Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Clostridium Difficile Infection and Liver Disease Saif Musa, Carl Moran, Tony Rahman Department of Gastroenterology & Hepatology, St. George’s Hospital, Blackshaw Rd, London, UK Abstract The rates of the predominantly hospital acquired infection, Clostridium difficile, have increased throughout the world. Several risk factors and susceptible patient populations have been identified. Patients with pre-existing liver disease represent an important cohort; recent evidence suggests that Clostridium difficile infection (CDI) is associated with a worse outcome and increased health care costs. This review focuses on the epidemiology, risk factors, pathogenesis, treatment options and outcomes associated with CDI in patients with liver disease. Keywords Clostridium difficile – Clostridium difficile infection enterocolitis – pseudomembranous – epidemiology – liver diseases – risk factors and treatment. Introduction Reports of liver disease (LD) patients infected by the bacterium Clostridium difficile (C. difficile) first emerged more than 25 years ago [1-5]. Since then, Clostridium difficile infection (CDI) has been described in a variety of LD patients including those with acute and chronic (cirrhotic) conditions and those post liver transplantation (LT) [1-15]. Important risk factors have been identified and recent evidence suggests infected LD patients have increased morbidity, mortality and health care costs [6, 16,17]. This narrative review focuses on the epidemiology, risk factors, treatment options and outcomes in LD patients with CDI. Received: 21.07.2010Accepted: 28.08.2010 J Gastrointestin Liver Dis September 2010 Vol.19 No 3, 303-310 Address for correspondence: Dr. Tony M. Rahman Department of Gastroenterology and Hepatology, St. George’s Hospital Blackshaw Road, London SW17 0QT, UK Email: [email protected] Epidemiology of Clostridium difficile infection and LD Clostridium difficile infection can either be classified as hospital or community acquired; the prevalence of LD has been described in both. In terms of nosocomial disease, retrospective single centre studies have revealed CDI is common amongst LT patients [8], and patients of a hepatology unit [13]. The former revealed 30/136 (22%) hospital acquired cases occurred in LT patients and the latter showed that compared to other hospital wards, higher rates of infection were evident on the hepatology ward (0.9% vs 0.29%). Most of the affected patients (22/23) in the latter case controlled study had cirrhotic LD [Child Pugh A (17%), B (50%) or C (28%)]. Two large multicentre studies have also described the frequency of LD amongst hospitalised patients. The first, the Canadian Nosocomial Infection Surveillance Program (CNISP) reported 62/1430 (4%) CDI cases had underlying LD [16], and the second, a retrospective study from the United States (US) revealed 1,165/59,385 (2%) CDI cases discharged from hospital either had cirrhosis or cirrhosis related complications [6]. Both of these findings require further clarification; the definition of LD used by the CNISP was not mentioned and the reported rate in cirrhotics may have included asymptomatic carriers. The proportion of nosocomial cases with acute or chronic (non-cirrhotic) LD has yet to be determined; cases in acute LD have rarely been described [1, 4]. One single centre US study has used the term ‘mild LD’ but failed to describe this any further. This investigation reported that 13/382 (3%) hospital acquired cases had mild LD [18]. The prevalence of LD amongst community acquired cases has also been rarely described [19, 20]. One case controlled study revealed 2/1233 (0.2%) community acquired cases had cirrhosis [20]. A number of studies have described the rates of CDI in certain LD [6-8, 10, 14, 18, 20, 21]. Investigations involving hospitalised patients have revealed that 2% of mild LD patients and 5.5% of cirrhotics are diagnosed with CDI [18, 21]. One case controlled study has demonstrated that 2/19 (11%) cirrhotic patients develop community acquired 304 CDI [20]. Although diarrhoea on hospital admission has been reported in 7/54 (13%) cirrhotic patients with CDI [6], it is not clear whether all/any really fulfil the criteria for community acquired CDI. The recurrence rate of CDI varies from 15-35%; most are thought to be caused by another strain [22]. Recurrent episodes of CDI have rarely been described in patients with LD; rates post LT vary from 22-27% [8, 9]. Rates of CDI in patients with deceased donor LT vary from 3% to 8% [8, 14] and post ‘live’ donor LT transplant vary from 5% to 11% [9, 10]. Most cases (≥50%) occur within the first month of LT [8, 9, 14]; reports in patients > 1 year post LT are rare [8, 23]. The observed variance in rates may be attributed to the method of diagnosis, the timing/number of stool tests performed and study duration. Investigation periods have varied from less than four years [8] to more than eight [9]. A number of different techniques have been used to identify cases including enzyme immunoassays (EIA), stool cultures and polymerase chain reaction assays [7-9,11-13]. The specific method used may have influenced the diagnostic rate. Enzyme immunoassays have been most frequently used and whilst they are simple to perform and provide rapid results, several types are available each exhibiting a range of sensitivities and specificities compared