, but at a rate greater than the general population. Four retrospective case–control analyses (from 1993–2007) of U.S. hospital discharge databases, specifically Nation-wide Inpatient Sample (NIS) showed increased rates of CDI in hospitalized IBD patients compared to controls.19–22 One population-based study by Ngueyn et al21 reported that the overall prevalence rate of CDI was nearly eight times greater than that of non-IBD gastrointestinal patients (37.3 cases vs. 4.8 cases per 1000 discharges). Similar trends were seen by Ricciardi et al22 and Anathankrishan et al,19,20 who reported increasing coincident hospitalization rates from 1998–2005 for CDI and IBD; specifically CDI-UC had increased from 2.4% to 3.9% and for CDI-CD from 0.8% to 1.2%. Large retrospective, single-centered studies in North America demonstrated similar findings. Over a 4-year period, from 1998 to 2004, Rodemann et al4 observed a doubling of CDI among patients with CD and tripling in UC. A comparable pattern was also seen by Issa et al2 from 2004 to 2005, with rates of CDI in IBD patients increasing from 1.8% to 4.6%.
While single-center and larger population-based studies have independently shown an increase in the severity and incidence of CDI, a recent systematic review has cautioned against drawing conclusions on the incidence of CDI in IBD and on temporal trends due to concerns for possible detection bias or miscoding.23 In summary, rates of C. difficile infection have seen a significant increase globally and a similar trend has been observed in patients with IBD. However, due to the heterogeneity of the studies, a lack of standardized clinical definitions, diagnostic techniques, or mandatory reporting, a full meta-analysis has not been conducted.
Clostridium difficile is a Gram-positive, spore-forming bacterium with the primary mode of transmission being a human-to-human fecal–oral route, although animals may serve as a reservoir for human infections. Colitis may alter the make up of the microflora and/or luminal environment, thereby permitting C. difficile infection to occur without antibiotic exposure. Most naturally occurring pathogenic strains of C. difficile produce two potent exotoxins that cause tissue injury by modifying small GTPases of the target cells leading to disorganization of the cell cytoskeleton and ultimately cell death.24 These are called toxin A and toxin B, which correspond to the genes tcdA and tcdB that are located in the pathogenicity locus (PaLoc). Within the PaLoc, there are regulatory genes that can upregulate or downregulate production of the toxins called tcdR and tcdC, respectively. The toxins have a high molecular mass and are part of the Large Clostridial Toxins (LCTs) family. There is controversy over which toxin is more crucial to pathogenicity. Most naturally occurring strains produce both toxins and early studies have shown that purified toxin A alone could induce pathology in animal models.25 Outbreaks have occurred in strains lacking toxin A (A– B+ strains) and in isogenic modified strains of C. difficile, only toxin B was required for infection.26 Using a different isogenic model and different outcome measures, either toxin A or B alone or together lead to virulence while double knockout strains were avirulent.27 Based on these results, diagnostic modalities and treatment options should encompass both toxins.
In addition to toxin A and B, pathogenic strains, including the NAP1/B1/027 strain which led to outbreaks in North America and Europe, produce an ADP-ribosylating binary toxin (CDT), although its role in disease is unclear.28 This hypervirulent strain has a characteristic pulsed-field gel electrophoresis (PFGE) pattern (North American PFGE type 1), restriction endonuclease analysis pattern (BI), and PCR ribotype 027. This strain is resistant to fluoroquinolones and has a mutated tcdC that has been proposed to facilitate increased production of toxin A and toxin B, which may lead to its increased virulence.29 The underlying influence of this epidemic strain on IBD patients has not been specifically investigated; however, the finding that patient's infected with this hypervirulent strain have worse outcomes may not be universal.30
Despite conflicting data, the overall impression is that CDI worsens both short- and long-term outcomes in IBD patients. Historically, in the general population, 1%–5% of CDI is severe, leading to intensive care admission, colectomy, or death.31,32 In IBD patients with CDI, there have been conflicting reports regarding the risk of colectomy. Population-based cohorts, defined by admission diagnoses, found an adjusted odds ratio (OR) of 6.6 for bowel surgery in IBD-CDI patient compared to non-IBD CDI controls.19 However, the same study reported that the C. difficile-infected IBD group was only half as likely to undergo bowel surgery as patients admitted for IBD alone (adjusted OR = 0.6). A retrospective single-center cohort study comparing 1-year outcomes of UC patients admitted with a flare and coexistent C. difficile infection to those with flare only showed that 44% of the UC-CDI patients had gone to colectomy compared to only 25% of the non-infected UC control group.33 Another single-center retrospective study found a 20% colectomy rate in IBD-infected individuals as compared to 1% in non-IBD-infected individuals.2 Other authors, however, have shown no difference in colectomy rates when comparing infected and noninfected IBD patients within 3 months after diagnosis.34 One population-based cohort by Nguyen et al21 found a negative relationship between CDI and colectomy in IBD patients, although this may be attributed to successful treatment of CDI as a cause of symptoms rather than admission due to IBD flare, which may have a worse prognosis. Additional prospective studies are needed to clarify the short-term risks of colectomy in IBD patients with CDI.
