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Abstract: In the last three decades, the dramatic worldwide increase in incidence and severity of Clostridioides difficile infection (CDI) (formerly Clostridium difficile infection) has made CDI a global public health challenge. Surgery is a known risk factor for development of CDI yet surgery is also a treatment option in severe cases of CDI. The World Society of Emergency Surgery guidelines for management of CDI in surgical patients were published in 2015. In 2019, the guidelines were revised and updated according to the grading of recommendations assessment, development and evaluation methodology. This executive summary is intended to consolidate knowledge on the management of CDI focusing on aspects that a general and emergency surgeon should know about the prevention and the management of CDI, by providing a practical and concise version of the original guidelines., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The term probiotic refers to live microorganisms that survive passage through the gastrointestinal tract and have beneficial effects on the host. Many strains of probiotic microorganisms have been shown to inhibit growth and metabolic activity as well as the adhesion to intestinal cells of enteropathogenic bacteria, to modulate the gut microbiota and to have immunostimulatory or regulatory properties. The use of probiotic microorganisms for the prevention and the treatment of Antibiotic Associated Diarrhea is an obvious measure and perhaps the most usual application of probiotics. This overview summarizes the most commonly used probiotic microorganisms for DAA and IBD.

The involvement of host immunity in the gut microbiota-mediated colonization resistance to Clostridioides difficile infection (CDI) is incompletely understood. Here, we show that interleukin (IL)-22, induced by colonization of the gut microbiota, is crucial for the prevention of CDI in human microbiota-associated (HMA) mice. IL-22 signaling in HMA mice regulated host glycosylation, which enabled the growth of succinate-consuming bacteria Phascolarctobacterium spp. within the gut microbiome. Phascolarctobacterium reduced the availability of luminal succinate, a crucial metabolite for the growth of C. difficile, and therefore prevented the growth of C. difficile. IL-22-mediated host N-glycosylation is likely impaired in patients with ulcerative colitis (UC) and renders UC-HMA mice more susceptible to CDI. Transplantation of healthy human-derived microbiota or Phascolarctobacterium reduced luminal succinate levels and restored colonization resistance in UC-HMA mice. IL-22-mediated host glycosylation thus fosters the growth of commensal bacteria that compete with C. difficile for the nutritional niche.

In the last three decades, Clostridium difficile infection (CDI) has increased in incidence and severity in many countries worldwide. The increase in CDI incidence has been particularly apparent among surgical patients. Therefore, prevention of CDI and optimization of management in the surgical patient are paramount. An international multidisciplinary panel of experts from the World Society of Emergency Surgery (WSES) updated its guidelines for management of CDI in surgical patients according to the most recent available literature. The update includes recent changes introduced in the management of this infection., Competing Interests: Not applicable.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

The most common cause of antibiotic-associated diarrhea is Clostridium difficile infection (CDI). Recurrent C. difficile infection (rCDI) often occurs after successful treatment of CDI. Due to the increased incidence and the difficulty in treating rCDI, it is becoming an important clinical issue. Identifying risk factors is helpful for early detection, treatment, and prevention of rCDI. Advanced age, use of antibiotics, gastric acid suppression, and infection with a hypervirulent strain are currently regarded as the major risk factors for rCDI. Several treatment modalities, including vancomycin, fidaxomicin, and fecal microbiota transplant (FMT), are suggested for rCDI treatment. However, there is currently no definitive treatment method with sufficient evidence for rCDI. Recent studies have focused on FMT and have shown positive results for rCDI. Prevention of rCDI by measures such as hand washing and isolation of patients is very important. However, these preventive measures are often overlooked in clinical practice. Here, we review the risk factors, treatment, and prevention of rCDI.

Clostridium difficile (C. diff) is the most common causative agent of antibiotic-associated diarrhea and colitis. This spore-forming, obligate anaerobic, gram-positive bacillus is becoming responsible for an increasing number of infections worldwide, both in community and in hospital settings, whose severity can vary widely from an asymptomatic infection to a lethal disease. While discontinuation of antimicrobial agents and antibiotic treatment of the infection remain the cornerstone of therapy, the use of probiotics, especially Saccharomyces boulardii, and more recently of fecal microbiota transplantation have become valid forms of prevention and/or therapy and are here critically examined.