to the reference method (the cytotoxin stool cell culture assay) [24]. During the first month post deceased donor LT, only 5/35 EIA positive specimens were culture positive [7]. The spectrum of disease associated with CDI also includes patients with asymptomatic disease. Currently little is known about rates of asymptomatic carriage or hospital acquisition in LD patients; most of the data available refers to patients post LT [9, 25, 26]. Approximately 3% of the healthy adult population are colonised by C.difficile, increasing to over 20% in hospitalised patients [27]. Liver transplantation has been shown to be an independent risk factor for hospital acquisition (relative risk 4.2, 95% confidence interval [CI] 1.3-13.7) [25]. One small prospective study (n=15) revealed nine (60%) patients were colonised during the first 35 days post transplant [26]. Two thirds of cases were colonised by toxin producing strains; none were stool culture or toxin positive at the time of study induction. A more recent study involving less frequent stool testing, determined 16/27 (60%) LT patients with C.difficile were asymptomatic [9]. Only one patient was however carrying a toxin producing strain. As stool results on study entry were not reported, it is not possible to say whether the asymptomatic carriers were present from the time of admission or were cases of hospital colonisation or a combination of both. Asymptomatic carriage amongst cirrhotic patients may be as high as 20% [28]. Risk factors for Clostridium difficile infection in patients with liver disease Few studies have described the risk factors associated with CDI in LD patients (Table I); those identified relate to cirrhotic and LT patients [6, 8, 9, 13]. Although formal comparisons between the rates and risk factors for CDI in Musa et al Table I. Risk factors associated with Clostridium difficile infection in patients with liver disease Hepatology inpatients [13]: Autoimmune hepatitis diagnosis Previous antibiotic use (Beta-lactams, Co-amoxiclav) Cirrhotic inpatients[6]: Inpatient antibiotic use Outpatient proton pump inhibitor use Post live donor liver transplant [9]: Male sex Pre-operative serum creatinine ≥1.5mg/dL Post deceased donor liver transplant [8] : Primary non-function liver disease diagnosis United Network Organ Status Non-primary liver transplantation Elevated model end stage liver disease score Renal impairment in donor Post-operative intra-abdominal bleed Post-operative biliary complications Post-operative bacterial/systemic infection Post-operative wound complications Post-operative residency on intensive care patients receiving a deceased donor LT or live donor LT have yet to be done, different risk factors have been reported. Independent risk factors during the first three months of ‘live’ donor LT include male gender (odds ratio - OR 4.56, 95% CI 1.02-33.3) and an elevated pre-operative serum creatinine ≥1.5mg/dl (OR 15.99, 95% CI 3.85-68.3) [9]. Impaired host immunity in patients with deranged renal function may explain the latter finding. In contrast, a number of other risk factors have been identified in patients post deceased donor LT (Table I); stratification by CDI onset (early or intermediate) has revealed some important differences [8]. Early CDI (<28 days of LT) is associated with a higher model end stage liver disease (MELD) score, intraabdominal haemorrhage, increased numbers of grafts and re-transplantation. In contrast, intermediate CDI (29-365 days post LT), is more likely in patients with vascular complications, bacterial infections and those requiring endoscopic retrograde cholangiopancreatography or percutaneous cholangiography [8]. Biliary complications, bile leaks and systemic infections are common to both. As the relationship in terms of antibiotic exposure was not assessed, there is the possibility that antibiotics used to treat complications were more important than the underlying cause. Biliary complications are also common after ‘live’ donor LT, however, the relationship to CDI has not been reported [29]. Antecedent antibiotic therapy is the most important risk factor for CDI, and antibiotic use in patients with cirrhosis and post LT is significant. Patients requiring LT routinely receive antibiotics as part of their management and whilst pre-operative antibiotic use [9], and selective decontamination have not been shown to increase the risk of CDI [30], the use of additional post-operative antibiotics maybe important [8]. This study demonstrated that 69% CDI patients post LT received additional antibiotics. One C. difficile and liver disease prospective, double blinded, randomised control trial has evaluated the risk of CDI in LT patients receiving selective bowel decontamination [30]. No significant difference in rates was observed between patients (n=37) receiving 80 mg gentamicin, 100mg polymyxin E and 2 million units of nystatin and patients (n=43) receiving 2 million units nystatin alone (5.4% vs 2.3%, p=0.905). In terms of post-operative antibiotics, the class/type may be of more importance than the number [9]. This study failed to demonstrate any association between CDI and the number of post-operative antibiotics (<6 vs ≥6). In terms of cirrhotic patients, one recent retrospective case controlled study has identified in-patient antibiotic use as an independent predictor of CDI (OR 11.6, 95% CI 2.63-51.05) [6]. The type of antibiotic