Other measures of disease severity in IBD patients with CDI include length of stay (LOS), ICU admissions, and mortality. Depending on study design, some studies have demonstrated increased LOS in CDI-IBD patients,2,19,21 whereas single-center cohorts showed similar LOS to the CDI controls.2,4,33 Similarly, there are conflicting data regarding mortality rates in IBD patients with CDI. Population-based studies have shown increased case fatality rates in infected UC patients.21,22 Specifically, among those with concomitant CDI and UC, the unadjusted in-hospital mortality rate was higher when compared to uninfected patients with UC (4.1% vs. 0.9%, P < 0.0001). In contrast, a systematic review had commented that in combining case–control studies, the mortality rate for infected IBD patients was only 1% (3/797), a rate similar to reported mortality in noninfected IBD individuals.23
Despite the limitations in available outcome studies, there is concern that the effect of CDI can result in increased morbidity, healthcare costs, and mortality. Further prospective data are needed to help clarify the effect of CDI on the course of IBD.
HOST IMMUNE RESPONSE
Understanding the variable host immune response after exposure to C. difficile may help explain the disproportionate burden in the IBD population. IBD patients are susceptible to increased immune stimulation, epithelial dysfunction, or enhanced mucosal permeability. This may lead to loss of colonization resistance or a dysregulated immune response to C. difficile and an increased risk of overt CDI.35
The variable host response to CDI is influenced by both adaptive and innate immune responses. In the healthy adult population about 60% had immunoglobulins to antitoxin A and B.36 In hospitalized non-IBD patients, these antibodies are not protective against colonization, but after colonization by C. difficile there was protection against symptomatic disease and recurrence.9,37,38 Therefore, the development of antibodies may allow a person to become an asymptomatic carrier. Carriage will vary throughout lifetime, with up to 60%–70% of newborns colonized at birth,39 decreasing to about 2% in healthy adults. The carriage rate in outpatient IBD patients is higher than the general population (8.2% vs. 1%)3; however, IBD patients are more likely to have symptomatic disease. Why IBD patients appear to have both higher colonization rates and incidence of active disease has not been clarified and further research is needed, but it may be related to an altered gut microbiome as well as an inability to form an appropriate antibody response.
For surveillance purposes, categorization of the infection includes identifying the source of infection and the clinical setting; community-acquired, healthcare facility-associated (CO-HCFA) vs. healthcare facility-acquired, healthcare facility-associated (HO-HCFA) vs. community-acquired (CO) vs. indeterminate.18 Community-acquired infection has been defined as a lack of hospitalization in at least 12 weeks prior to symptoms.