Background: Despite advancements, recurrent Clostridium difficile infections (CDI) remain an urgent public health threat with insufficient response rates to currently approved antibiotic therapies. Microbiota-based treatments appear effective, but rigorous clinical trials are required to optimize dosing strategies and substantiate long-term safety., Methods: This randomized, double-blind, placebo-controlled phase 2B trial enrolled adults with 2 or more CDI recurrences to receive: 2 doses of RBX2660, a standardized microbiota-based drug (group A); 2doses of placebo (group B); or 1 dose of RBX2660 followed by 1 dose of placebo (group C). Efficacy was defined as prevention of recurrent CDI for 8 weeks following treatment. Participants who had a recurrence within 8 weeks were eligible to receive up to 2 open-label RBX2660 doses. The primary endpoint was efficacy for group A compared to group B. Secondary endpoints included the efficacy of group C compared to group B, combined efficacy in the blinded and open-label phases, and safety for 24 months., Results: The efficacy for groups A, B, and C were 61%, 45%, and 67%, respectively. The primary endpoint was not met (P = .152). One RBX2660 dose (group C) was superior to placebo (group B; P = .048), and the overall efficacy (including open-label response) for RBX2660-treated participants was 88.8%. Adverse events did not differ significantly among treatment groups., Conclusions: One, but not 2, doses of RBX2660 was superior to placebo in this randomized, placebo-controlled trial. These data provide important insights for a larger phase 3 trial and continued clinical development of RBX2660., Clinical Trials Registration: NCT02299570.

Background: The choice of antibiotics for systemic infections in patients with a high risk of Clostridium difficile infection (CDI) remains a clinical practice dilemma. Although some studies suggest that tetracyclines may be associated with a lower risk of CDI than other antibiotics, other results are conflicting. We conducted a systematic review and metaanalysis of studies that assessed the risk of CDI with tetracyclines compared to other antibiotics., Methods: We conducted a systematic search of Medline, Embase, and Web of Science from January 1978 through December 2016 to include studies that assessed the association between tetracycline use and risk of CDI. Weighted summary estimates were calculated using generalized inverse variance with a random-effects model using RevMan 5.3. Study quality was assessed using the Newcastle-Ottawa scale., Results: Six studies (4 case control, 2 cohort) with patient recruitment between 1993 and 2012 were included. Metaanalysis using a random-effects model, demonstrated that tetracyclines were associated with a decreased risk of CDI (odds ratio [OR], 0.62; 95% confidence interval [CI], 0.47-0.81; P < .001). There was significant heterogeneity, with an I2 of 53% with no publication bias. Subgroup analysis of studies that evaluated the risk of CDI with doxycycline alone also demonstrated a decreased risk of CDI (OR, 0.55; 95% CI, 0.40-0.75; P < .001)., Conclusions: Metaanalyses of existing studies suggest that tetracyclines may be associated with a decreased risk of CDI compared with other antimicrobials. It may be reasonable to use tetracyclines whenever appropriate to decrease CDI associated with antibiotic use., (© The Author(s) 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Purpose of Review: Probiotics may prevent Clostridium difficile infection (CDI), a leading healthcare-associated infection in the United States. However, prior studies were limited by heterogeneity in products and patient populations. Recent clinical evidence and new approaches to probiotic development are reviewed., Recent Findings: Probiotic use may reduce incident CDI in high-risk populations by as much as 50%, though prior clinical trials have yielded conflicting results. Combining probiotics with prebiotics improves growth and engraftment in the host. Bacillus clausii and Lactobacillus reuteri secrete compounds that directly inhibit C. difficile. Organisms that produce secondary bile acids, such as Clostridium scindens, enhance C. difficile colonization resistance. Nontoxigenic C. difficile, which provides nutritional niche competition, may prevent CDI. Refinements to fecal microbiota transplantation (FMT) blur the line between probiotics and FMT. These include a quality-controlled stool product (RBX2660), purified Firmicutes spores (SER-109) and sterile fecal filtrate. Bacteriophages may treat CDI but have unknown safety and efficacy in humans., Summary: There have been a number of advances in probiotics and our understanding of their role in prevention of CDI, but a number of important safety and efficacy questions remain. An improved understanding of the native microbiota structure and function will allow for continued development of rationally designed probiotic therapy to provide enhanced protection against CDI.