administered may have influenced this result. Third generation cephalosporins (48% vs 20%) and beta lactams (19% vs 7%) were more commonly prescribed amongst affected individuals; both are considered as high risk antibiotics for CDI [31]. Interestingly, outpatient antibiotic use (ciprofloxacin) was not shown to be a significant risk factor [6, 17]. Fluoroquinolone use has been linked to recent outbreaks and the emergence of a hypervirulent C. difficile strain in North America [32, 33]. The risk of CDI in LD patients requiring the rifamycin class of antibiotic requires further clarification; evidence suggests that rifaximin reduces the risk of hepatic encephalopathy and may prove an important treatment option [34, 35, 36]. In contrast to the suggested relationship with rifampicin [1, 3], rifaximin does not significantly increase the risk of infection [33, 34] and may be an effective therapy in recurrent cases [37]. Rifaximin administration in conjunction with lactulose (n=140) has not been shown to significantly increase the risk of CDI, compared to patients (n=159) receiving lactulose alone (1.4% vs 0%) [34]. This result needs to be interpreted with caution; lactulose may have played an important ‘protective’ role by reducing short chain fatty acid production and suppressing C.difficile growth/proliferation [28]. Immunosuppressant medications are an important risk factor for CDI in other patient populations including recipients of renal transplants and patients with inflammatory bowel disease [38-40]. Immunosuppressant medication is often required in certain LD, especially auto-immune hepatitis and post LT. Autoimmune hepatitis is associated with an increased risk of nosocomial CDI (26% cases vs 2% controls, p<0.01) [13]. The criteria used by this study to define autoimmune hepatitis included evidence of interface hepatitis, absence of other causes of liver disease, and the presence of autoantibody titer > 1:40. Patients post LT require immunomodulators such as tacrolimus, steroids and mycophenolate to reduce the risk of rejection. Although ‘acute rejection’ per se does not appear to increase the risk of CDI [8, 9], specific ‘acute rejection’ treatments may. Patients requiring whole plasma exchange have demonstrated a trend towards increased rates of infection [8]. Several immunosuppressants are currently being used/developed for patients with LT and whether certain drugs are more 305 frequently associated with CDI has yet to be evaluated [41]. Corticosteroid use has been identified as a significant risk factor for relapses in transplant patients (risk ratio 4.19, 95% CI 1.41-13.06) [11]. Another common risk factor associated with CDI - age - has not been not shown to be important in cirrhotic or post LT patients [6, 9, 13]. The relationship between proton pump inhibitor (PPI) use and CDI remains unclear; studies involving both community and hospital acquired cases have produced conflicting results [20, 32, 42, 43]. Reduced gastric acid is believed to play an important role in ensuring survival of any ingested active (vegetative) forms of C. difficile [44]. In addition PPIs may also suppress the immune response to infection [45]. The only study to evaluate the relationship between PPI use and CDI in LD patients has involved cirrhotic patients. This investigation revealed that outpatient PPI use was an independent risk factor for CDI (OR 37.6, 95% CI 6.22227.6) [6]. This finding suggests that a judicious prescribing policy may be required in this cohort [17]: one prospective study has shown that 39/51 (63%) of cirrhotics receive PPIs inappropriately [46]. Other possible risk factors in cirrhotics have also been described [6]. Although the tertiary referral component (58 infected vs 108 non-infected cirrhotics) of this study failed to show any association with age, gender or ethnicity, the nationwide component (n=1,165 infected vs 82,065 noninfected cirrhotics) demonstrated that infected cirrhotics were more likely (p<0.001) to be older (61 vs 58 years), female (46.0% vs 38.5%), Caucasian (57.4% vs 51.4%) and have a raised Charlson co-morbid score ≥ 3 (14.0 % vs 11.9%). In addition, CDI was found to be more common (p<0.001) amongst cirrhotics with hepatorenal syndrome (4.8% vs 3.0%), pneumonia (14.2% vs 7.8%), spontaneous bacterial peritonitis (0.9% vs 0.5%) and a urinary tract infection (21.3% vs 12.1%) and less common in cirrhotics with encephalopathy (16.9% vs 19.0%) or a variceal bleed (4.1% vs 7.9%). Comparisons between patients with LD and CDI to those with CDI alone have rarely been done [6]. This large population based study demonstrated that infected cirrhotics (n=1,165) were more likely (p<0.001) to be younger (61 vs 69 years), male (54.0% vs 40.8%) and Hispanic (11.6% vs 5.1%) than non-cirrhotic CDI patients (n=58,220) and less likely to have a raised Charlson comorbid score ≥ 3 (14.0% v18.8%), pneumonia (14.2% vs 17.2%) or a urinary tract infection (21.3% vs 26.1%). Both cohorts excluded LT patients. Pathogenesis Clostridium difficile is predominantly transmitted as spores via the faecal-oral route. Following ingestion, primary bile salts and their derivatives facilitate germination to the vegetative (active) state within the small bowel. The bacteria then migrates to the colon where under favourable conditions (antibiotic mediated disruption of colonic flora), proliferation occurs and strains capable of producing toxins (A,B) cause 306 intestinal inflammation and disease [47, 48]. Disturbances and thus reduced levels of colonic bacteria possessing the enzyme 7-alpha hydroxylase activity, such as Lactobacillus and Bifidobacteria species, are believed to play an important role in facilitating C. difficile growth [47]. Altered gut flora has been reported in LD patients [49-52], and may provide a favourable environment for C.difficile colonisation and proliferation. All of these studies have been conducted in Asia. Compared to normal controls, cirrhotic patients (mostly with viral hepatitis) have been shown to have significantly reduced levels of Bifobacterium and increased levels of Clostridium, respectively [49]. In addition to antibiotic use, possible reasons for the changes in gut flora include delayed intestinal motility and increased intestinal pH [49]. Reduced levels of Bifobacterium have also been reported in patients with chronic severe hepatitis and chronic hepatitis [51], and both Lactobacilli and Bifidobacteria amongst alcoholic patients [52]. Experimental animal models of acute liver failure have also demonstrated reduced levels of Lactobacillus in the ileum and colon [52]. Selective bowel decontamination is predominantly aimed at aerobic gram-negative bacteria. Maintenance of the gram positive flora (including Bifidobacteria and Lactobacilli) may provide a plausible explanation for the lack of any association between selective bowel decontamination and CDI in LT patients [30]. Not all patients colonised by toxin producing strains develop disease; protective host factors include an intact immune system and a lack of significant co-morbidity [53,54]. Disturbed immune function has been observed in patients with LD [13, 55] and may account for the apparent increased risk in patients with autoimmune hepatitis [13]. Hypogammaglobulinaema may be an important risk factor in LT patients; just over a quarter of LT patients have reduced immunoglobulin levels (IgG levels <560 mg/dl) [55]. Risk factors for reduced IgG levels include a diagnosis of non A/B hepatitis, rare LD such as autoimmune hepatitis and reduced platelet transfusion requirements. Although this study did not assess outcome in terms of CDI, hypogammaglobulinaema is associated with CDI in other patient populations e.g. those post cardiac transplantation [55, 56]. Clinical features The clinical manifestations associated with CDI are diverse, ranging from asymptomatic carriage through to severe colitis and life threatening sepsis [22]. Symptom onset is variable and may range from one day to several weeks following antimicrobial exposure [57]. Typical features of CDI include watery diarrhoea and abdominal discomfort. Systemic features develop in patients with more severe disease and in some cases an ileus/megacolon may develop [22]. Recent national and international guidelines now incorporate a number of clinical, laboratory and radiological parameters to define severity [58-60]. Clinical features associated with CDI in LD have been mostly described in LT patients, diarrhoea, fever and Musa et al abdominal pain are common presenting symptoms in this cohort [9, 12, 61]. Diarrhoea may last for up to 43 days (range 5-43 days) [9]. Diarrhoea is extremely common in the first few weeks post LT and it is important to rule out other infectious (e.g. Cytomegalovirus) or non-infectious (e.g. drugs) causes [62]. Severe cases of CDI have also been reported in this cohort [8, 9, 14, 63, 64]. Although hospitalised transplant patients are more likely to develop symptomatic CDI [25], one retrospective study has failed to show any significant difference in severity (death, intensive care unit admission or colectomy within 30 days of diagnosis) between transplant (n=80) and non-transplant patients (n=86) [11]. Fever (67%) and diarrhoea (13%) are also common amongst cirrhotic patients with CDI [6]. Extra-intestinal CDI has been reported in patients with LD [65], including splenic and liver abscesses [5,15]. Liver disease patients with ascites are susceptible to developing bacterial peritonitis and there have been a few instances in which C. difficile has been cultured from peritoneal fluid [5, 65, 66]. Diagnosis Several methods of diagnosis are available including microbiology (stool culture/toxin testing), histology and endoscopy. The reference method of diagnosis is the stool cytotoxin culture assay (detects Toxin B). Use of this technique has now largely been superseded by the more rapid technique of EIA. Concerns over the sensitivity and specificity of EIA have resulted in a growing consensus to confirm all positive EIA cases with the reference method [24]. Use of a ‘two’ or ‘three’ step approach to diagnosis is believed to be more cost effective than using the reference method alone [22]. Most studies involving LD patients have used EIA to diagnose CDI [7-9, 11, 12], additional testing of positive EIA cases has rarely been done [7, 9]. Stool toxin analysis by polymerase chain reaction has also been done [13]. Stool sampling from patients with an ileus may not be possible; in such cases endoscopy and radiological findings may provide important clues. Histological and endoscopy findings in patients with CDI vary from non specific colitis to pseudomembranous colitis (severest form of disease) [57]. Pseudomembranous colitis has been described in LT patients and unique histological findings have also been