Infection with C. difficile may result in symptomless carriage to fulminant colitis. C. difficile carriage has been estimated at 1%–2% in outpatient healthy adults,3 3%–30% in hospitalized patients,38,40 16% in an acute care facility,41 and 5%–7% among elderly in long-term care facilities.42 Asymptomatic carriage in the IBD population has recently been categorized in a prospective outpatient-based study on IBD patients in clinical remission and without recent hospitalization, antibiotics, corticosteroids, or immunomodulatory maintenance therapy. Rates of colonization were higher than the general healthy population (8.2% vs. 1%); specifically, there was a higher prevalence of C. difficile carriage in UC patients (9.4%) than in CD patients (6.9%).3
The time from exposure to onset of symptoms has been estimated to be 48–72 hours.1 Active infection is characterized by diarrhea, fever, nausea, abdominal pain, and possibly abdominal tenderness; however, in some clinical situations these symptoms may be absent and a high index of suspicion is needed.6 Laboratory abnormalities include leukocytosis with a left shift, anemia, or hypoalbuminemia. In severe disease, patients may develop ileus, colonic dilation with minimal diarrhea that can progress to toxic megacolon, perforation or multiorgan system failure. CDI in IBD patients may show atypical features including bloody bowel movements and may be indistinguishable from an IBD flare.5 Imaging is not routinely required in IBD patients but may be useful in developing a differential diagnosis for abdominal pain and can help identify obstruction, perforation, bowel wall thickening, or megacolon in individuals with severe symptoms.
Endoscopic evaluation in non-IBD patients may have a classic appearance of pseudomembranes that are described in about 50% of cases.43 However, in IBD these features are were only present in 13% of hospitalized patients with CDI, a finding that was independent of immunosuppressant use.44 Patients with pseudomembranes had an associated fever compared to those without the endoscopic finding, although they had no difference in clinical outcome or underlying IBD severity. Other studies found no pseudomembranes in CDI-IBD patients, but rather a nonspecific mucopus was the most common endoscopic finding. Additionally, the classic histological findings were not seen in IBD patients with concomitant CDI.2 Therefore, routine endoscopy has little utility in helping to distinguish active IBD from C. difficile-associated disease, or in classifying severity of CDI in IBD.
In IBD patients, those with UC seem to be at greater risk for active CDI, although it had also been seen in CD patients with colonic disease.45 Although rare, CDI enteritis has been seen postcolectomy. A meta-analysis that included over 100 articles of reported enteritis showed that the majority had prior gastrointestinal surgery, 51% of the cases had IBD, and the overall morality rate was 31%. IBD patients with C. difficile enteritis had less mortality than non-IBD patients, possibly secondary to younger age, less comorbidity, and a heightened awareness.46
Pouchitis is characterized by inflammation of the reconstructed pouch after ileal pouchanal anastomosis (IPAA) surgery and is commonly empirically treated with antibiotics, including nonabsorbable antibiotics.47 In a prospective study of UC patients status post-IPAA undergoing pouch endoscopy, 18.3% were found to be C. difficile-positive. In this cohort, six of six patients treated for C. difficile entered clinical remission with clearance of toxin, and a decrease in mucosal inflammation in four.48 Additionally, a case of fulminant CDI in a UC patient status post-IPAA leading to multiorgan failure and death has been reported.49
Traditional risk factors for primary CDI include antibiotic use, prolonged hospitalization, age over 65, severe underlying disease, chemotherapy, use of nasogastric tubes, gastrointestinal surgeries, and increased comorbidities.38,50,51 Essentially all classes of antibiotics have been associated with CDI, although the most commonly implicated antibiotics are clindamycin, penicillins, cephalosporins, and fluorquinolones, possibly via changing intestinal flora and allowing unopposed proliferation of C. difficile.6 In IBD patients, antibiotics use does not seem to play as critical a role in the development of CDI as in the general population, perhaps due to an alteration of the colonic microbiota.52,53 Unlike the general population, IBD patients tend to be younger and acquire their infection in the outpatient setting. Unique IBD risk factors include steroid use and IBD subtype, specifically UC or colonic CD.
