Impact of Clostridium difficile on Inflammatory Bowel Disease

Ashwin N Ananthakrishnan; David G Binion

Expert Rev Gastroenterol Hepatol. 2010;4(5):589-600. © 2010 Expert Reviews Ltd.

Abstract and Introduction
Abstract

Clostridium difficile infection (CDI) has been increasing in incidence among those with underlying inflammatory bowel disease (IBD) and is associated with substantial morbidity, the need for surgery and even mortality. The similar clinical presentation between CDI and a flare of underlying IBD makes prompt diagnosis essential to prevent deterioration which would accompany an escalation of immunosuppression in the absence of appropriate antibiotic therapy. Classical risk factors (antibiotic or healthcare exposure) or clinical findings (pseudomembranes) may not be found in many IBD patients with CDI and should not be considered essential for entertaining the diagnosis. Enzyme immunoassays detecting both toxins A and B remain the most widely used test for diagnosis and have acceptable sensitivity, but may require testing of multiple samples in select situations. Both vancomycin and metronidazole appear to be effective and treatment with oral vancomycin is preferred in those with severe disease, including those who require hospitalization. Appropriate infection control measures are essential to restrict patient-to-patient spread within healthcare environments and to prevent recurrences. Several novel therapies are currently under study, including new antibiotic agents and monoclonal antibodies targeted against the toxins. There is a need to broaden these studies to the IBD population. There is also the need to prospectively examine whether CDI has long-term disease-modifying consequences in those with underlying IBD.
Introduction

Clostridium difficile is a gram-negative anaerobe originally described as an etiologic agent for pseudomembranous colitis in 1978.[1] Classical C. difficile infection (CDI) was seen in patients who had recently used antibiotics or were exposured to a healthcare environment. The past 10 years have seen an explosion in the rate of CDI, particularly among hospitalized patients,[2–5] and significant changes in its epidemiology. In the USA in 2006, there were an estimated 300,000 hospitalizations nationally complicated by CDI,[6] with the estimated economic costs ranging between US $431 million and 3 billion annually.[7] There is greater recognition of community-acquired CDI in patients with no antibiotic or healthcare environment exposure.[8] While older age and comorbidity are well-recognized risk factors for CDI, there are now several reports of CDI among younger healthy outpatients. In addition, there may be other novel subgroups at an increased risk for CDI, including, most recently, those with underlying inflammatory bowel disease (IBD); Crohn's disease (CD) and ulcerative colitis (UC).[9–12] In patients with IBD, CDI has been associated with a greater morbidity, need for colectomy, mortality and substantial healthcare costs.[10,11,13,14] Paralleling the rise in CDI among non-IBD patients, an increase in frequency of CDI amongst IBD patients is well documented from several single-center[11,12] and national studies.[9,10,14]

Both CDI and IBD flares often present with similar symptoms but have markedly divergent management plans. Treatment of CDI requires directed antibiotic therapy with minimizing immunosuppression, while the management of an IBD flare involves escalation in immunosuppressive therapy. Thus, it is important for the treating clinician to have a high index of suspicion for CDI in IBD patients and to initiate early testing and appropriate therapy. While a comprehensive overview of CDI is beyond the scope of this article, we aim to summarize the available literature on the epidemiology, diagnosis and management of CDI among patients with IBD. We supplement areas where there is a gap in the literature specifically in the IBD population by extrapolating data from non-IBD patients. We conclude our article by suggesting directions for future research.

Epidemiology
Prevalence in IBD

Clostridium difficile infection was previously considered uncommon among IBD patients, even among those presenting with a disease flare, so much so that some studies questioned the relevance of routinely looking for C. difficile as an inciting pathogen among patients with a disease flare.[15–19] There has been a wide range in the prevalence of CDI in IBD patients, with the estimates depending on the following factors: inclusion of all IBD patients or only those with a disease flare; demographic and disease characteristics; and distribution of other risk factors for CDI, such as immunosuppression. However, while the exact prevalence may vary, what is consistent among all the different studies is that there has been a striking increase in the frequency of CDI in patients with IBD. In an analysis of the Nationwide Inpatient Sample (NIS), a national hospitalization discharge database from the USA, Ananthakrishnan et al. found a significant increase in the frequency of CDI complicating hospitalizations for both CD (eight out of 1000 in 1998 to 12 out of 1000 in 2004) and UC (24 out of 1000 in 1998 to 39 out of 1000 in 2004).[10] Extending this analysis to 2007 revealed a continuing rise in the frequency of CDI among all IBD hospitalizations [Ananthakrishnan AN; Unpublished Data]. Several single-center reports have also confirmed these findings. Rodemann et al. similarly identified a doubling in CDI among CD patients and a tripling in rate among UC patients between 1998 and 2004.[12] In the study by Issa et al., the rate of increase of CDI seen in IBD patients (1.8% in 2004; 4.6% in 2005) even exceeded the rate of increase found in non-IBD patients, a cohort that is typically older and has a greater comorbid burden.[11] Jodorkovsky et al. examined the rates of CDI among 99 patients admitted to Mount Sinai hospital (NY, USA) with a UC flare and identified C. difficile in 47%.[13] Supporting data from Europe[20] and pediatric IBD populations[21] emphasize both the widespread nature of the problem and the potential for presentation in any age group.
Risk Factors

The risk factors for CDI in IBD patients can be broadly divided into environmental (or extrinsic) risk factors, intrinsic host risk factors, which are common to both IBD and non-IBD patients, and disease-specific risk factors unique to IBD.