reported [14]. Two patients had mucosal evidence of neutrophilic capillaritis/venulitis. Clinicians should also be alert to the possibility of CDI in cirrhotic patients with computerised tomography evidence of right colon pneumatosis or diffuse colonic pneumatosis/pancolonic thickening [67]. Treatment Management of CDI can be either medical and/ or surgical. Current medical treatment involves oral metronidazole for mild to moderate CDI cases and oral vancomycin +/- intravenous metronidazole for severe/ life threatening cases [58, 60, 68]. Important additional measures C. difficile and liver disease include barrier nursing, antibiotic rationing, avoidance of antimotility agents and hand washing. Disease severity of CDI is a continuum and progression may occur hence regular/daily assessment is recommended [58, 60, 68]. Several other treatment options are available/being evaluated [31, 69], including the antibiotics rifaximin, tigecycline, fidaxomicin and nitazoxanide. In addition, immunotherapy and faecal transplantation may also prove to be effective in the future. Recurrent CDI can occur in up to 35% of cases and treatment maybe difficult, often requiring longer courses of vancomycin or metronidazole. Other possible treatment options include cholestyramine, tolevamer, immunoglobulin infusions and the infusion of colonic bacteria [22, 31, 69]. Treatment of asymptomatic carriers is ineffective and not recommended [70]. Although development of a vaccine for high risk patients may prove beneficial, its application may be limited in immunosuppressed patients. Patients that fail to respond to medical therapy may require a colectomy; symptom resolution is expected within a mean time of 3-6 days [22]. Colectomy rates vary from 0.17% [71] to 3.5% [72] and are associated with a high mortality (11.1-66%) [73, 74]. The recommended surgical treatments are a subtotal colectomy and ileostomy [75], or a total colectomy and ileostomy [76]. Indications for colectomy include the development of peritonitis and toxic megacolon, leucocytosis (>20x109/L) and a raised lactate (2.2-4.9 mmol/L) may also serve as important markers [77]. In terms of LD, the majority of reports and studies have used vancomycin to treat CDI [1, 3, 4, 6, 9, 15, 23, 78]. Metronidazole has also been successfully used [8]. Cholestyramine has rarely been required [1]. Cholestyramine binds to bile acid and is widely used to treat pruritus in patients with cholestatic LD; its mechanism of action against C.difficile involves binding toxins. Colectomies have rarely been required [6, 8, 64, 79]; mortality rates following a colectomy are much higher in cirrhotic than non-cirrhotic patients [80]. Recurrences have also been infrequently reported [1, 9, 15, 75]; episodes have been successfully treated with either repeat courses of vancomycin or metronidazole. One recent case series has also demonstrated that rifaximin may prove an effective treatment option for recurrent CDI in patients post LT [37]. The use of probiotics containing specific strains of Lactobacilli and Bifidiobacteria have been shown to reduce the rates of bacterial infection in patients post LT and have also been shown to improve liver function in patients with alcoholic liver disease and non-alcoholic fatty liver disease [52, 81, 82]. In addition, combination therapy with rifaximin and probiotics may also reduce the risk of hepatic encephalopathy [35]. Use of specific probiotic strains may not be effective in all patients with LD; the effect in patients with viral hepatitis has been less dramatic [83]. Modulation of the intestinal flora may also help to prevent/ reduce rates of CDI. Probiotics may act by augmenting the antibody response against Toxin A, suppressing C. difficile colonisation, adhesion and invasion and by directly inhibiting 307 the actions of Toxin A and B [69]. Lactulose may also have a preventative role against CDI in LD patients, possibly by reducing colonic exposure to toxins [28]. Outcome Amongst CDI cases, patients with comorbid LD are at an increased risk of a severe outcome including admission to an intensive care unit, surgery (colectomy) and/or death (OR 2.62, 95% CI 1.12-6.15) [16]. One retrospective study investigating CDI cases on ICU (n=278) revealed that 18/278 (6.5%) of patients had underlying cirrhosis; 5/18 (28%) of these cases died [84]. Amongst CDI cases requiring a colectomy, the presence of LD is infrequently reported: 11% may have cirrhosis [79], and 5% may have had a LT [64]. Only one study has investigated the morbidity, mortality and associated healthcare costs in CDI patients with LD. This large retrospective study, involving cirrhotic patients [6], demonstrated that infected cirrhotics (n=1,165) were more likely (p<0.001) to die (13.8% vs 9.6%), have prolonged hospital stays (mean stay 14.4 vs 12.7 days) and higher healthcare costs ($79,351 vs $ 57,708) than patients with CDI alone (n=58,220). In terms of cirrhotic patient population alone, those with CDI (n=1,165) are more likely to die (OR 1.79, 95% CI 1.51-2.12), require longer lengths of hospital stay (7.1 days, 95% CI 6.2-8.1 days) and incur higher healthcare costs ($40,596, 95% CI $ 31,870-$49,321), than those not infected (n= 82,065) (p<0.001). The mortality rate was influenced by ethnic (African American>Caucasians> Hispanics), insurance group (uninsured>private>Medicare) and geographical differences (midwest America<north