In the general population, although hospital-acquired infection is more common, the rates of community-acquired CDI (CA-CDI) have been increasing, with reported rates from 3%–40%.54,55 This is in contrast to IBD patients, who seem to have more CA-CDI. In retrospective population studies based on discharge codes, CDI occurs more frequently in the outpatient setting in IBD patients (up to 76% of cases).2,4,56 In the pediatric IBD population, a nested retrospective case–control study found that for recurrent CDI, 90% of IBD patients vs. 70% of controls had community-acquired infection.56
Chemotherapy has been an established risk factor for CDI in oncology patients, and immunosuppression with corticosteroids has also been associated with CDI in post-transplant patients, with increased mortality in non-IBD hospitalized patients with CDI on steroids.57 Specifically, in a population-based IBD cohort from British Columbia, corticosteroids, independent of dose or duration, were shown to be associated with an increased risk of CDI; however, initiation of steroids was associated with a tripling of the risk for C. difficile infection.58 The same study did not show such an association with other immunosuppressive drugs including immunomodulators (methotrexate, azathioprine, 6-mercaptopurine) or infliximab.58 There are conflicting data on immunomodulators, with some studies showing an increased risk for CDI with purine analogs,2 although others did not find this association.34
Other medications that have been implicated in CDI are acid-suppressing medications, specifically histamine blockers and proton pump inhibitors (PPI). While the data have been observational and mostly retrospective, there is at least a modest association between PPI use and CDI in hospitalized patients (possibly in a dose-dependent fashion), especially in patients on antibiotics,38,51,59–62 although other reports do not show an association.63–65
Prediction modeling for primary, severe, and recurrent CDI would help to clarify those populations at risk, allow for preventative measures, and targeted therapy. For primary CDI, logistic regression models, utilizing elderly, hospitalized patients on antibiotics, found that those with severe or extremely severe underlying disease (modified Horn's Index of 3 or 4) had incidence rates of CDI of 8.7% in the derivation cohort and 11% in the validation cohort.66 There have been several attempts to predict severe infection based on clinical markers, endoscopic findings, and laboratory values, although more prospective validation studies are needed.67
Recurrent infection, in a meta-analysis, was higher with continued use of antibiotics other than those used to treat CDI (OR: 4.23; 95% confidence interval [CI]: 2.10–8.55; P < 0.001), use of acid antisecretory medications (OR: 2.15; 95% CI: 1.13–4.08; P = 0.019), and older age (OR: 1.62; 95% CI: 1.11–2.36; P = 0.0012).68 Additional risk factors for recurrent infection include low antitoxin antibodies,69 although modeling these antibodies did not add additional ability to predict recurrent infection over clinical parameters.70
A key concept in the diagnosis of C. difficile is to test only in symptomatic patients with unformed stools, unless an ileus is present.9,18,71 Additional testing on symptomatic patients with an initial negative stool study or to test posttreatment cure is not recommended. There are several different modalities for C. difficile testing including culture, tissue culture cytotoxicity assay (CTA), enzyme immunoassay (EIA), polymerase chain reaction (PCR), and glutamine dehydrogenase (GDH, common antigen) testing (Table 1). Stool culture combined with CTA is the most sensitive and essential for epidemiological data, but not clinically practical given slow turnaround time and cost.72 GDH assays, toxin detecting, and DNA-based testing are commercially available.
EIA against toxins A and B is rapid, cost-effective, practical, and used by about 90% of all U.S. hospitals; however, the sensitivity of these tests is 63%–94%, with a specificity of 75%–100% when compared to culture plus CTA, leading to false-negative results.73,74 Given the identification of toxin A-negative strains, both toxin A and B should be included in diagnostic modalities.75 Although common practice, repeat stool testing does not yield a significantly increased detection rate of C. difficile and is not necessary. In patients who had multiple stool samples tested for CDI by EIA, almost 91% were accurately diagnosed based on the results of the first stool sample, with subsequent testing yielding a positive result in only 8.6% of patients.76 If substantial clinical suspicion remains despite a negative stool toxin EIA, then empiric therapy and/or testing using a more sensitive assay is recommended.
Assays that include EIA detection (not latex agglutination) for GDH have a high negative predictive value, which makes them an ideal screening test.77,78 Combination algorithms that use GDH EIA as an initial triage test may decrease costs, but as the specificity of the GDH assay is low a second test is needed to confirm a positive result. Confirmatory testing can include CTA, EIA for toxin A/B, and PCR against C. difficile DNA. If GDH is positive but EIA for toxin A/B is negative, a third, more sensitive test (e.g., CTA or PCR) is needed to determine a final result.