Extrinsic Risk Factors The classical risk factor for CDI is exposure to broad-spectrum antibiotics.[22–25] Initially, clindamycin and subsequently fluoroquinolones were the antibiotics most commonly implicated, although CDI has been reported to occur following the use of several different antibiotics, particularly fluoroquinolones,[26,27] but also including vancomycin and metronidazole, which are widely used for its treatment. Antibiotics disrupt the normal intestinal flora, which is then thought to allow for proliferation of C. difficile, a more resistant organism.[28] Hospital-wide antibiotic use policies and consequent selective pressure has also been proposed to account for the rising incidence of CDI. However, the prominent role of antibiotics as a risk factor appears to be decreasing with a greater proportion of infections being community-acquired and in those with no prior antibiotic exposure.[8] In IBD patients, recent antibiotic use was seen in less than two-thirds of the patients with CDI and should not be considered a prerequisite for entertaining a suspicion for CDI.[11] Exposure to the healthcare environment, particularly hospitalization, is another important risk factor for CDI. However, in the study by Rodemann et al., a significant proportion of the positive C. difficile toxin assays in IBD patients were within 1–2 days of hospitalizations, suggesting acquisition in the community.[12] Healthy carriers and colonized patients may also increase transmission of infection; the rate of C. difficile carriage in neonates may be as high as 80%.[6]

In addition to general comorbidity, immunosuppression is a well-recognized risk factor for CDI in IBD and non-IBD patients (organ transplant recipients and oncology patients).[22,23,25,28] Issa et al. identified maintenance immunosuppression to be associated with a greater risk for CDI (odds ratio [OR]: 2.58; 95% CI: 1.28–5.12),[11] as did a second study from Belgium.[20] A few authors have demonstrated an elevated risk of CDI in patients on gastric acid-suppressive therapy, particularly proton pump inhibitors.[29,30] This association has not been replicated in the IBD population.[20,31] However, given the potential for other infectious and metabolic consequences of long-term proton pump inhibitorsuse, long-term use should be utilized with caution and for an appropriate indication.

Intrinsic Risk Factors Older age and higher burden of comorbidity are well-recognized risk factors for CDI.[23–25,32] This is particularly relevant in IBD because the proportion of older individuals appears to be rising among both ambulatory and hospitalized IBD patients.[33–35] In their analysis of the NIS, Nguyen et al. found that each one-point increase in the Charlson comorbidity index was associated with a 13% increase in the risk for CDI.[14] Other host risk factors include antibody response to toxin A (TcdA), with patients who produce lower IgG response to TcdA being more likely to develop symptomatic disease.[36,37] A recent randomized trial demonstrated a reduction in the recurrence rates after an initial CDI episode with the use of monoclonal antibodies targeted against toxins A and B.[38]

IBD-specific Risk Factors It remains to be examined in prospective cohorts if IBD itself is an independent risk factor for CDI. However, recent reports documenting disproportionately greater incidence, morbidity and mortality in IBD patients compared with the non-IBD cohorts suggest that this may indeed be the case. The exact mechanisms behind this underlying risk have not yet been defined. Potential causes include are reduced levels of defensins in IBD,[39] use of immunosuppression and antibiotics, disruption of the intestinal mucosal barrier and alteration in the gut microbiome. Colonic involvement seems to be nearly universally present in those with IBD who develop symptomatic infection, although CDI has been reported both from ileal pouches[40] and the small bowel after colectomy.[41] In the study by Issa et al., colonic involvement with IBD was associated with a threefold greater risk (OR: 3.12; 95% CI: 1.28–5.12).[11] CDI is also more common among UC than CD patients.[10] The extent of colonic disease may be a risk factor, with CDI being more likely in those with pancolitis (compared with limited distal colitis).[42] It has been difficult to establish whether the greater disease activity seen in infected compared with uninfected individuals[21] suggests that disease severity is an independent risk factor for CDI or merely a consequence of infection.
Pathogenesis

Clostridium difficile is a spore-forming anaerobe that exerts its pathogenesis by the production of toxins. The two most important toxins in C. difficile pathogenesis are TcdA and toxin B (TcdB), encoded by the genes tcdA and tcB, respectively, within the pathogenicity locus.[6,43] In addition, there are several regulatory genes, including tcdC, tcdE and tcdR, that function as positive or negative regulators for TcdA and TcdB production.[44] Both TcdA and TcdB are cytotoxins that bind to receptors at different locations within the enterocyte. By glycosylation of the Rho and Ras proteins, C. difficile disrupts the cellular cytoskeleton, loosens the intercellular tight junctions and results in secretory diarrhea.[6,43,45–47] While prior studies suggested that TcdA was the toxin predominantly responsible for the enterotoxic effects of C. difficile, recent research has demonstrated that strains producing TcdB alone (but not TcdA+ TcdB− strains) are virulent in hamsters, suggesting a more prominent role for TcdB in disease pathogenesis.[6] The vast majority of human infections are due to strains producing both toxins; however, a small minority of infections may be due to strains that produce TcdA (11%) or TcdB (7%) alone, emphasizing the importance of diagnostic tests that detect both toxins.[48,49] A third toxin, the binary toxin, is encoded on a separate part to the C. difficile genome and is composed of two proteins.[6,44] Binary toxin-producing strains may have a mutation in the negative regulatory gene, tcdC, resulting in a greater amount of TcdA and TcdB production compared with nonbinary toxin strains.[6,50,51]