Background: Health care-acquired Clostridium difficile infection (HACDI) is associated with adverse outcomes at both the organization and patient level. Factors that increase risk for development of HACDI have been identified. Objectives of this study were to develop a predictive screening tool to identify patients at risk for HACDI and implement a bundle of mitigation interventions., Methods: A predictive screening tool was developed based on risk factors identified in the literature and validated by retrospective analysis of all HACDI cases occurring in critically ill patients during 2013. The tool was used to screen all patients admitted to an intensive care unit. Evidence-based interventions (bundle) were implemented for patients identified as being at high risk for HACDI. Effectiveness of the model was measured by reduction of HACDI rate during the intervention period compared with the preintervention period., Results: During the 12-month intervention period 217 high-risk patients were identified as infected with Clostridium difficile. Sixty-two of these met exclusion criteria, resulting in a study population of 157 patients. During the preintervention phase, 10 cases of HACDI occurred (overall incidence rate, 14.7). During the 12-month study period, 2 cases of HACDI were identified (incidence rate, 3.12). The reduction was statistically significant., Conclusion: A strategy for identifying patients at increased risk and implementation of multidisciplinary risk-mitigation strategies is effective in reducing incidence of HACDI., (Copyright © 2016 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

Objectives: Clostridium difficile infection (CDI) is a global healthcare problem. Recent evidence suggests that the availability of iron may be important for C. difficile growth. This study evaluated the comparative effects of iron-depleted (1% Fe(3+) saturated) bovine apo-lactoferrin (apo-bLf) and iron-saturated (85% Fe(3+) saturated) bovine holo-lactoferrin (holo-bLf) in a human in vitro gut model that simulates CDI., Methods: Two parallel triple-stage chemostat gut models were inoculated with pooled human faeces and spiked with C. difficile spores (strain 027 210, PCR ribotype 027). Holo- or apo-bLf was instilled (5 mg/mL, once daily) for 35 days. After 7 days, clindamycin was instilled (33.9 mg/L, four times daily) to induce simulated CDI. Indigenous microflora populations, C. difficile total counts and spores, cytotoxin titres, short chain fatty acid concentrations, biometal concentrations, lactoferrin concentration and iron content of lactoferrin were monitored daily., Results: In the apo-bLf model, germination of C. difficile spores occurred 6 days post instillation of clindamycin, followed by rapid vegetative cell proliferation and detectable toxin production. By contrast, in the holo-bLf model, only a modest vegetative cell population was observed until 16 days post antibiotic administration. Notably, no toxin was detected in this model. In separate batch culture experiments, holo-bLf prevented C. difficile vegetative cell growth and toxin production, whereas apo-bLf and iron alone did not., Conclusions: Holo-bLf, but not apo-bLf, delayed C. difficile growth and prevented toxin production in a human gut model of CDI. This inhibitory effect may be iron independent. These observations suggest that bLf in its iron-saturated state could be used as a novel preventative or treatment strategy for CDI., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.)