PCR-based assays have been developed and are available commercially because they are rapid, sensitive, and specific. FDA-approved kits include the GeneOhm (BD), proGastro (Prodesse), GeneXpert (Cepheid), and Illumigene (Meridian). The turnaround time is several hours and the assays are more sensitive that toxin EIAs (about 90% vs. 40%–80%, compared with culture or molecular methods) and also have high specificity.79 Generally, molecular-based assays are more expensive for reagents and start-up costs for the initial equipment. At present, although there are no official recommendations regarding routine testing using PCR, these assays are increasingly replacing toxin EIAs for first- or second-line stool testing. Some assays have also been designed to test for hypervirulent strain, specifically NAP1/B1/027 by testing for the toxin B gene, the binary toxin gene, and the negative regulator gene with sensitivities of 96.6%–99.7% and specificity of 93.0%–98.6%.80,81 Some, however, question the clinical utility, since treatment regimens are based on clinical severity and not strain specificity.82 As colonization by toxogenic C. difficile is common, even in the absence of clinical disease, more specific PCR-based modalities lead to more false-positive results.83 This problem is exacerbated in the IBD population who may have clinical diarrhea at baseline, and PCR-based technologies would detect the presence of C.difficile but may not have clinical relevance. As there are no currently accepted guidelines regarding the use of PCR-only modalities, individualizing patient care will be paramount. Table 1 summarizes the various diagnostic assays for C. difficile.
Important treatment decisions regarding CDI in IBD patients include how to manage concomitant immunosuppression, initial choice of antibiotic for primary infection, and treatment of recurrent or refractory infections (Table 2). Most of these questions have not been specifically addressed in IBD patients in a prospective fashion. Prevention remains the cornerstone of infection control and includes universal hand hygiene and surveillance programs. Alcohol-based cleaning agents are ineffective at clearing spores from hands and therefore soap and water has been advocated if there is a CDI outbreak.84 Chlorhexadine 4% solutions have also been shown to decrease spores71 but this is not universally accepted. Upon diagnosis or clinical suspicion, all possible offending antibiotics should be stopped, as some cases may resolve without further treatment and concomitant antibiotic use delays recovery and promotes CDI recurrences.
As an IBD flare can mimic CDI and CDI may precipitate a flare, optimal management of immunosuppression during treatment of CDI is important, but there are little data to help guide appropriate treatment decisions. A retrospective multicenter European study found an increased risk of death in those patients treated with antibiotics and immunomodulators (AB+IM) (defined as prednisone >20 mg/day, azathioprine, 6-mercaptopurine, methotrexate, biologics, cyclosporine, tacrolimus) for C. difficile-associated IBD exacerbation as compared to antibiotics alone (AB).85 Limitations of this study include small sample size, lack of randomization to treatment groups, and nonstandardized antibiotics or steroid regimens. In a survey of gastroenterologists, there was significant disagreement on whether combination AB+IM or AB alone should be given to IBD patients with CDI-associated flares.86 As there are no guidelines, expert opinion recommends caution in starting new immunosuppressive agents or escalating therapy without appropriate antibiotic coverage.87
No randomized control trials compare treatment regimens in IBD patients, but in the general population antibiotic choice is guided by severity of CDI.88 Mild/moderate disease is treated with metronidazole 500 mg orally (PO) three times daily (TID) or 250 mg PO four times daily (QID) for 10–14 days and severe disease with vancomycin 125 mg PO QID for 10–14 days.18,89 For complicated disease that includes ileus, toxic megacolon, or shock, the recommended treatment is vancomycin 500 mg QID90 with or without metronidazole 500 mg IV TID.91 Vancomycin enemas are recommended if oral therapy is not possible, for example, if there is an ileus.92,93
Recurrence occurs in about 15%–30% of patients after the initial course of treatment.94 For recurrent disease, a repeat course of metronidazole or vancomycin is the recommended choice depending on disease severity. Metronidazole is not recommended beyond the first recurrence due to concerns for peripheral neuropathy following extended use, especially in the elderly. Prolonged, tapered, and pulsed-dose vancomycin is the preferred approach for multiple recurrences of CDI.6,18,95,96 Although there are several different protocols, one regimen is vancomycin 125 mg QID for an initial 10–14 day course followed by 125 mg twice daily for 1 week, followed by 125 mg daily for 1 week and then 125 mg on alternate days for 2–8 weeks.97 Alternative therapies for recurrence include newer antibiotics, probiotics, immunotherapy, fecal transplantation, and decreasing use of immunosuppressive agents.