Between 2002 and 2005, outbreaks of C. difficile with a greater virulence than previously seen was identified in several hospitals in the province of Quebec (Canada).[5] Molecular typing led to the identification of an epidemic hypervirulent strain of C. difficile termed the BI/NAP1/027 (group BI by restriction endonuclease analysis, North American pulse-field type NAP1, ribotype 027).[52–54] This strain has since been reported from several countries where it was responsible for regional outbreaks. So far, there have been no reports of increased morbidity or mortality in IBD patients attributable to this strain. Bossuyt et al. reported no disproportionate increase in the incidence of CDI among their IBD cohort attributable to this strain.[20] A second hypervirulent strain, ribotype 078, has been recently reported from the Netherlands and appears to be more likely to cause community-acquired (17.5 vs 6.7%) disease in a younger population, with similar rates of severe diarrhea and mortality.[55]

A Role for Asymptomatic Carriage?

The ability of an individual to produce antibodies to TcdA may determine whether a patient develops symptomatic disease or is asymptomatically colonized on exposure to C. difficile.[6] The prevalence of such colonized individuals is estimated to be between 1 and 4% in healthy adults, but may be higher among those with IBD.[56] Clayton et al. found an asymptomatic carriage rate of 8% in their cohort of patients with mild IBD who were not on any immunosuppressive therapy, and found no increase in adverse events when these patients were followed for a period of 6 months.[56] However, whether such 'asymptomatic carriage' exists in those with more severe underlying colitis requiring immunosuppression or biologic therapy has not yet been studied.

Evaluation of Patients with Suspected CDI
Signs & Symptoms

Clinical recognition of CDI in the setting of IBD is challenging owing to the overlap in symptoms between the two groups. Patients with both conditions often present with watery diarrhea and mucous, with overt bleeding being more common in those with an IBD flare. Abdominal pain, fever and leukocytosis may be seen in both groups. In addition, laboratory evaluation may reveal anemia or hypoalbuminemia, both indicators of general or disease-specific comorbidity. In IBD patients, relapse during the prior year is an important predictor of disease course during the subsequent year. Sudden untriggered disease flares in patients with otherwise long-standing quiescent IBD should raise the suspicion for CDI. The monitoring of IBD patients with severe CDI is similar to those with acute severe colitis and should include close monitoring of their vital signs (particularly heart rate), as tachycardia may be a sign of impending megacolon or free perforation. Even in the absence of overt diarrhea, persistent or rising leukocytosis or fever in hospitalized patients should also trigger testing for C. difficile. Radiologic evaluation is often normal, but in patients with severe disease, it may be useful to diagnose megacolon or free perforation. Most of these physical examinations and radiologic findings are nonspecific and do not aid in differentiating CDI from active IBD colitis.
Endoscopy

The classic endoscopic appearance of C. difficile colitis is the 'pseudomembrane', a collection of necrotic debris and secretions from sloughing of the mucosa.[32,57] Histologic examination reveals the typical 'volcano' lesion with an eruption of inflammatory cell infiltrate and debris in the area of ulceration. This typical finding has been disappointingly uncommon in patients with underlying IBD,[11,20] and there are some reports to suggest that it is also rare in cancer patients on immunosuppression as. In the studies by Issa et al. and Bossuyt et al., none of the IBD patients with CDI demonstrated pseudomembranes.[11,20] However, there are two reasons for lower gastrointestinal endoscopy in patients with suspected severe CDI. First, it can help assess the severity of the active disease, which may have important implications for medical and surgical management. Second, it allows one to obtain biopsies to rule out secondary infections, such as cytomegalovirus, which may be present in some patients with severe, steroid-refractory colitis.

Diagnosis of CDI

The requirements of an ideal test to diagnose CDI are both a high sensitivity and specificity, and relatively quick turnover time to allow differentiating between disease flare and superimposed IBD, as treatment plans for the two differ significantly. A full discussion of the various diagnostic tests available and their performance is beyond the scope of this article, but recent publications and guidelines offer a good summary of the available tests.[23,58] The most sensitive method for the detection of C. difficile in stools is the stool culture, however, this does not differentiate toxigenic and nontoxin-producing strains.[23,24,32] Stool culture combined with in vitro detection of toxin or cell culture cytotoxicity assay are regarded as the reference standards for the diagnosis of CDI.[23] However, these tests are time consuming and require both technical expertise and laboratory facilities, which are not widely available.

