Fecal calprotectin and fecal indole predict outcome of fecal microbiota transplantation in subjects with recurrent Clostridium difficile infection.

Fecal calprotectin and indole were studied in 134 subjects with recurrent CDI before and after FMT. Reduced fecal calprotectin (p = 0.0353, 95% CI 0.1305-0.1439) and rising levels of indole (p < 0.0001, 95% CI < 0.0001-0.0003) predicted successful treatment. A ratio of recal calprotectin/indole may provide prognostic value for FMT (p = 0.0004, 95% CI 0.22-0.87).

Etiology of travellers' diarrhea.

Eleven published studies of the etiology of travellers' diarrhea (TD) were reviewed define the etiology of TD and to exam newly developed technology such as Real-Time multiplex polymerase chain reaction (PCR) to identify multiple pathogens in one assay to define the cause of TD. Using PCR methods bacterial pathogens were found in 72% of patients acquiring diarrhea in Latin America and in 80% in travellers with illness acquired in Southeast Asia). In these studies, enterotoxigenic Escherichia coli as the predominant pathogen (42% in Latin America and 28% in Southeast Asia). Ciprofloxacin-resistant Campylobacter was commonly associated with TD in Southeast Asia. Multiplex PCR has improved the detection of enteropathogens and allowed better assessment returning travellers hospitalized with TD and those with persistent diarrhea.

Randomised clinical trial: faecal microbiota transplantation for recurrent Clostridum difficile infection - fresh, or frozen, or lyophilised microbiota from a small pool of healthy donors delivered by colonoscopy.

BACKGROUND: Faecal microbiota transplantation (FMT) has become routine in managing recurrent C. difficile infection (CDI) refractory to antibiotics. AIM: To compare clinical response and improvements in colonic microbiota diversity in subjects with recurrent CDI using different donor product. METHODS: Seventy-two subjects with ≥3 bouts of CDI were randomised in a double-blind study to receive fresh, frozen or lyophilised FMT product via colonoscopy from 50 g of stool per treatment from eight healthy donors. Recipients provided stools pre- and 7, 14 and 30 days post-FMT for C. difficile toxin and, in a subset, microbiome composition by 16S rRNA gene profiling. RESULTS: Overall resolution of CDI was 87% during 2 months of follow-up after FMT. Stool samples before FMT had significantly decreased bacterial diversity with a high proportion of Proteobacteria compared to donors. Cure rates were highest for the group receiving fresh product seen in 25/25 (100%), lowest for the lyophilised product 16/23 (78%; P = 0.022 vs. fresh and 0.255 vs. frozen) and intermediate for frozen product 20/24 (P = 0.233 vs. fresh). Microbial diversity was reconstituted by day 7 in the subjects receiving fresh or frozen product. Improvement in diversity was seen by day 7 in those randomised to lyophilised material with reconstitution by 30 days. CONCLUSIONS: Comparative efficacy in faecal microbiota transplantation was observed in subjects receiving fresh or frozen faecal product from the same donors. The lyophilised product had a slightly lowered efficacy compared with fresh product, but it resembled other treatments in microbial restoration 1 month after faecal microbiota transplantation.

Economic burden of primary compared with recurrent Clostridium difficile infection in hospitalized patients: a prospective cohort study.

BACKGROUND: Few studies have investigated the additional healthcare costs of recurrent C. difficile infection (CDI). AIM: To quantify inpatient treatment costs for CDI and length of stay among hospitalized patients with primary CDI only, compared with CDI patients who experienced recurrent CDI. METHODS: This was a prospective, observational cohort study of hospitalized adult patients with primary CDI followed for three months to assess for recurrent CDI episodes. Total and CDI-attributable hospital length of stay (LOS) and hospitalization costs were compared among patients who did or did not experience at least one recurrent CDI episode. FINDINGS: In all, 540 hospitalized patients aged 62±17 years (42% males) with primary CDI were enrolled, of whom 95 patients (18%) experienced 101 recurrent CDI episodes. CDI-attributable median (interquartile range) LOS and costs (in US$) increased from 7 (4-13) days and $13,168 (7,525-24,456) for patients with primary CDI only versus 15 (8-25) days and $28,218 (15,050-47,030) for patients with recurrent CDI (P<0.0001, each). Total hospital median LOS and costs increased from 11 (6-22) days and $20,693 (11,287-41,386) for patients with primary CDI only versus 24 (11-48) days and $45,148 (20,693-82,772) for patients with recurrent CDI (P<0.0001, each). The median cost of pharmacological treatment while hospitalized was $60 (23-200) for patients with primary CDI only (N=445) and $140 (30-260) for patients with recurrent CDI (P=0.0013). CONCLUSION: This study demonstrated that patients with CDI experience a significant healthcare economic burden attributed to CDI. Economic costs and healthcare burden increased significantly for patients with recurrent CDI.