Despite advances in the diagnosis and treatment of Clostridium difficile infection (CDI) and prevention efforts to reduce the spread of C. difficile, CDI remains a significant challenge to healthcare systems worldwide. Further advances in prevention of CDI may need to focus on those who continue to be exposed to the organism and who are susceptible. Interventions directed toward this susceptible population, particularly hospitalized patients who receive antibiotics, may be effective. There is moderate evidence on the effectiveness of probiotics to prevent primary CDI, but there are few data to support use in secondary prevention of recurrent CDI. This review discusses the literature available on the use of probiotics to prevent primary and secondary CDI., (Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: Up to 60% of foals develop diarrhea within 6 months after birth. Preventive measures are limited but potentially probiotics could be used., Objective: To evaluate the effect of a newly designed probiotic on the incidence of foal diarrhea in a randomized field trial., Animals: Seventy-two healthy neonatal foals., Methods: Randomized, placebo-controlled field trial. Foals were administered a placebo or probiotic for 3 weeks and monitored for an additional week. A total of 3 fecal samples were taken from each foal at biweekly intervals. Statistical modeling was applied for comparison of incidence and duration of diarrhea and fecal shedding of Clostridium perfringens and Clostridium difficile between treatment and age groups., Results: The overall incidence of diarrhea was 41 of 72 (59%) and did not differ (P = 0.37) between treatment groups. Foals treated with probiotics were more likely to develop diarrhea requiring veterinary intervention (P = 0.007). Age had a significant effect on incidence of diarrhea (P < 0.001); foals 8-15 days old having the highest probability of developing diarrhea. Duration of diarrhea and soft feces were not significantly different between groups. The prevalence of C. perfringens shedding was 55% with no difference between treatment groups (P = 0.23). The prevalence of C. difficile shedding was 11%., Conclusion and Clinical Importance: There was no benefit of administering a 3-week course of probiotics, but potential adverse effects were noted. Whether the probiotics lacked a clinical effect, or the choice of strains or dose was inadequate, is unknown. Clostridial shedding was not influenced by probiotics despite in vitro activity of probiotics., (Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Clostridium difficile infection (CDI) is the major cause of antibiotic-associated diarrhea and pseudomembranous colitis, a disease associated with significant morbidity and mortality. The disease is mostly of nosocomial origin, with elderly patients undergoing anti-microbial therapy being particularly at risk. C. difficile produces two large toxins: Toxin A (TcdA) and Toxin B (TcdB). The two toxins act synergistically to damage and impair the colonic epithelium, and are primarily responsible for the pathogenesis associated with CDI. The feasibility of toxin-based vaccination against C. difficile is being vigorously investigated. A vaccine based on formaldehyde-inactivated Toxin A and Toxin B (toxoids) was reported to be safe and immunogenic in healthy volunteers and is now undergoing evaluation in clinical efficacy trials. In order to eliminate cytotoxic effects, a chemical inactivation step must be included in the manufacturing process of this toxin-based vaccine. In addition, the large-scale production of highly toxic antigens could be a challenging and costly process. Vaccines based on non-toxic fragments of genetically engineered versions of the toxins alleviate most of these limitations. We have evaluated a vaccine assembled from two recombinant fragments of TcdB and explored their potential as components of a novel experimental vaccine against CDI. Golden Syrian hamsters vaccinated with recombinant fragments of TcdB combined with full length TcdA (Toxoid A) developed high titer IgG responses and potent neutralizing antibody titers. We also show here that the recombinant vaccine protected animals against lethal challenge with C. difficile spores, with efficacy equivalent to the toxoid vaccine. The development of a two-segment recombinant vaccine could provide several advantages over toxoid TcdA/TcdB such as improvements in manufacturability., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

We recently published our findings indicating that anti-TcdB antibodies were effective as treatment for C. difficile infection, but that anti-TcdA actually worsened prognosis in the gnotobiotic piglet model. To further investigate the roles of the two toxins, we administered purified toxins separately or together, systemically, to piglets and found that both toxins, either alone or together, are able to elicit severe lesions systemically and are also able to cross into the gut lumen and cause large intestinal lesions typical of infection. We also found that anti-TcdA administered before systemic challenge with TcdA again did not protect from development of disease, but, in this case, did not appear to worsen prognosis. Further work is still needed, but these findings add to the growing knowledge regarding the roles of the C. difficile toxins.

The Clostridium difficile toxins A and B are primarily responsible for symptoms of C. difficile associated disease and are prime targets for vaccine development. We describe a plasmid-based system for the production of genetically modified toxins in a non-sporulating strain of C. difficile that lacks the toxin genes tcdA and tcdB. TcdA and TcdB mutations targeting established glucosyltransferase cytotoxicity determinants were introduced into recombinant plasmids and episomally expressed toxin mutants purified from C. difficile transformants. TcdA and TcdB mutants lacking glucosyltransferase and autoproteolytic processing activities were ~10 000-fold less toxic to cultured human IMR-90 cells than corresponding recombinant or native toxins. However, both mutants retained residual cytotoxicity that could be prevented by preincubating the antigens with specific antibodies or by formalin treatment. Such non-toxic formalin-treated mutant antigens were immunogenic and protective in a hamster model of infection. The remaining toxicity of untreated TcdA and TcdB mutant antigens was associated with cellular swelling, a phenotype consistent with pore-induced membrane leakage. TcdB substitution mutations previously shown to block vesicular pore formation and toxin translocation substantially reduced residual toxicity. We discuss the implications of these results for the development of a C. difficile toxoid vaccine.

The epidemiology of Clostridium difficile infections (CDIs) has dramatically changed over the last decade in both North America and Europe, and it has become more frequent, more severe, more refractory to standard therapy, and more likely to relapse. These changes have been associated with the emergence of a "hypervirulent" strain known as BI/NAP1/027 which has become endemic in some areas, although, other hypervirulent genotypes (e.g. PCR ribotype 078) have also been described. To reduce the incidence of CDIs, the diagnostic guidelines on diagnosis and treatment methods have been recently updated. The aim of this review is to highlight the recent epidemiological data on CDIs and to provide an overview of the pathogenicity of the infection, diagnostic approaches, old and new treatment options, and current knowledge of infection control measures., (Copyright © 2012 Elsevier España, S.L. All rights reserved.)