east America) [OR 0.75, 95 % CI 0.64 –0.88, p<0.01) [6]. Mortality was not influenced by hospital status (teaching vs non-teaching) or setting (urban vs rural). After adjusting for all these factors, CDI remained an independent risk factor for in-hospital death amongst cirrhotics (OR 1.55, 95% CI 1.29–1.85). This study also demonstrated the mortality risk associated with CDI was similar to those from other cirrhotic related complications such as hepatic encephalopathy (OR 1.94, 95% CI 1.83-2.06), variceal bleeding (OR 1.63, 95% CI 1.49-1.78), spontaneous bacterial peritonitis (OR 1.98, 95% CI 1.45-2.70) and ascites (OR 1.30, 95% CI 1.22-1.38), highlighting the importance of CDI in this patient population. In terms of LT patients, cases with CDI rarely die or require colectomy [8, 9, 14]. Conclusions It is important to recognise that whilst the proportion of CDI cases that have underlying LD is relatively small, affected patients are at risk of increased morbidity and mortality. The significance of CDI amongst cirrhotic patients and those post LT is increasingly being reported. However, little is known about the rates and significance in patients with acute and chronic non-cirrhotic LD. A small number of studies have identified risk factors associated with CDI in certain LD (post LT and cirrhotic) patient populations. 308 These require further validation and assessment in other LD groups. Metronidazole and vancomycin are the main treatment options available. Use of probiotics, in certain liver conditions, and lactulose may help reduce rates of infection. Recurrent cases have rarely been reported and the apparent increase in socio-economic costs merit further evaluation. Conflicts of interest None declared. References 1. Fournier G, Orgiazzi J, Lenoir B, Dechavanne M. Pseudomembranous colitis probably due to rifampicin. Lancet 1980; 1: 101. 2. Moriarty HJ, Scobie BA. Pseudomembranous colitis in a patient on rifampicin and ethambutol. N Z Med J 1980; 91: 294-295. 3. Bommelaer G, Larpent JL, Rumeau JL, Ribet A. Pseudomembranous colitis and rifampicin. Lancet 1980; 2: 1192. 4. Klaui H, Leuenberger P. Pseudomembranous colitis due to rifampicin. Lancet 1981; 2: 1294. 5. Saginur R, Fogel R, Begin L, Cohen B, Mendelson J. Splenic abscess due to Clostridium difficile. J Infect Dis 1983; 147: 1105. 6. Bajaj JS, Ananthakrishnan AN, Hafeezullah M, et al. Clostridium difficile is associated with poor outcomes in patients with cirrhosis: A national and tertiary center perspective. Am J Gastroenterol 2010; 105: 106-113. 7. Kawecki D, Chmura A, Pacholczyk M, et al. Detection of Clostridium difficile in stool samples from patients in the early period after liver transplantation. Transplant Proc 2007; 39: 2812-2815. 8. Albright JB, Bonatti H, Mendez J, et al. Early and late onset Clostridium difficile-associated colitis following liver transplantation. Transpl Int 2007; 20: 856-866. 9. Hashimoto M, Sugawara Y, Tamura S, et al. Clostridium difficileassociated diarrhea after living donor liver transplantation. World J Gastroenterol 2007; 13: 2072-2076. 10. Pomposelli JJ, Verbesey J, Simpson MA, et al. Improved survival after live donor adult liver transplantation (LDALT) using right lobe grafts: program experience and lessons learned. Am J Transplant 2006; 6: 589-598. 11. Gellad ZF, Alexander BD, Liu JK, et al. Severity of Clostridium difficile-associated diarrhea in solid organ transplant patients. Transpl Infect Dis 2007; 9:276-280. 12. Stelzmueller I, Goegele H, Biebl M, et al. Clostridium difficile colitis in solid organ transplantation--a single-center experience. Dig Dis Sci 2007; 52:3231-3236. 13. Vanjak D, Girault G, Branger C, Rufat P, Valla DC, Fantin B. Risk factors for Clostridium difficile infection in a hepatology ward. Infect Control Hosp Epidemiol 2007; 28: 202-204. 14. Wong NA, Bathgate AJ, Bellamy CO. Colorectal disease in liver allograft recipients -- a clinicopathological study with follow-up. Eur J Gastroenterol Hepatol 2002; 14: 231-236. 15. Sakurai T, Hajiro K, Takakuwa H, Nishi A, Aihara M, Chiba T. Liver abscess caused by Clostridium difficile. Scand J Infect Dis 2001; 33: 69-70. 16. Gravel D, Miller M, Simor A, et al; Canadian Nosocomial Infection Surveillance Program. Health care-associated Clostridium difficile infection in adults admitted to acute care hospitals in Canada: a Canadian Nosocomial Infection Surveillance Program Study. Clin Infect Dis 2009; 48: 568-576. 17. Garcia-Tsao G, Surawicz CM. Editorial: Clostridium difficile infection: Yet another predictor of poor outcome in cirrhosis. Am J Gastroenterol 2010;105:114-116. Musa et al 18. Dubberke 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; 45:15431549. 19. Kyne L, Merry C, O’Connell B, Keane C, O’Neill D. Communityacquired Clostridium difficile infection. J Infect 1998; 36: 287288. 20. Dial S, Delaney JA, Barkun AN, Suissa S. Use of gastric acidsuppressive agents and the risk of community-acquired Clostridium difficile-associated disease. JAMA 2005; 294: 2989-2995. 21. Bajaj JS, Zadvornova Y, Hafeezullah M, Saeian K. Clostridium difficile infection is associated with proton pump inhibitors in patients with cirrhosis. Hepatology 2007; 46: Suppl: 580A. (Abstract). 22. Gerding DN, Muto CA, Owens RC Jr. Treatment of Clostridium difficile infection. Clin Infect Dis 2008; 46 (Suppl 1):S32-42. 