Several new antibiotics have been studied including fusidic acid, nitazoxanide,98,99 teicoplanin, rifampin,100 rifaximin,101,102 bacitracin, and fidaxomicin.103,104 Most of these antibiotics have been studied in small series of patients and are not typically used for primary treatment but are considered only after recurrence. Specifically, nitazoxanide has been shown to be noninferior to metronidazole, but patients with severe disease or IBD were excluded. In the comparison of nitazoxanide with vancomycin for initial or first recurrence, no definitive conclusions could be made given the small sample size and lack of power, but the authors concluded that there was a trend toward noninferiority. In several uncontrolled case series, rifaximin following a course of antibiotics for CDI led to decreased recurrence of infection,101,105 but some studies had also shown the development of rifaximin resistance.106 A double-blind, placebo-controlled pilot study randomized 68 non-IBD subjects who had finished a course of either metronidazole or vancomycin for an episode of CDI to receive rifaximin 400 mg TID or placebo for 20 days. Overall, recurrent diarrhea was less in the rifaximin group (49% in placebo vs. 21% in rifaximin; P = 0.018). A trend toward a reduction in recurrent diarrhea caused by confirmed CDI was observed also, but the numbers of cases were fewer and the result was not statistically significant (31% vs. 15%; P = 0.11).102
A meta-analysis comparing antibiotics (mostly to vancomycin and metronidazole) found that for moderate CDI there was no statistically significant difference in efficacy between vancomycin and other antibiotics including metronidazole, fusidic acid, nitazoxanide, or rifaximin.89,107 It also concluded that teicoplanin had better bacteriologic cure and borderline superior symptomatic cure when compared to vancomycin, but this drug is not available in the U.S.89,108 However, all these studies are limited by small numbers, exclusion of severe CDI, and a high risk of bias. An updated systematic review focused on 11 trials that included 1463 participants, three compared vancomycin to metronidazole and eight compared metronidazole or vancomycin with another agent (nitazoxanide, fidaxomicin, bacitracin), combination (metronidazole plus rifampin), or placebo. In this systematic review, no antibiotic was found superior for the initial cure of C. difficile, although fidaxomicin was found to have a lower rate of recurrence.109
Fidaxomicin was FDA-approved for CDI in May 2011 and is a poorly absorbed macrocyclic antibiotic. In a prospective randomized, controlled, intention-to-treat analysis, clinical cure in the fidaxomicin group (200 mg BID x 10 days) was noninferior compared to vancomycin group (125 QID x 10 days); 88.2% with fidaxomicin and 85.8% with vancomycin. Recurrence, defined as the reappearance of diarrhea within 4 weeks after cessation of therapy, was lower in the fidaxomicin group (15.4% vs. 25.3%, P = 0.005).103 However, this study excluded patients with IBD and further data are needed to assess the efficacy in this population. In another study of patients taking concomitant antibiotics, fidaxomicin was found to be significantly more effective than vancomycin in achieving clinical cure (90.0% for fidaxomicin and 79.4% for vancomycin, P = 0.04) and in decreasing recurrence (16.9% vs. 29.2%; P = 0.048) regardless of concomitant antibiotic used.104
Tigecycline, a broad-spectrum intravenous antibiotic with good fecal penetration, prevents protein synthesis and has been studied for refractory CDI. Case reports have suggested that tigecycline may be successful for treatment of severe or complicated CDI when prior therapy has failed.110 Despite these promising results, it should only be used with caution due to risk for superinfection with resistant organisms such as Proteus mirabilis bacteremia or other complications.111
Probiotics can help repopulate the gastrointestinal tract with normal microflora. Specifically, Saccharomyces boulardii may be effective in the prevention of CDI in high-risk antibiotic recipients, but this finding is based on small, individual studies, and further, larger, well-controlled studies are needed to confirm these positive initial findings.112–114 A meta-analysis that pooled four prospective, randomized trials using probiotics in combination with vancomycin or metronidazole found no benefit in three of four studies, but one study showed a decrease risk of recurrence versus placebo in those treated with S. boulardii (relative risk [RR] 0.59; 95% CI 0.35–0.98).115 Based on their ability to prevent the overgrowth of potentially pathogenic organisms and stimulate the intestinal immune defense system,116 probiotics are being increasingly used as an adjuvant or alternative therapy for IBD,117 but any synergistic benefit in the setting of C. difficile has not been clarified.118 Therefore, as probiotics have not shown a definitive prevention of recurrence and may increase the risk of fungemia in critically ill patients, they are not routinely recommended.18,113,115