Background: A dramatic increase in morbidity and mortality from Clostridium difficile infection (CDI) due to the recent emergence of virulent, antibiotic-resistant strains has led to a search for alternatives to antibiotics, including vaccines and immune-based therapy that target the 2 key toxins-TcdA and TcdB., Methods: We investigated the efficacy of specific human monoclonal antibodies (HuMab) and alpaca polyclonal antibodies against each toxin separately and in combination in the gnotobiotic piglet model of CDI. Additionally, the HuMab and polyclonal antibodies were exploited to investigate the precise contribution of each toxin to systemic and/or gastrointestinal (GI) tract disease., Results: Our results indicate that TcdB is an important virulence factor associated with GI and systemic pathology. Administration of anti-TcdB antibody alone or with anti-TcdA protected 100% of piglets from development of systemic CDI and minimized GI lesions. Conversely, 100% of piglets administered only anti-TcdA developed severe GI and systemic disease, with 67%-83% fatality, faring worse than placebo-treated control animals., Conclusions: These results highlight the importance of TcdB in the pathogenesis of CDI and the effectiveness of TcdB-specific antibody in treating CDI. However, the results raise new questions regarding the nature of TcdA interaction with therapeutic antibodies.

Goals: We aim to present a data detailing our success with fecal microbiota transplantation (FMT) and to provide a simple treatment protocol., Background: Relapse is a common problem in patients treated for Clostridium difficile infection, often requiring prolonged courses of oral vancomycin with limited alternative treatment options. Administration of the entire fecal flora from a healthy individual to restore beneficial physiological species is referred to as FMT (also termed fecal bacteriotherapy or stool transplant). Although introduced over 50 years ago with high cure rates in published case series, FMT is neither routine practice nor widely available to patients., Study: Twenty-six patients with relapsing C. difficile infection underwent FMT over a 28-month period. FMT was performed during colonoscopy by direct infusion of minimally processed donor stool., Results: Twenty-four female and 2 male patients underwent FMT. The mean duration of CDI was 12.6 months (range, 4 to 84 mo) before FMT. These patients have been followed for a mean duration of 10.7 months (range, 2 to 30 mo). Twenty-four patients have remained free of significant diarrhea or CDI. One experienced loose stool and resumed vancomycin despite remaining C. difficile negative; she developed CDI recurrence 11 months post-FMT after taking cephalexin. Another had diarrhea 2 months post-FMT. Stool was not tested for C. difficile; she received 1 week of vancomycin and CDI did not recur after this., Conclusions: FMT through colonoscopy was simple, safe, and 92% effective in preventing further diarrhea or CDI relapse in this group of 26 patients with recurrent CDI.

Clostridium difficile infection (CDI) is one of the most prevalent nosocomial infections. A dramatic increase in the incidence and severity of CDI has been noted in the past decade. Current recommendations suggest metronidazole as first-line therapy in mild to moderately severe CDI and oral vancomycin in individuals with severe CDI, or when metronidazole fails or is contradicted. Alterations of the colonic microbiota, usually caused by antimicrobial therapy, seem to play a critical role in CDI pathogenesis. Probiotics are live microorganisms that confer a health benefit to the host, and have been used in CDI. Although a wide variety of probiotics have been studied, the exact role of probiotics in preventing and treating CDI is not clear. In this study, we reviewed the current literature and recommendations on the most commonly studied protiotic agents (Saccharomyces boulardii, Lactobacillus species, and probiotic mixtures) used to prevent or treat CDI. Lactobacillus-containing probiotic mixtures and S. boulardii may be effective in the prevention of CDI in high-risk antibiotic recipients but this finding is based on small, individual studies, and further, larger, well-controlled studies are needed to confirm preliminary positive findings and to better delineate the efficacy of probiotics in CDI prevention or treatment.