Introduction: understanding mechanisms of the actions of rifaximin in selected gastrointestinal diseases.

BACKGROUND: Historically, the beneficial effects of the nonsystemic oral agent rifaximin on various gastrointestinal (GI) disorders have been attributed to direct antibiotic activity on gut microbiota. However, data are accumulating to suggest that other nonantibacterial effects may be involved in rifaximin efficacy. AIM: To explore the mechanisms of action of rifaximin that may underlie its clinical benefits in travellers' diarrhoea, hepatic encephalopathy and other cirrhosis complications, inflammatory bowel diseases, and irritable bowel syndrome with diarrhoea. METHODS: Gastroenterology experts convened a round-table discussion to address clinical and pre-clinical rifaximin data pertaining to select GI diseases and the potential mechanisms of action that underlie rifaximin efficacy profiles. As preparation, the literature was searched for publications related to rifaximin, its mechanisms of action, and its efficacy in travellers' diarrhoea, hepatic encephalopathy and other cirrhosis-related complications, inflammatory bowel diseases and irritable bowel syndrome. RESULTS: Gut microbiota dysbiosis and proinflammatory activities are thought to significantly contribute to disease pathophysiology of these conditions. Rifaximin may resolve gut microbiota dysbiosis by promoting GI colonisation of beneficial bacterial species without drastic alterations in overall diversity. Rifaximin-induced changes in the production and metabolism of bacteria-produced agents (e.g. deoxycholic acid, lipopolysaccharides) also may help preserve normal gut microbiota. Rifaximin may suppress local and systemic inflammatory processes by preserving epithelial function (e.g. limiting bacterial translocation), modulating bacterial virulence and reducing proinflammatory cytokine production. CONCLUSION: The commonality of pathological mechanisms underlying multiple GI diseases and the ability of rifaximin to modulate the gut microenvironment (i.e. gut microenvironment modulator) may explain its diverse efficacy profile.

Review article: the antimicrobial effects of rifaximin on the gut microbiota.

BACKGROUND: Disruption of the gut microbiota through use of systemic antimicrobials or activation of the mucosal inflammatory response by pathogens can cause dysregulation of the intestinal mucosa. AIM: To explore the mechanisms of action of rifaximin that may underlie its clinical benefits in travellers' diarrhoea (TD). METHODS: A literature search was performed using the terms 'rifaximin' and 'L/105' in combination with the terms 'in vitro activity', 'diarrhea', 'microbiota' and 'gut flora'. RESULTS: Rifaximin has been traditionally identified as a nonsystemic, broad-spectrum, bactericidal antibiotic. Evidence shows that the activity of rifaximin against enteropathogens in this setting is likely enhanced by its increased solubility in the presence of bile acids in the small intestine. Results of clinical studies show that although rifaximin is efficacious in TD, a clinical cure often occurs without apparent bacterial eradication and with minimal effect on the gut microbiota, suggesting an effect of rifaximin other than direct antibiotic activity. CONCLUSIONS: Although definitive studies on the effect of rifaximin on the gut microbiota in large cohorts of healthy volunteers or patients have not been published, pre-clinical studies provide some insight. These studies have shown that rifaximin may have effects on both the pathogen and host, including direct effects on pathogenic bacteria (such as reducing the expression of bacterial virulence factors) and indirect effects on the host (such as inhibiting bacterial attachment and internalisation at the intestinal mucosa and reducing mucosal inflammation).

Rifaximin: An Antibiotic with Important Biologic Effects.