Enzyme immunoassays (EIA s)that detect TcdA and/or TcdB are the most commonly used tests for the detection of C. difficile and offer the advantages of being rapid and easy to perform. The mean sensitivity and specificity for the different EIAs available range from 50 to 90%, depending on the type of EIA and reference standard compared with lower sensitivities when compared with toxigenic cultures.[23,24,58] The specificity of EIA is fairly high (80–90%), but the positive predictive values (PPV) and negative predictive values (NPV) vary by prevalence of CDI in the population of interest (PPV: 52–70%, NPV: 98–100% at a C. difficile prevalence of 5%; PPV: 65–95%, NPV: 70–95% at a C. difficile prevalence of 50%).[58] The EIA tests require the presence of 100–1000 pg of either toxin for detection.[23,24] First-generation EIAs detected only TcdA, but more recent tests detect both TcdA and TcdB, which is important because up to 10% of CDI may be due to strains that only produce TcdB. A more recently available test is the real-time PCR nucleic acid amplification test that detects genes regulating the production of toxins A (tcdC) and B (tcdB and tcdC). It has a much greater sensitivity (85–100%), specificity (94–100%), PPV and NPV than the EIA at all prevalence estimates of CDI.[58] However, the individual or comparative performance of these tests, specifically in an IBD cohort, has not been examined. Another question that has been debated in the literature is the need for the testing of multiple samples in those with suspected CDI. While studies in non-IBD populations have yielded conflicting results,[59] in our experience with IBD patients, we found that the first sample was positive in only 54% of cases, with the detection rate rising to 92% with the fourth sample.[11]

Impact of CDI on IBD Outcomes
Short-term Outcomes

C. difficile has been shown to impact both short- and long-term outcomes in patients with IBD. Acute complications related to fulminant CDI are megacolon and free perforation leading to peritonitis. C. difficile that occurs in the setting of severe underlying illness can also precipitate multiorgan dysfunction leading to death. In a study of the nationwide inpatient sample, we found that CDI was independently associated with fourfold greater mortality in the presence of underlying IBD compared with hospitalized IBD patients without CDI (OR: 4.7; 95% CI: 2.9–7.9).[10] Other studies, including those from our center, have demonstrated a substantial rate of colectomy in those with severe CDI.[11,13,60] In 2005, our rate of emergent colectomy in hospitalized IBD patients with CDI was 45%;[11] a second study from Mount Sinai hospital identified a colectomy rate of 23%.[13] Although these reports are from tertiary referral IBD centers and probably represent a skewed population, in our analysis of the NIS, we found that CDI was associated with a significantly greater risk for bowel surgery (OR: 6.6; 95% CI: 4.7–9.3) among IBD compared with non-IBD patients, with a higher rate of surgery in those with UC compared with CD.[10]

In addition to morbidity and mortality, CDI is also associated with a significant increase in healthcare utilization and costs. Although length of hospitalization is a risk factor for acquisition of C. difficile, CDI itself may be associated with a 40–60% increase in length-of-stay and hospitalization costs.[10,14] Our study identified a 3-day excess hospitalization stay and over US $11,000 in hospitalization charges associated with CDI.[10]

We also recently examined temporal trends in CDI outcomes between 1998 and 2007 [Ananthakrishnan AN; Unpublished Data] and found that the absolute mortality in the C. difficile-IBD cohort increased from 5.9% in 1998 to 7.2% in 2007 (p = 0.052), with a nonsignificant increase in colectomy rate (3.8–4.5%). More importantly, compared with non-C. difficile hospitalized IBD controls, there was an increase in the relative mortality risk associated with C. difficile from 1998 (OR: 2.38; 95% CI: 1.52–53.72) to 2007 (OR: 3.38; 95% CI: 2.66–64.29) with a similar increase in total colectomy odds from 1998 (OR: 1.39; 95% CI: 0.81–82.37) to 2007 (OR: 2.51; 95% CI: 1.90–93.34).
Long-term Outcomes

There are limited data on long-term outcomes after CDI in IBD patients owing to a short duration of follow-up in most studies. The most commonly observed long-term complication is recurrent CDI, which may occur in 10–35% of patients after an initial episode and up to 65% of those patients with multiple episodes (see later).[61–63] Accurate determination of long-term outcomes after a single episode of CDI in IBD patients requires the exclusion of patients who develop disease recurrences. Jodorkovsky et al. identified an increase in the rate of emergency room visits, UC-related hospitalizations and colectomy (OR: 2.38; 95% CI: 1.01–5.6) extending up to 1 year after the initial infection, but did not account for recurrent CDI.[13] Chiplunker et al. compared the course of IBD for a 1-year period before and after diagnosis of CDI, with each patient being their own control. There was a mean increase by one additional hospitalization (0.89; 95% CI: 0.51–1.27) in the year following CDI in 81 IBD patients with 46 patients (56.8%) requiring an escalation in maintenance therapy for IBD (new initiation of biologics in 23 patients, escalation of current biologic agent in seven patients and new or escalation in dose of immunomodulators in 16 patients).[64] While enteric infections have been proposed as risk factors for the development of IBD, their role as triggers of disease flares or modulation of natural history of disease is unclear.[65] Whether enteric infection associated with intestinal inflammation irreversibly alters the gut homeostasis leading to more severe disease even after the initial episode has resolved is unknown.

Treatment
General Measures

All patients with documented CDI should have the offending antibiotic discontinued whenever possible or switch to an antibiotic with a narrower targeted spectrum. This may be the sole intervention required to achieve a clinical cure in a small proportion of patients, but only if they have mild symptoms, and respond to that intervention within 48 h.[20] Most patients with underlying IBD will require targeted antibiotic therapy against C. difficile. In hospitalized patients, appropriate infection control measures (discussed later) should also be adopted to prevent both patient-to-patient transfers of infection and reinfection within the same patient.