Infection with Clostridium difficile is currently the leading cause of infectious diarrhea in hospitalized patients, and recent surveillance data indicate that C. difficile has surpassed methicillin-resistant Staphylococcus aureus as the number one cause of hospital-acquired infections in some areas of the USA. In addition, concern over C. difficile has increased over the past decade due to the appearance of new hypervirulent strains. Metronidazole and vancomycin have remained the treatments of choice for initial therapy of primary infection with C. difficile for the past 25 years, but the persistence of spores leads to a recurrence of infection in an estimated 20-25% of patients. Patients who have one recurrent episode have up to a 65% chance of having additional recurrence. While the judicious use of antimicrobials in accordance with antibiotic stewardship guidelines remains the most effective method for the control of C. difficile, the high recurrence rate, increasing incidence, and changing epidemiology of C. difficile has led to an increased interest in the study of alternative strategies for the prevention and treatment of C. difficile disease. These alternative strategies attempt to eliminate C. difficile spores, replenish the normal gut flora, reduce the C. difficile toxin load in the bowel, or bolster the patient's own immune response to the C. difficile toxins. To evaluate the available evidence on these alternative strategies, we conducted a literature search of MEDLINE (1966-March 2011) and International Pharmaceutical Abstracts (1970-March 2011). Available citations from these articles were also utilized. The aim of this review is to summarize the available evidence for alternative treatment strategies for C. difficile disease and to make recommendations for their place in therapy., (Copyright © 2011 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Clostridium difficile is the causative agent of primary and recurrent antibiotic-associated diarrhea and colitis in hospitalized patients. The disease is caused mainly by two exotoxins, TcdA and TcdB, produced by the bacteria. Recurrent C. difficile infection (CDI) constitutes one of the most significant clinical issues of this disease, occurs in more than 20% of patients after the first episode, and may be increasing in frequency. However, there is no well-established animal model of CDI relapse currently available for studying disease pathogenesis, prevention, and therapy. Here we report the establishment of a conventional mouse model of recurrence/relapse CDI. We found that the primary episode of CDI induced little or no protective antibody response against C. difficile toxins and mice continued shedding C. difficile spores. Antibiotic treatment of surviving mice induced a second episode of diarrhea, while a simultaneous reexposure of animals to C. difficile bacteria or spores elicited a full spectrum of CDI similar to that of the primary infection. Moreover, mice treated with immunosuppressive agents were prone to more severe and fulminant recurrent disease. Finally, utilizing this model, we demonstrated that vancomycin only delayed disease recurrence, whereas neutralizing polysera against both TcdA and TcdB completely protected mice against CDI relapse. In conclusion, we have established a mouse relapse CDI model that allows for future investigations of the role of the host immune response in the disease's pathogenesis and permits critical testing of new therapeutics targeting recurrent disease.

Clostridium difficile is the most common cause of health care-associated and antibiotic-associated diarrhoea. These guidelines are intended to provide advice to clinicians on the clinical assessment, diagnosis and management of C. difficile infection (CDI). Hypervirulent strains of C. difficile, including PCR ribotype 027 strains recently identified in Australia, have been associated elsewhere with epidemic spread and high rates of severe disease and death. Diagnostic tests include stool culture, polymerase chain reaction-based assays, cell-culture cytotoxicity assays and enzyme immunoassays detecting C. difficile glutamate dehydrogenase, and/or toxin A and/or B. To treat an initial episode and a first recurrence, metronidazole is the preferred antibiotic, with oral vancomycin reserved for severe disease and subsequent recurrences. Surgery should be considered for fulminant disease., (©The Medical Journal of Australia 2011)

This article examines risk factors, pathogenesis, symptoms and management of Clostridium difficile infection, which is the major cause of enteric infections among people aged over 65 years in healthcare settings. Symptoms range from mild to profuse watery diarrhoea, which may be accompanied by severe life-threatening inflammation of the intestine. Transmission is by the faecal-oral route, via the hands of health workers and from environmental reservoirs. Eradication is difficult because C. difficile forms spores that survive for months in dust and on surfaces. Strategies to prevent and control C. difficile include thorough hand hygiene, isolation precautions, environmental cleaning and restricted use of broad spectrum antibiotics.

We report our continued experience with rifaximin as a post-vancomycin treatment strategy in six patients with multiple recurrences of C. difficile infection (CDI). Four of the six patients (67%) had no further diarrhea episodes, but two patients failed shortly after or during the rifaximin treatment. C. difficile isolates from one of the two patients who failed treatment had an MIC of >256 microg/ml to rifampin. Serial therapy with vancomycin, followed by rifaximin remains an option for some patients with multiple CDI recurrences.