Stool transplantation, also known as fecal microbiota transplantation (FMT), intestinal microbiota transplantation (IMT), or fecal bacteriotherapy has shown promise in numerous small reports as an effective treatment of recurrent or refractory CDI.18,119–123 In three case series with 12–26 patients, response rates have been >90% with initial treatment and high sustained responses.120,122,124 A meta-analysis that included 27 studies and 317 patients found that FMT was highly effective, resulting in clearance of CDI in 92% of cases, although the effectiveness varied by route of instillation, relationship to stool donor, volume of FMT given, and treatments received before infusion.125 Death was seen in 4% of patients, all in one study.119 Combined adverse events included upper gastrointestinal hemorrhage (n = 1), IBS symptoms (n = 4), infectious IBS symptoms (n = 1), constipation (n = 1, and signs of irritable colon.125 There are limited data for CDI treatment in IBD patients, although some initial studies included patients with IBD but subgroup analysis was not performed.119 Additionally, there are some practical considerations including standardization of methodology, risk of additional infections, especially for IBD patients on immu-nosuppression, and optimal patient selection. Further randomized prospective trials are needed to clarify the role of stool transplantation in patients with IBD and CDI.
As discussed above, humoral immunity, specifically the development of antibodies to both toxin A and B, is important in protection against symptomatic disease and recurrence. This provides the rationale for the use of immunotherapy in the treatment of recurrent disease. Specifically, intravenous passive immunization in the form of pooled immunoglobulin preparations supplies both IgG antitoxin A and B and has been used since the early 1990s. Observational studies and case reports have mixed results and no randomized controlled trials have been conducted. A recent review of the topic found a high mortality rate (57%) in 21 patients treated with IVIG for severe CDI and concluded that IVIG may be useful for uncomplicated infection, but its role is limited in patients with end organ dysfunction.126 Future immunotherapy treatment options under study include human monoclonal antibodies directed against toxin A and B,127 vaccines, and modulating the innate immune response.67 Table 2 summarizes treatment options for patients with C. difficile.
Clostridium difficile has been recognized as the major cause of antibiotic-associated diarrhea for over 40 years and had previously been linked with older, hospitalized, debilitated patients on antibiotics. Emerging risk factors have changed these demographics, and now younger patients in community settings without antibiotic use are at risk. Patients with IBD, specifically UC and colonic CD patients, are particularly vulnerable, with more severe clinical outcomes and increased incidence of infection and colonization. Diagnosis of infection in IBD patients has been limited by atypical clinical and endoscopic presentations. Treatment options are confounded by concomitant immunosuppression, altered bowel microflora, and possibly by differences in humoral response. Initial antibiotics used to treat CDI including metronidazole and vancomycin has not been studied prospectively in IBD patients. Newer antibiotics including fidaxomicin, probiotics, IVIG/antibody therapy, and fecal transplantation have been used for recurrent infection but there are limited data in IBD patients.
In IBD patients, especially those with colonic disease or status-post IPAA, presenting with diarrhea or a change in bowel habits, practitioners need to test for C. difficile and consider CDI with symptoms of a disease flare. Special care to rule out C. difficile should be pursued prior to escalating or starting new immunosuppressive agents. Antibiotic choice for a primary infection should be based on clinical parameters, but there should be a low threshold for prescribing vancomycin. Recurrent infection should be treated with vancomycin or fidaxomicin. Curtailing the rising incidence of morbidity in the IBD population will take adequate prevention, identification, and treatment.
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Clostridium difficile; inflammatory bowel disease; ulcerative colitis; Crohn’s disease; antibiotic associated diarrhea; pseudomembranous colitis; colonization; toxin A; toxin B; binary toxin; vancomycin; metronidazole; fidaxomicin; nitazoxanide; teicoplanin; fecal transplantation
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