Medical Treatment
Metronidazole

As the pathogenesis of CDI relates to toxin production without systemic or tissue invasion, the efficacy of antibiotics against C. difficile relates to their ability to achieve adequate luminal concentration within the colon. Metronidazole has been the first-line agent in the treatment of CDI for decades and has demonstrated good efficacy in several observational studies and randomized trials.[24,25,63,66] Orally administered metronidazole is absorbed into the systemic circulation and subsequent biliary excretion is felt to play the key role for the drug to ultimately reach the colonic lumen. Both oral and intravenous metronidazole have similar efficacy against CDI, with intravenous therapy potentially achieving greater luminal concentration. The Infectious Disease Society of America guidelines recommend oral metronidazole dosed at 500 mg every 8 h either orally or intravenously, with an efficacy of 75–90% against CDI. Recent data have raised concern for an increase in the recurrence of CDI after treatment with metronidazole with an increase in frequency from 20% in 1991–2002 to 45% in 2003–2004 and 35% in 2005–2006.[67–70] Hu et al. examined the use of metronidazole for the treatment of CDI in 89 patients and identified cephalosporin use (OR: 32), presence of CDI on admission (OR: 23) and transfer from another hospital (OR: 11) as risk factors for the failure of treatment with metronidazole (overall failure rate: 35%).[70] Another potential drawback of oral metronidazole is gastrointestinal intolerance with symptoms of metallic taste, nausea and emesis in some patients, and the risk of peripheral neuropathy with long-term use.
Vancomycin

Vancomycin is the only US FDA-approved antibiotic for the treatment of CDI.[71] Orally administered vancomycin is not absorbed significantly in the small intestine and achieves fecal concentration above 1000 µg/g (maximum reported mean inhibitory concentration for vancomycin against C. difficile is 16 µg/g), which is several-fold higher than the ratio of fecal concentration-to-maximum mean inhibitory concentration achieved with metronidazole.[72] Doses of 125, 250 and 500 mg orally four-times daily have demonstrated comparable efficacy and recurrence rates.[73] Compared with placebo, the rate of clinical response with vancomycin is sixfold greater (relative risk: 6.75; 95% CI: 1.16–48.43).[74] Intravenous vancomycin does not have any efficacy in the treatment of CDI and should not be used. Oral vancomycin may be well tolerated in patients who are intolerant to metronidazole. One disadvantage with oral vancomycin is the expense, with an expected cost of a 10-day therapy ranging between US $300 and 600.[72] An alternative in hospitalized patients is to administer the intravenous formulation of vancomycin orally, which is less expensive. The emergence of the BI/NAP1/027 strain may have also resulted in reduced overall efficacy of vancomycin; some authors have postulated this to be due to the tremendous increase in the amount of toxin from the binary toxin-producing epidemic C. difficile strain.
Choice of First-line Agent

There is considerable debate in the literature regarding the agent of choice to treat the initial episode of CDI.[71,72,75] The advantages of using metronidazole as a first-line therapy are its lower cost (estimated cost of a 10-day course is US $20).[72] In addition to the increased cost, widespread use of oral vancomycin also raises concern for the potential spread of vancomycin-resistant enterococci, although this has not been consistently demonstrated.[71] Two recent randomized controlled trials compared the efficacy of the two.[76,77] Zar et al. randomized 150 patients to treatment with metronidazole 250 mg four-times daily or vancomycin 125 mg four-times daily. They constructed a severity score composed of age, low albumin, leukocytosis, presence of fever (one point each) and pseudomembranous colitis (two points). Vancomycin had a significantly superior cure rate compared with metronidazole in those with severe CDI (score ≥2; 97 vs 76%; p = 0.02) but not in those with mild disease (98 vs 90%; p = 0.36).[76] In a second study comparing vancomycin, metronidazole and tovelamer, patients with severe CDI achieved a significantly better response to vancomycin (85 vs 65%; p < 0.05) with equivalent results in those with mild (85 vs 79%) and moderate disease (80 vs 75%).[77] The rates of relapse were equal in both groups. These data seem to suggest favoring the use of vancomycin as a first-line agent in those with severe disease, although a uniform definition of what constitutes severe CDI has not yet been defined.[72]

There are limited data to guide the choice of the initial agent in patients with IBD and no randomized controlled trials with either drug. It is our practice in most patients with disease severe enough to require hospitalization, to initiate treatment with oral vancomycin 1–2 g/day administered in divided doses. In patients with significant ileus and decreased gastrointestinal motility (and thus, delay in achieving therapeutic colonic luminal concentration of vancomycin), we add intravenous metronidazole to the therapy. In ambulatory patients with mild disease, metronidazole can be the first agent of choice, with the use of vancomycin reserved for those with a relapse, recurrence or intolerance to metronidazole.
Management of Immunosuppression during CDI