Clostridium difficile infection (CDI) has emerged as a major complication associated with the use of systemic antimicrobial agents. Broad-spectrum antimicrobial agents disrupt the ecological bacterial balance in the colon and create an opportunity for C. difficile overgrowth with attendant production of toxins and clinical symptoms of colitis. Recommended therapies for CDI include oral administration of metronidazole or vancomycin for 10-14 days. However, 5% to 35% of patients experience infection relapse after completion of treatment. Recently, patients who failed to resolve their infection with conventional therapies and went on to develop chronic relapsing CDI were successfully treated with fecal bacteriotherapy. Stool obtained from a healthy individual was instilled from either end of the GI tract. Although the published experience with fecal bacteriotherapy is still limited, the published treatment results for 100 patients have demonstrated an average success-rate close to 90%. Fecal bacteriotherapy is a low tech procedure which is easy to perform, and breaks the cycles of repeated antibiotic use, which in turn reduces the risk of antibiotic associated resistance and adds potential cost savings when compared to repeated antibiotic administration and hospitalizations.

Background: The association of Clostridium difficile infection (CDI) with antecedent antibiotic use suggests that perturbation of normal intestinal flora is an important inciting factor. Therefore, the use of probiotics for the prevention and/or therapy of CDI is considered to be theoretically effective., Methods: A non-systematic review of the literature evaluating the prophylactic and therapeutic efficacy of oral bacterial or yeast products for CDI, as well as the "quality control" and deleterious effects of these agents., Results: There is no convincing literature which supports the use of bacterial/yeast products to prevent CDI. There is one prophylactic study from the United Kingdom which showed efficacy, but it has been widely criticized as flawed or not generalizable. One other small case-series described the efficacy of Saccharomyces boulardii in preventing CDI relapse, but only in a subset of patients. Many bacterial/yeast products do not contain what they are purported to contain, and may contain other bacterial/fungal constituents not listed on the label. S. boulardii preparations may predispose to bloodstream infections in recipients, and have been associated with fungemia in contiguous patients when prepared at the bedside in intensive care settings., Conclusions: There is no persuasive evidence to support the use of bacterial/yeast products for the prevention or treatment of CDI. Oral preparations may not contain what is indicated on the label. Widespread use of some products may lead to bloodstream infections in susceptible individuals, and careless use of S. boulardii in an intensive care setting may place other patients at risk. At the present time, oral bacterial/yeast products do not have a role in the prevention or therapy of CDI.

Background: The incidence and severity of Clostridium difficile infection (CDI) are increasing, and previously described interventions for controlling the spread of CDI are not easily generalized to multiple healthcare institutions., Objective: We tested prevention and treatment bundles to decrease the incidence of CDI and the mortality associated with CDI at our hospital., Design: Observational before-after study of adult patients admitted to a tertiary care, university-affiliated hospital during the period from January 2004 through December 2008., Methods: In January 2006, we launched an educational campaign and introduced a prevention bundle-a series of specific processes aimed at preventing the transmission of C. difficile among hospitalized patients, including enhanced isolation practices, laboratory notification procedures, and steps coordinating infection control and environmental services activities. In April 2006, we implemented a treatment bundle-a set of hospital-wide treatment practices aimed at minimizing the risk of serious CDI complications. We tracked quarterly incidence rates and case-fatality rates for healthcare-associated CDI cases at our hospital. Our main outcome was the healthcare-associated CDI incidence rate, measured as the number of healthcare-associated cases of CDI per 1,000 patient-days., Results: We followed patients for a total of 1,047,849 patient-days. The healthcare-associated CDI incidence rates fell from an average of 1.10 cases per 1,000 patient-days before intervention to 0.66 cases per 1,000 patient-days after intervention. This statistically significant decrease amounts to a 40% reduction in incidence after the intervention., Conclusions: Our intervention was successful in reducing the incidence of CDI at our hospital. On the basis of our experience, we propose the use of a checklist of hospital interventions to decrease the incidence of healthcare-associated CDI.

This article outlines a project to improve the effective application of root cause analysis to reduce rates of Clostridium difficile infection. Using a learning intervention and redefining infection-control practices produced better compliance with the root cause analysis tool on six medical elderly wards.

Clostridium difficile is the most common cause of infectious diarrhea in hospitalized patients. Its effects are mediated by C difficile toxins A and B. Recent outbreaks of severe colitis have been associated with a new strain of the bacterium that produces large amounts of the toxins. Although oral metronidazole and oral vancomycin can be used to treat C difficile-associated disease, intraluminal vancomycin is preferable for more severe C difficile colitis. Early surgical intervention can improve outcomes with fulminant colitis, although overall mortality remains high.