Rifaximin is a poorly absorbed rifamycin drug with unique pharmacokinetic properties: bile solubility making it highly active against pathogenic and non-pathogenic bacterial flora in the bile-rich small bowel and low water solubility making it active only against highly susceptible bacteria, primarily anaerobes, in the aqueous colon. The drug has anti-inflammatory gut mucosal stabilization properties that are important to its sustained effects in non-infectious diseases. Rifaximin is used chronically or recurrently for hepatic encephalopathy and diarrhea-predominant irritable bowel syndrome. Monitoring of long-term use of rifaximin for development of resistance and then determining whether developed resistance is associated with reduced efficacy are needed. Studies of changes of intestinal flora during therapy and the health implications of these changes are also needed.

Review article: evidence for the role of gut microbiota in irritable bowel syndrome and its potential influence on therapeutic targets.

BACKGROUND: Irritable bowel syndrome (IBS) is a prevalent gastrointestinal disease with a substantial social and economic burden. Treatment options remain limited and research on the aetiology and pathophysiology of this multifactorial disease is ongoing. AIM: To discuss the potential role of gut microbiota in the pathophysiology of IBS and to identify possible interactions with pathophysiologic targets in IBS. METHODS: Articles were identified via a PubMed database search ['irritable bowel syndrome' AND (anti-bacterial OR antibiotic OR flora OR microbiota OR microflora OR probiotic)]. English-language articles were screened for relevance. Full review of publications for the relevant studies was conducted, including additional publications that were identified from individual article reference lists. RESULTS: The role of gut microbiota in IBS is supported by varying lines of evidence from animal and human studies. For example, post-infectious IBS in humans is well documented. In addition, certain probiotics and nonsystemic antibiotics appear to be efficacious in the treatment of IBS. Mechanisms involved in improving IBS symptoms likely go beyond mere changes in the composition of the gut microbiota, and accumulating animal data support the interplay of microbiota with other IBS targets, such as the gut-brain axis, visceral hypersensitivity, mucosal inflammation and motility. CONCLUSION: The role of the gut microbiota is still being elucidated; however, it appears to be one of several important factors that contributes to the aetiology and pathophysiology of the irritable bowel syndrome.

Clostridium difficile infection in hospitalized cancer patients in Beijing, China is facilitated by receipt of cancer chemotherapy.

The purpose of this study was to determine the presence of Clostridium difficile infection (CDI) and risk factors for infection in hospitalized patients with diarrhea in a cancer hospital in Beijing, China. A total of 277 patients with hospital-associated diarrhea (HAD) were studied of which 41 (15%) were positive for fecal C. difficile toxin A/B. For each CDI case identified, a control with HAD but negative C. difficile specimen was enrolled to look for CDI risk factors. Receipt of cancer chemotherapy occurred in 20 (49%) patients with CDI and 9 (22.0%) patients with non-CDI HAD (OR3.39, 95%CI 1.78-10.05). Median length of chemotherapy before HAD developed was 39 days for those with CDI and 22 days for patients with CDI-negative HAD (P = 0.0391). The study found that CDI is commonly seen in cancer patients in China with increasing risk for patients who receive chemotherapy.

Systematic review: the use of proton pump inhibitors and increased susceptibility to enteric infection.

BACKGROUND: The use of proton pump inhibitors (PPIs) is increasing worldwide. Suppression of gastric acid alters the susceptibility to enteric bacterial pathogens. AIM This systematic review was undertaken to examine the relationship between PPI use and susceptibility to enteric infections by a specific pathogen based on published literature and to discuss the potential mechanisms of PPI enhanced pathogenesis of enteric infections. METHODS PubMed, OVID Medline Databases were searched. Search terms included proton pump inhibitors and mechanisms of, actions of, gastric acid, enteric infections, diarrhoea, Clostridium difficile, Salmonella, Shigella and Campylobacter. RESULTS The use of PPIs increases gastric pH, encourages growth of the gut microflora, increases bacterial translocation and alters various immunomodulatory and anti-inflammatory effects. Enteric pathogens show variable gastric acid pH susceptibility and acid tolerance levels. By multiple mechanisms, PPIs appear to increase susceptibility to the following bacterial enteropathogens: Salmonella, Campylobacter jejuni, invasive strains of Escherichia coli, vegetative cells of Clostridium difficile, Vibrio cholerae and Listeria. We describe the available evidence for enhanced susceptibility to enteric infection caused by Salmonella, Campylobacter and C. difficile by PPI use, with adjusted relative risk ranges of 4.2-8.3 (two studies); 3.5-11.7 (four studies); and 1.2-5.0 (17 of 27 studies) for the three respective organisms. CONCLUSIONS Severe hypochlorhydria generated by PPI use leads to bacterial colonisation and increased susceptibility to enteric bacterial infection. The clinical implication of chronic PPI use among hospitalized patients placed on antibiotics and travellers departing for areas with high incidence of diarrhoea should be considered by their physicians.