An important issue that arises in treating IBD patients with CDI is the management of concurrent immunosuppression. The presentation between an IBD flare and CDI is often similar, but the treatment paths are markedly divergent with the escalation of immunosuppression for an IBD flare compared with reduction in immunosuppression in those with active CDI. Ben-Horin et al. retrospectively analyzed the outcomes in 51 IBD–CDI patients treated with antibiotics and 104 treated with both antibiotics and immunomodulators.[78] The proportion of patients achieving the primary outcome of death, colectomy within 3 months, in-hospital megacolon, bowel perforation or shock was higher in those with combination treatment (12%) compared with those with antibiotics alone (0%; p = 0.01), with this difference remaining significant on multivariate analysis. However, a limitation of such analysis of retrospective data is the potential for confounding by indication – that is, those with the most severe disease may tend to receive combination therapy whereas those with mild IBD may have their immunosuppression withdrawn. Given the association between immunosuppression and CDI, it is our practice not to escalate immunosuppressive or biologic therapy in the setting of active untreated CDI. However, in patients with fulminant colitis at high risk for colectomy, it is often unavoidable to adopt the combination approach with antibiotics and immunomodulators with the hopes of preventing colectomy.
Other Agents

Probiotics have demonstrated promise in the prevention of antibiotic-associated diarrhea, but have not convincingly demonstrated efficacy in the treatment of CDI.[75] A recent Cochrane review concluded that there were insufficient data to recommend the use of probiotics either alone or in combination with antibiotic therapy for the treatment of CDI.[79] Among the different agents, Sacharomyces boulardii has demonstrated some promise, with two preliminary studies demonstrating efficacy for the treatment of primary infection or recurrent disease.[79] The potential mechanism of action of probiotics is to restore the balance of the intestinal flora. There is a theoretical concern with the use of the agents in patients with significant immunosuppression owing to concerns for higher mortality, such as have been reported in patients with pancreatitis. Further work is necessary to determine whether there is any role for probiotics in the treatment of primary CDI in the IBD setting.

Rifaximin is a nonabsorbed oral antibiotic approved for the treatment of travelers' diarrhea and has demonstrated in vitro activity against C. difficile.[80] Concerns of antibiotic resistance have limited its widespread use for CDI, but a single study demonstrated efficacy of 90% in treating an initial episode of CDI, comparable with vancomycin.[9] Another situation where rifaximin has been used is in the treatment of recurrent, particularly multiply recurrent disease with a prolonged course of rifaximin overlapping with vancomycin taper.[81–83]

Several other antibiotics, including teicoplanin, nitazoxanide and fusidic acid, have demonstrated efficacy against CDI, with teicoplanin achieving better outcomes than even vancomycin.[25,61,75] Anion-binding resins (cholestyramine and colestipol) may also be used in conjunction with antibiotic therapy to alleviate symptoms, but have not been proven effective in the treatment of CDI.[61,75]

Surgical Treatment

Patients with CDI who develop megacolon or free colonic perforation require emergent surgery, but the timing of surgery in those with disease unresponsive to medical therapy has not been extensively studied. Protracted antibiotic (and potentially immunosuppressive) treatment in those with severe underlying disease may increase the likelihood of complications should the patient eventually need surgery. Overall mortality in patients eventually requiring surgery remains high (40–60%) owing to both the severity of illness and underlying general and IBD-related comorbidity of patients who contract CDI.[84,85] The procedure of choice is total or subtotal colectomy with an end ileostomy. Segmental resection or hemicolectomy have been associated with worse outcomes. The early involvement of the surgical team is important in the management of patients with severe disease with optimization of nutritional status prior to surgery being associated with superior outcomes.[86]

Recurrent CDI

Disease recurrence is seen in 15–35% of patients after an initial episode of CDI, with the rate rising to 35–65% after the first recurrence.[87] A small proportion of patients (10–15%) may have more than two recurrences. There are two mechanisms for recurrent symptoms. One may be a disease relapse (if it occurs within 7–14 days of therapy), while true recurrence may occur with the same strain or as a result of reinfection with a different strain. A recent meta-analysis of 1382 patients identified several risk factors for recurrent disease, including continued use of antibiotics (OR: 0.23; 95% CI: 2.10–8.55), antacid medication use (OR: 2.15; 95% CI: 1.13–4.08) and older age (1.62; 95% CI: 1.11–2.36).[62] At our hospital, recurrence occurred in ten out of 81 IBD patients with CDI (12.3%).[64] Lower levels of serum anti-TcdA and anti-TcdB antibody may be predictive of disease recurrence, as may infection with the epidemic B1/NAP/027 strain.[87]

Treatment of recurrent CDI depends on the severity of the initial and recurrent episode. In patients with mild disease (in non-IBD patients), repeat courses of the initial antibiotic (metronidazole or vancomycin) has been suggested.[24,25,63,87] However, there is a limited evidence base for this recommendation. In patients with multiple recurrent disease, vancomycin is preferred to metronidazole. Some patients may benefit from a prolonged course of vancomycin with gradual taper over several weeks.[87,88] There appears to be a benefit to the use of a 'rifaximin chaser' for 2–4 weeks after a course of treatment with oral vancomycin.[83,89,90] Another suggested option is the use of S. boulardii after a 10-day course of treatment with high-dose vancomycin (2 g/day) with one study showing a reduction in recurrence rate from 50 to 16.7% with this approach (p = 0.05).[91] Other options include the use of rifampin for 7 days, intravenous immunoglobulin (IVIG) (single dose of 400 mg/kg) or fecal bacteriotherapy from a healthy donor (one case series demonstrated a benefit in 15 out of 18 patients).[87] In select patients, long-term use of maintenance vancomycin therapy has also been suggested (125 mg once- or twice-daily), although there are limited data to support this approach. A recent Phase II trial randomized 200 patients after an initial episode of CDI to a single infusion of monoclonal antibody directed against TcdA and TcdB or placebo in addition to standard antibiotic therapy. The rate of recurrence was significantly lower in the antibody group (7%) compared with placebo (25%; p < 0.001), suggesting that this may be a valid treatment option in high-risk patients if efficacy and safety are confirmed in larger clinical trials.[38]

It is also important in patients with recurrent CDI to control potential sources of re-infection, which may include the healthcare environment or exposure to family members who may be healthy carriers of CDI. Appropriate hand-hygiene measures are essential and should be followed by the patient and family members.