23. Limaye AP, Turgeon DK, Cookson BT, Fritsche TR. Pseudomembranous colitis caused by a toxin A(-) B(+) strain of Clostridium difficile. J Clin Microbiol 2000; 38: 1696-1697. 24. Planche T, Aghaizu A, Holliman R, et al. Diagnosis of Clostridium difficile infection by toxin detection kits: a systematic review. Lancet Infect Dis 2008; 8:777-784. 25. Samore MH, DeGirolami PC, Tlucko A, Lichtenberg DA, Melvin ZA, Karchmer AW. Clostridium difficile colonization and diarrhea at a tertiary care hospital. Clin Infect Dis 1994; 18: 181-187. 26. Hove H, Tvede M, Mortensen PB. Antibiotic-associated diarrhoea, Clostridium difficile, and short-chain fatty acids. Scand J Gastroenterol 1996; 31: 688-693. 27. Barbut F, Petit JC. Epidemiology of Clostridium difficile-associated infections. Clin Microbiol Infect 2001; 7:405-410. 28. Ito Y, Moriwaki H, Muto Y, Kato N, Watanabe K, Ueno K. Effect of lactulose on short-chain fatty acids and lactate production and on the growth of faecal flora, with special reference to Clostridium difficile. J Med Microbiol 1997; 46: 80-84. 29. Olthoff KM, Merion RM, Ghobrial RM, et al; A2ALL Study Group. Outcomes of 385 adult-to-adult living donor liver transplant recipients: a report from the A2ALL Consortium. Ann Surg 2005; 242: 314–323. 30. Hellinger WC, Yao JD, Alvarez S, et al. A randomized, prospective, double-blinded evaluation of selective bowel decontamination in liver transplantation. Transplantation 2002; 73: 1904-1909. 31. Monaghan T, Boswell T, Mahida YR. Recent advances in Clostridium difficile-associated disease. Gut 2008; 57:850-860. 32. Pépin J, Saheb N, Coulombe MA, et al. Emergence of fluoroquinolones as the predominant risk factor for Clostridium difficile-associated diarrhea: a cohort study during an epidemic in Quebec. Clin Infect Dis 2005; 41:1254-1260. 33. Loo VG, Poirier L, Miller MA, et al. A predominantly clonal multiinstitutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality. N Engl J Med 2005; 353: 24422449. 34. Bass NM, Mullen KD, Sanyal A, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med 2010; 362:1071-1081. 35. Lighthouse J, Naito Y, Helmy A, et al. Endotoxinemia and benzodiazepine-like substances in compensated cirrhotic patients: a randomized study comparing the effect of rifaximine alone and in association with a symbiotic preparation. Hepatol Res 2004; 28:155160. 36. Maclayton DO, Eaton-Maxwell A. Rifaximin for treatment of hepatic encephalopathy.Ann Pharmacother 2009; 43:77-84. 37. Neff G, Zacharias V, Kaiser TE, Gaddis A, Kemmer N. Rifaximin for the treatment of recurrent Clostridium difficile infection after liver transplantation: A case series. Liver Transpl 2010; 16:960-963. C. difficile and liver disease 38. West M, Pirenne J, Chavers B, et al. Clostridium difficile colitis after kidney and kidney-pancreas transplantation. Clin Transplant 1999; 13: 318-323. 39. Bárány P, Stenvinkel P, Nord CE, Bergström J. Clostridium difficile infection--a poor prognostic sign in uremic patients? Clin Nephrol 1992; 38: 53-57. 40. Issa M, Vijayapal A, Graham MB, et al. Impact of Clostridium difficile on inflammatory bowel disease. Clin Gastroenterol Hepatol 2007; 5: 345-351. 41. Geissler EK, Schlitt HJ. Immunosppression for liver transplantation Gut 2009; 58:452-463. 42. Dial S, Alrasadi K, Manoukian C, Huang A, Menzies D. Risk of Clostridium difficile diarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case-control studies. CMAJ 2004; 171:33-38. 43. Lowe DO, Mamdani MM, Kopp A, Low DE, Juurlink DN. Proton pump inhibitors and hospitalization for Clostridium difficileassociated disease: a population-based study. Clin Infect Dis 2006; 43:1272-1276. 44. Jump RL, Pultz MJ, Donskey CJ. Vegetative Clostridium difficile survives in room air on moist surfaces and in gastric contents with reduced acidity: a potential mechanism to explain the association between proton pump inhibitors and C. difficile-associated diarrhea? Antimicrob Agents Chemother 2007; 51:2883-2887. 45. Zedtwitz-Liebenstein K, Wenisch C, Patruta S, Parschalk B, Daxböck F, Graninger W. Omeprazole treatment diminishes intra- and extracellular neutrophil reactive oxygen production and bactericidal activity. Crit Care Med 2002; 30:1118-1122. 46. Kalaitzakis E, Bjornsson E. Inadequate use of proton-pump inhibitors in patients with liver cirrhosis. Eur J Gastroenterol Hepatol 2008; 20: 512 –518. 47. Sorg JA, Sonenshein AL. Bile salts and glycine as cogerminants for Clostridium difficile spores. J Bacteriol 2008; 190:2505-2512. 48. Voth DE, Ballard JD. Clostridium difficile toxins: mechanism of action and role in disease. Clin Microbiol Rev 2005; 18: 247–263. 49. Zhao HY, Wang HJ, Lu Z, Xu SZ. Intestinal microflora in patients with liver cirrhosis. Chin J Dig Dis 2004; 5: 64-67. 50. Liu Q, Duan ZP, Ha DK, Bengmark S, Kurtovic J, Riordan SM. Synbiotic modulation of gut flora: effect on minimal hepatic encephalopathy in patients with cirrhosis. Hepatology 2004; 39: 1441-1449. 51. Li L, Wu Z, Ma W, Yu Y, Chen Y. Changes in intestinal microflora in patients with chronic severe hepatitis. Chin Med J (Engl) 2001; 114: 869-872. 52. Kirpich IA, Solovieva NV, Leikhter SN, et al. Probiotics restore bowel flora and improve liver enzymes in human alcohol-induced liver injury: a pilot study. Alcohol 2008; 42: 675-682. 53. Warny M, Vaerman JP, Avesani V, Delmée M. Human antibody response to Clostridium difficile toxin A in relation to clinical course of infection. Infect Immun 1994; 62: 384-389. 