High Horn's index score predicts poor outcomes in patients with Clostridium difficile infection.

Several variables have been proposed to predict the prognosis of patients with Clostridium difficile infection (CDI), but a clinically useful tool to stratify resource utilization has not been determined. Horn's index, a severity score based on underlying clinical illness, reliably predicts patients at high risk of CDI. The purpose of this study was to assess the use of Horn's index to stratify patients with CDI at high risk of poor clinical and economic outcomes. Hospitalized patients diagnosed with CDI were followed prospectively for three months. Horn's index scores were calculated for each patient on the day of the positive toxin test for C. difficile, and used to stratify differences in outcome variables (length of hospital stay, mortality and hospital costs). Eighty-five CDI patients (50% male, 64% Caucasian) were recruited. Discharge mortality was 0% for patients with Horn's index scores of 1 or 2, 5% for those with a score of 3, and 50% for those with a score of 4 (P < 0.001). Three-month mortality was 0%, 5%, 17% and 60% for patients with Horn's index scores of 1, 2, 3 and 4, respectively (P = 0.0004). Median three-month hospital costs were $8,585, $12,670, $29,077 and $68,708 for patients with Horn's index scores of 1, 2, 3 and 4, respectively (P < 0.001). Patients with Horn's index scores of 3 or 4 had a significantly longer hospital stay [mean 33.4 (standard deviation, SD 33.3) days] than patients with scores of 1 or 2 [mean 15.1 (SD 16.2) days, P = 0.001]. This study found Horn's index to be a simple and useful method for identifying CDI patients at high risk of poor clinical and economic outcomes.

Characterization of norovirus-associated traveler's diarrhea.

BACKGROUND: Traveler's diarrhea is the most common medical complaint of international visitors to developing regions. Previous findings suggested that noroviruses (NoVs) are an underappreciated cause of traveler's diarrhea. METHODS. In the present study, we sought to define the presence of NoVs in 320 acute diarrheic stool samples collected from 299 US students who traveled to Guadalajara, Cuernavaca, or Puerto Vallarta, Mexico, during the period from 2007 through 2008. Conventional and quantitative real-time polymerase chain reaction assays were used to detect and determine NoV loads in stool samples. NoV strains were characterized by purification of viral RNA followed by sequencing of the viral capsid protein 1 gene. Sequences were compared using multiple sequence alignment, and phylogenetic trees were generated to evaluate the evolutionary relatedness of the viral strains associated with cases of traveler's diarrhea. RESULTS: NoV RNA was detected in 30 (9.4%) of 320 samples. Twelve strains belonged to genogroup I, and 18 strains belonged to genogroup II. NoV prevalence was higher in the winter season than in the summer season (23% vs 7%, respectively; P = .001). The cDNA viral loads of genogroup I viruses were found to be 500-fold higher than those of genogroup II strains. Phylogenetic analysis revealed a diverse population of NoV strains over different locations and years. CONCLUSIONS: NoV strains are important causes of traveler's diarrhea in Mexico, especially during the wintertime, and US students in Mexico may represent a suitable group for future NoV vaccine efficacy trials.

In vitro susceptibility of Clostridium difficile to rifaximin and rifampin in 359 consecutive isolates at a university hospital in Houston, Texas.