Refractory CDI

In the cohort of patients without response to metronidazole therapy, oral vancomycin in the doses described above may achieve clinical cure, especially in those with severe CDI. A higher daily dose of vancomycin (2 g/day) may be tried in patients refractory to standard dose therapy. In those with significantly delayed small intestinal motility or ileus where there is concern regarding a delay in achievement of adequate colonic luminal concentration of oral vancomycin, intravenous metronidazole may be a useful adjunctive therapy. Another route for vancomycin has been intracolonic administration, either through a rectal tube or a foley catheter.[25,63,75] The doses described in the literature have varied but typically include 1g of vancomycin mixed with 100–1000 ml of normal saline administered two- to four-times daily.

Severity of CDI may, in part, be related to lower antitoxin antibody levels. This is the principle behind the use of IVIG in patients with refractory disease.[92] One of the first published reports of the use of IVIG in the treatment of severe CDI involved 14 patients who had failed a median of three courses of treatment with either metronidazole and/or vancomycin with a mean length of symptoms prior to IVIG infusion of 29 days.[93] They were administered IVIG in a dose of 150–400 mg/kg as a single infusion. Nine patients (64%) responded in a median of 10 days (range: 2–26 days), one had a partial response and the remaining four patients died of other causes within 3 weeks. Abougergi et al. described their experience with the use of IVIG in 21 patients with CDI;[94] only nine patients (43%) survived their hospitalization, emphasizing the overall poor prognosis in this cohort. A subgroup of patients with underlying immunoglobulin deficiency may also develop IBD and in such patients, IVIG may be especially beneficial.

Another novel therapy that has been tried in refractory CDI is infusion of feces from healthy hosts either rectally or through a nasoduodenal tube (fecal bacteriotherapy). The principle behind this is to encourage reconstitution of normal intestinal flora and break the cycle of antibiotic use. The experience with this therapy is limited, with no published reports specifically within the cohort of patients with IBD. However, it appears to have good success rates of 80–90% in select cohorts.[25] Early surgical consultation is essential in the management of patients with refractory or severe CDI.

CDI in Special Situations in IBD
C. difficile Infection in the Ileal Pouch

Total proctocolectomy with ileal pouch anal anastomosis is the most common operation performed for elective treatment of patients with UC and familial adenomatous polyposis. At least one episode of pouchitis occurs in up to half the patients who undergo this surgery. There have now been several reports describing inflammation of the ileal pouch owing to C. difficile.[40,95,96] A study by Shen and colleagues from the Cleveland Clinic (OH, USA) suggested that approximately a fifth (18.3%) of 115 patients with an ileal pouch anal anastomosis were positive for C. difficile toxin by stool ELISA. Independent risk factors for positivity included left-sided colitis prior to the surgery (OR: 8.4) or male gender (OR: 5.12).[40] There was no difference in antibiotic or immunomodulator use between the two groups. CDI has also been reported in segments of diverted bowel[97] and responds to therapy with metronidazole or topical vancomycin.
C. difficile Enteritis

Although classically described as causing colitis, there are now several reports of CDI involving the small bowel in patients with a colectomy.[41,98–101] In our experience of six patients who developed this complication between 2004 and 2006, all presented with a marked increase in ileostomy output with some patients having systemic symptoms of fever and leukocytosis.[41] The ileostomy output tested positive for the C. difficile toxin and all patients responded to treatment with oral metronidazole and/or vancomycin. At least 20 other cases have been reported in the literature, including one report of C. difficile enteritis owing to the epidemic BI/NAP/027 strain.[102] While some reports indicated high morbidity and mortality with this condition, subsequent series demonstrated favorable outcomes once the disease was recognized and appropriate treatment instituted.

Infection Control

The high potential for the transfer of infection between patients, particularly within the hospital and through healthcare providers, makes it essential to follow appropriate infection control and hygiene policies in those with proven or suspected CDI given the resistant nature of the spores.[103] The commonly used alcohol-based hand gels have no effect on the vegetative spores of C. difficile. Instead, thorough hand washing with soap and water is recommended before and after contact with these patients.[104,105] Chlorhexidine hand washes appear to be at least as effective as soap and water washes. Isolation of patients with suspected or diagnosed CDI should be followed along with the use of gowns and gloves for all patient contact.[105] For environmental decontamination, the quaternary ammonium solutions may be inferior to hypochlorite, the preferred antiseptic for environmental decontamination.[103,105] However, as hypochlorite alone may be insufficient to remove organic matter, it may be used in combination with a detergent. Standard endoscope decontamination procedures may be followed after lower gastrointestinal endoscopy in patients with CDI.[103]