54. Sunenshine RH, McDonald LC. Clostridium difficile-associated disease: New challenges from an established pathogen. Cleve Clin J Med 2006; 73:187-197. 55. Doron S, Ruthazer R, Werner BG, Rabson A, Snydman DR. Hypogammaglobulinemia in liver transplant recipients: incidence, timing, risk factors, and outcomes. Transplantation 2006; 81: 697703. 56. Muñoz P, Giannella M, Alcalá L, et al. Clostridium difficile-associated diarrhea in heart transplant recipients: is hypogammaglobulinemia the answer? J Heart Lung Transplant 2007 26:907-914. 57. Poutanen SM, Simor AE. Clostridium difficile-associated diarrhea in adults. CMAJ 2004; 171: 51-58. 309 58. Health Protection Agency. Clostridium difficile infection: How to deal with the problem, 2009. http://www.hpa.org.uk/web/HPAwebFile/ HPAweb_C/1232006607827 (accessed July 2010). 59. Kuijper EJ, Coignard B, Tüll P; ESCMID Study Group for Clostridium difficile; EU Member States; European Centre for Disease Prevention and Control. Emergence of Clostridium difficileassociated disease in North America and Europe. Clin Microbiol Infect 2006; 12 (Suppl 6): 2-18. 60. Cohen 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; 31:431-455. 61. Niemczyk M, Leszczyńiski P, Wyzgał J, Paczek L, Krawczyk M, Luczak M. Infections caused by Clostridium difficile in kidney or liver graft recipients. Ann Transplant 2005; 10: 70-74. 62. Arslan H, Inci EK, Azap OK, Karakayali H, Torgay A, Haberal M. Etiologic agents of diarrhea in solid organ recipients. Transpl Infect Dis 2007; 9:270-275. 63. Kusne S, Dummer JS, Singh N, et al. Infections after liver transplantation. An analysis of 101 consecutive cases. Medicine (Baltimore) 1988; 67:132-143. 64. Dallal RM, Harbrecht BG, Boujoukas AJ, et al. Fulminant Clostridium difficile: an underappreciated and increasing cause of death and complications. Ann Surg 2002; 235: 363-372. 65. García-Lechuz JM, Hernangómez S, Juan RS, Peláez T, Alcalá L, Bouza E. Extra-intestinal infections caused by Clostridium difficile. Clin Microbiol Infect 2001; 7: 453-457. 66. De Leeuw P, de Mot H, Dugernier T, Wautelet J, Bohy E, Delmée M. Primary infection of ascitic fluid withClostridium difficile. J Infect 1990; 21: 77-80. 67. Guingrich JA, Kuhlman JE. Colonic wall thickening in patients with cirrhosis: CT findings and clinical implications. AJR Am J Roentgenol 1999; 172: 919-924. 68. Bauer MP, Kuijper EJ, van Dissel JT; European Society of Clinical Microbiology and Infectious Diseases. European Society of Clinical Microbiology and Infectious Diseases (ESCMID): treatment guidance document for Clostridium difficile infection (CDI). Clin Microbiol Infect 2009; 15:1067-1079. 69. Bauer MP, van Dissel JT, Kuijper EJ. Clostridium difficile: controversies and approaches to management. Curr Opin Infect Dis 2009; 22:517-524. 70. Johnson S, Homann SR, Bettin KM, et al. Treatment of asymptomatic Clostridium difficile carriers (fecal excretors) with vancomycin or metronidazole. A randomized, placebo-controlled trial. Ann Intern Med 1992; 117:297-302. 71. Hermsen JL, Dobrescu C, Kudsk KA. Clostridium difficile infection: a surgical disease in evolution. J Gastrointest Surg 2008; 12:15121517. 72. Synnott K, Mealy K, Merry C, Kyne L, Keane C, Quill R. Timing of surgery for fulminating pseudomembranous colitis. Br J Surg 1998; 85:229-231. 73. Koss K, Clark MA, Sanders DS, Morton D, Keighley MR, Goh J. The outcome of surgery in fulminant Clostridium difficile colitis. Colorectal Dis 2006; 8:149-154. 74. Chan S, Kelly M, Helme S, Gossage J, Modarai B, Forshaw M. Outcomes following colectomy for Clostridium difficile colitis. Int J Surg 2009; 7:78-81. 75. Berman L, Carling T, Fitzgerald TN, et al. Defining surgical therapy for pseudomembranous colitis with toxic megacolon. J Clin Gastroenterol 2008; 42:476-480. 76. Jaber MR, Olafsson S, Fung WL, Reeves ME. Clinical review of 310 77. 78. 79. 80. Musa et al the management of fulminant Clostridium difficile infection. Am J Gastroenterol 2008; 103:3195-3203. Lamontagne F, Labbé AC, Haeck O, et al. Impact of emergency colectomy on survival of patients with fulminant Clostridium difficile colitis during an epidemic caused by a hypervirulent strain. Ann Surg 2007; 245:267-272. Byl B, Jacobs F, Struelens MJ, Thys JP. Extraintestinal Clostridium difficile infections.Clin Infect Dis 1996; 22:712. Ali SO, Welch JP, Dring RJ. Early surgical intervention for fulminant pseudomembranous colitis. Am Surg 2008; 74:20-26. Nguyen GC, Correia AJ, Thuluvath PJ. The impact of cirrhosis and portal hypertension on mortality following colorectal surgery: a nationwide, population-based study. Dis Colon Rectum 2009; 52: 1367-1374. 81. Rayes N, Seehofer D, Hansen S, et al. Early enteral supply of lactobacillus and fiber versus selective bowel decontamination: a controlled trial in liver transplant recipients. Transplantation 2002; 74: 123-127. 82. Rayes N, Seehofer D, Theruvath T, et al. Supply of pre- and probiotics reduces bacterial infection rates after liver transplantation--a randomized, double-blind trial. Am J Transplant 2005;5:125-130. 83. Loguercio C, Federico A, Tuccillo C, et al. Beneficial effects of a probiotic VSL#3 on parameters of liver dysfunction in chronic liver diseases. J Clin Gastroenterol 2005;39:540-543. 84. Kenneally C, Rosini JM, Skrupky LP, et al. Analysis of 30-day mortality for clostridium difficile-associated disease in the ICU setting. Chest 2007; 132:418-424.