AIM: This was an in vitro study to analyse the susceptibility of Clostridium difficile isolates to rifampin and rifaximin. METHODS: Stool samples from patients who had nosocomial diarrhoea and C difficile toxin B at a university hospital between August 2006 and December 2007 were cultured for C difficile. Susceptibility of C difficile isolates to rifaximin and rifampin was determined by agar dilution and E strips, respectively. C difficile isolates were analysed via PCR for genes encoding toxins A and B, for binary toxin (BT), and for partial deletions of the tcdC gene (tcdC-del). RESULTS: Rifaximin exhibited high-level activity against 359 C difficile isolates, with MIC(50) <0.01 microg/ml and MIC(90) 0.25 microg/ml; rifampin had MIC(50) <0.002 microg/ml and MIC(90) 4 microg/ml. Among isolates analysed, 55 (15%) were positive for BT and tcdC-del. 28 (8% of 359) isolates were resistant to rifampin (> or = 32 microg/ml), of which 6 (2% of 359) were resistant to rifaximin and rifampin with MIC values > or = 32 microg/ml. 2 of the 28 isolates resistant to rifampin were A(+)/B(+)/BT(+)/tcdC-del(+), 5 were A(+)/B(+)/BT(-)/tcdC-del(+), 4 were A(+)/B(+)/BT(+)/tcdC-del(-), 13 were A(+)/B(+)/BT(-)/tcdC-del(-), and 4 had no detectable toxin genes. Of the 11 isolates resistant to rifaximin alone, 1 was A(+)/B(+)/BT(-)/tcdC-del(+), 2 were A(+)/B(+)/BT(+)/tcdC-del(-), 6 were A(+)/B(+)/BT(-)/tcdC-del(-), and 2 had no detectable toxin genes. CONCLUSIONS: The study demonstrates that rifaximin has high-level activity against C difficile in vitro. Determination of resistance to rifampin by E strip did not predict rifaximin resistance.

Economic healthcare costs of Clostridium difficile infection: a systematic review.

Clostridium difficile infection (CDI) is the leading cause of infectious diarrhoea in hospitalised patients. CDI increases patient healthcare costs due to extended hospitalisation, re-hospitalisation, laboratory tests and medications. However, the economic costs of CDI on healthcare systems remain uncertain. The purpose of this study was to perform a systematic review to summarise available studies aimed at defining the economic healthcare costs of CDI. We conducted a literature search for peer-reviewed studies that investigated costs associated with CDI (1980 to present). Thirteen studies met inclusion and exclusion criteria. CDI costs in 2008 US dollars were calculated using the consumer price index. The total and incremental costs for primary and recurrent CDI were estimated. Of the 13, 10 were from the USA and one each from Canada, UK, and Ireland. In US-based studies incremental cost estimates ranged from $2,871 to $4,846 per case for primary CDI and from $13,655 to $18,067 per case for recurrent CDI. US-based studies in special populations (subjects with irritable bowel disease, surgical inpatients, and patients treated in the intensive care unit) showed an incremental cost range from $6,242 to $90,664. Non-US-based studies showed an estimated incremental cost of $5,243 to $8,570 per case for primary CDI and $13,655 per case for recurrent CDI. Economic healthcare costs of CDI were high for primary and recurrent cases. The high cost associated with CDI justifies the use of additional resources for CDI prevention and control.

Automated system to identify Clostridium difficile infection among hospitalised patients.

The purpose of this study was to assess whether data on stool frequency collected electronically could identify patients at high risk for Clostridium difficile infection (CDI). All patients with reports of diarrhoea were assessed prospectively for number of stools per day and number of diarrhoea days. C. difficile testing was requested independently from study investigators. Number of days with diarrhoea and maximum number of unformed stools was assessed as a CDI predictor. A total of 605 patients were identified with active diarrhoea of whom 64 (10.6%) were diagnosed with CDI. In univariate analysis, the maximum number of stools and number of diarrhoea days was associated with increased risk of CDI. Compared to patients with three diarrhoea stools per day (CDI incidence: 6.3%), CDI increased to 13.4% in patients with four or more diarrhoea stools per day [odds ratio (OR): 2.3; 95% confidence interval (CI): 1.3-4.2; P=0.0054]. Compared to patients with one day of diarrhoea (CDI incidence: 6.3%), CDI increased to 17.4% in patients with two diarrhoea days (OR: 3.1; 95% CI: 1.7-5.6) and to 27.1% in patients with three or more diarrhoea days (OR: 5.5; 95% CI: 2.6-11.7). These results were validated using logistic regression with number of days with diarrhoea identified as the most important predictor. Using an electronic data capture technique, number of days of diarrhoea and maximum number of diarrhoea stools in a 24h time period were able to identify a patient population at high risk for CDI.