Gaps in Research & Future Directions

The past 10 years have seen a dramatic increase in published literature on the incidence and impact of CDI on patients with IBD. Such literature has confirmed a rising incidence and excess morbidity and mortality associated with CDI in IBD patients. However, several unanswered questions remain. There is a need for multicenter prospective studies to better define risk factors for CDI among IBD patients, particularly to help understand how disease activity and ongoing therapy influence the risk of CDI independent of eachother, and what the absolute risks are in specific subgroups. A second question that remains to be answered is whether CDI exerts a disease-modifying effect on patients with IBD, altering their natural history of disease beyond the acute episode. There is some literature to support the role of enteric infections in precipitating disease flares, and there is some, albeit not high-quality, preliminary data to suggest that CDI may have a long-term impact on the course of IBD. More research is needed in this area. A more pressing need is to identify optimal diagnosis and treatment algorithms and for comparative effectiveness studies of metronidazole, vancomycin and/or other therapies in both the initial episode of CDI and recurrences. It is also unclear how to manage immunosuppressive therapy in patients with a disease flare triggered by active CDI, as well as subsequent management of immunosuppression, in such patients. It is essential to develop randomized controlled trials specifically to answer these questions within an IBD population.

Expert Commentary

Clostridium difficile infection is a growing threat to patients with IBD. The infection will destabilize patients in durable remission, as well as present simultaneously with the onset of IBD. The IBD patient population with colitis appears to be at greater risk for acquiring the infection and is at greater risk for poor clinical outcomes, including colectomy and death, compared with the general population. The reasons that the IBD patient population are more susceptible and suffer worse outcomes from C. difficile are not known. Strategies for detecting C. difficile are an evolving area and the optimal treatment regimen for IBD patients suffering from this infection is not defined at this time.

In this article, we explored the limited, existing data regarding C. difficile and IBD. Specific studies investigating optimal treatment regimens for the IBD patient population infected with C. difficile are currently lacking. The majority of information regarding the impact of CDI on IBD patients is limited to case series and expert opinion.

Five-year View

The reasons underlying IBD patient susceptibility to CDI demand exploration. The ability of IBD patients to mount an immunologic response to C. difficile toxin is not defined and this may represent a critical mechanism for irradicating infection and establishing stable colonization with this bacteria. Alternatively, the damaged IBD colonic mucosa may be more susceptible to CDI and the presence of bacteria may result in severe illness. Lastly, the effect of immunosuppressive agents, which are essential for the maintenance of remission in IBD, may be contributing to the severity of infection.

Specific trials investigating the optimal treatment of IBD patients with CDI will also need to be performed. This will include the investigation of specific antibiotic regimens, as well as rescue strategies with IVIG, vaccine studies and fecal transplantation. The severity of the IBD flare at the time of C. difficile treatment will be an important consideration in these studies, as the equivalence of antibiotics in mild-to-moderate colitis may not hold in patients with severe illness. Likewise, understanding the influence of concomitant IBD therapy on the ability to clear CDI will also require formal analysis.

Sidebar
Key Issues

* Clostridium difficileis increasing as a nosocomial pathogen and has exerted a powerful, negative impact on patients with inflammatory bowel disease (IBD). The clinical presentation of C. difficileinfection (CDI) is identical to an IBD colitis disease flare, making diagnosis of the infection problematic. However, the treatment for bacterial colitis and idiopathic IBD are diametrically opposite, making the need for rapid and accurate diagnosis essential.
* IBD patients with colitis are the highest-risk cohort for CDI, and clinical features, such as endoscopic pseudomembranes, are rarely identified. Antibiotic exposure is identified in approximately half of IBD patients with this infection.
* Optimal treatment of CDI in IBD patients is not defined at this time, but early use of oral vancomycin and limiting immunosuppression, particularly with corticosteroids, may improve outcome.

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Papers of special note have been highlighted as:
• of interest
•• of considerable interest

Thanks for the info David-alot of good reading! I've had c.diff. 3 times and may have it again, UGHH. Kaiser Hospital is especially slow to diagnose this. I should forward this to my doc.

You're welcome, sent you a PM

Awesome, I'll get this over to him first thing tomorrow. Thanks!

Whoo! Hoo! Great info, thanks!

Read this article too. The complications of Crohn's are so frustrating.
I read another article related to vancomycin & IBD but need 7 more posts to be able to post a URL. My son is still taking vancomycin (4 weeks on, 2 weeks off, now 2 weeks on). It seems to help him.

Antibiotics, CDI & Crohn's

I have Crohns that has pretty much been manageable over the past 10 years. Recently, my work required me to go kayaking with a group of new college students and I ended up scraping my ankle, which then got infected. I went to a Med Clinic, bc it was late at night, who prescribed me an antibiotic for 5 days (cephalexin I think). Two weeks later I went into a horrible Crohn's flare up which caused me diarrhea for about 4 weeks. I went in for a colonoscopy that my doctor couldn't even finish (30cm) because of inflammation. Now I've been placed on Prednisone, two antibiotics and I go in for a CAT scan next week. My dad, who is a chemist, actually brought to my attention that it may have been the antibiotics. I would have had no clue (I did share with my digestive dr today). I REALLY wish I would have discussed the first set of antibiotics with my digestive doctor, he thinks I may have developed CDI. Now I'm just praying I get better. It's amazing the ripple effect that occurs with Crohn's & antibiotics (among others)... Thank you for this information David!