Systematic review: the epidemiology and clinical features of travellers' diarrhoea.

BACKGROUND: Travellers' diarrhoea is the most common medical complaint among persons venturing into developing areas from industrialized regions. AIM: To review recent developments dealing with microbiological, clinical, pathophysiological and therapeutic aspects of travellers' diarrhoea. METHODS: The author's extensive file plus a review of publications listed in PubMed on January 22, 2009 on the topic of travellers' diarrhoea were reviewed. RESULTS: Travellers' diarrhoea is largely caused by detectable and undetected bacterial enteropathogens, explaining the remarkable effectiveness of antibacterial agents in prophylaxis and therapy of the illness. A number of host genetic polymorphisms have been recently linked with susceptibility to travellers' diarrhoea. Novel antisecretory agents are being developed for treatment considering their physiological effects in acute diarrhoea. All travellers should be armed with one of three antibacterial drugs, ciprofloxacin, rifaximin or azithromycin, before their trips to use in self therapy should diarrhoea occur during travel. Loperamide may treat milder forms of travellers' diarrhoea and can be employed with antibacterial drugs. CONCLUSIONS: Diarrhoea will continue to plague international travellers to high-risk regions. More studies of the incidence rate, relative important of the various pathogens by geographical region of the world, host risk factors and optimal therapeutic approach are needed.

Meta-analysis to assess risk factors for recurrent Clostridium difficile infection.

SUMMARY: Clostridium difficile infection (CDI) is the most common cause of hospital-acquired diarrhoea. It is estimated that 15-20% of patients experience recurrence of CDI. A limited number of studies have looked at the risk factors for recurrent CDI. We conducted a meta-analysis of observational studies and randomised controlled trials (RCTs) to assess risk factors for recurrent CDI. Studies were identified using the PubMed database and search terms 'Clostridium difficile associated diarrhoea' or 'pseudomembranous colitis'. Both observational studies and RCTs were included. In all, 1215 studies were identified of which 48 met the inclusion criteria. Twelve studies involving 1382 patients with CDI met the complete eligibility requirements. Odds ratios and information on study quality were abstracted by two investigators independently. To be included in the analysis, each risk factor was required to be evaluated by at least three separate studies. Continued use of non-C. difficile antibiotics after diagnosis of CDI (OR: 4.23; 95% CI: 2.10-8.55; P<0.001), concomitant receipt of antacid medications (OR: 2.15; 95% CI: 1.13-4.08; P=0.019), and older age (OR: 1.62; 95% CI: 1.11-2.36; P=0.0012) were significantly associated with increased risk of recurrent CDI. Significant prognostic risk factors were identified as risk factors for CDI recurrence. Additional or novel interventions may be required for these patients to prevent CDI recurrence.

A clinical risk index for Clostridium difficile infection in hospitalised patients receiving broad-spectrum antibiotics.

Identification of a population at high risk for Clostridium difficile infection (CDI) would enable CDI prevention strategies to be designed. The purpose of this study was to create a clinical risk index that would predict those at risk for CDI. A CDI risk index was therefore developed, based on a cohort of hospital patients given broad-spectrum antibiotics, and divided into a development and validation cohort. Logistic regression equations helped identify significant predictors of CDI. A scoring algorithm for CDI risk was created using identified risk factors and collapsed to create four categories of CDI risk. The area under the receiver operating characteristic (aROC) curve was used to measure goodness-of-fit. Among 54 226 patients, 392 tested positive for C. difficile. Age 50-80 years [odds ratio (OR: 0.5; P<0.0116)], age >80 years (OR: 2.5; P<0.0001), haemodialysis (OR: 1.5; P=0.0227), non-surgical admission (OR: 2.2; P<0.0001) and increasing length of stay in the intensive care unit (OR: 2.1; P<0.0001) were significantly associated with CDI. A simple risk index using presence of significant variables was significantly associated with increasing risk for CDI in both development (OR: 3.57; P<0.001; aROC: 0.733) and validation (OR: 3.31; P<0.001; aROC: 0.712) cohorts. An OR-derived risk index did not perform as well as the simple risk index. This easily implemented risk index should allow stratification of patients into risk group categories for development of CDI and help fashion preventive strategies.