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.

Objective: To study the effect of treating recurrent Clostridium difficile-associated diarrhoea (CDAD) with a suspension of donor faeces., Design: Uncontrolled interventional study., Method: Patients that, despite adequate antibiotic therapy, had developed at least 2 recurrences ofCDAD, including at least one recurrence that had been treated with a vancomycin tapering regimen, were included in the study. Relatives or volunteers served as faeces donor. All donors were previously examined for the presence of HIV, hepatitis B- and C-virus, and acute infection with cytomegalovirus or Epstein-Barr virus. The donor faeces were examined for the presence of C. difficile, Yersinia, Campylobacter, Shigella, Salmonella, and parasites. Before the infusion of donor faeces, the patients were treated for 4 days with vancomycin 500 mg q.i.d., followed by colon lavage. The suspension of 150 g of donor faeces dissolved in 300-400 ml of NaCl was infused into the jejunum via a duodenal catheter or into the caecum via colonoscopy., Results: 7 CDAD patients were included and treated, including 2 with the hypervirulent C. difficile-strain PCR ribotype 027, toxinotype III. In 5 patients, the defaecation frequency returned to normal almost immediately after treatment and the cultures and toxin tests for C. difficile were repeatedly negative. In the remaining 2 patients, the treatment was successful after a repeated infusion of faeces from a different donor., Conclusion: Treatment with donor faeces seems promising for patients who develop repeated recurrences despite adequate therapy and could be valuable in the future during (local) epidemics of the PCR ribotype 027 strain. A randomised nationwide study (FECAL trial) has been started in order to determine the efficacy of this treatment.

Purpose: Current and future treatment modalities for Clostridium difficile-associated disease (CDAD) are reviewed., Summary: C. difficile, an anaerobic, spore-forming, gram-positive [corrected] rod, is the enteric pathogen most frequently identified in patients with antibiotic-associated, nosocomially acquired diarrhea. Infection can lead to severe gastrointestinal illness which can develop into pseudomembranous colitis. Recent outbreaks in North America involved more virulent C. difficile strains, more severe infections, and more complicated treatment courses. Because of the potential for increased toxin-associated damage due to increased toxin exposure time, CDAD treatment often involves cessation of the inciting antibiotic, C. difficile-targeted antibiotic therapy, electrolyte normalization, fluid replacement, and antimotility agent avoidance. First-line therapy for CDAD is treatment with the antibiotic metronidazole. Vancomycin is often used in more severe cases and for treatment-resistant organisms. Treatment regimens may also include probiotics, bile-acid sequestrants, and, in limited cases, intravenous immunoglobulin (IVIG). Alternative treatments for refractory and persistent CDAD include intracolonic vancomycin, nitazoxanide, rifaximin, IVIG, and probiotics. Several target proteins have been proposed for C. difficile vaccine production, including the flagellar cap protein FliD, flagellin FLiC, a cell wall protein (Cwp) (comprising amino- and carboxyl-terminal domains), a protease Cwp 84, and toxins A and B. Rarely, pseudomembranous colitis, a severe complication of CDAD, must be treated through surgical intervention., Conclusion: CDAD is a major concern for health care systems and clinicians. New diagnostic tests with increased sensitivity for detecting CDAD with a short turnaround time are necessary for early treatment and prevention. Continued research for more effective treatments and vaccine development for CDAD is also needed.

Objectives: To investigate the effect of reinforcing a narrow-spectrum antibiotic policy on antibiotic prescription and Clostridium difficile infection (CDI) rates by feedback of antibiotic use to doctors, as part of a departmental audit and feedback programme., Design: A prospective controlled interrupted time-series (ITS) study, with pre-defined pre- and post-intervention periods, each of 21 months., Setting: Three acute medical wards for elderly people in a teaching hospital., Participants: Six thousand one hundred and twenty-nine consecutive unselected acute medical admissions aged >or=80 years., Interventions: A 'narrow-spectrum' antibiotic policy (reinforced by an established programme of audit and feedback of antibiotic usage and CDI rates) was introduced, following an unplanned rise in amoxicillin/clavulanate (Augmentin) use. It targeted broad-spectrum antibiotics for reduction (cephalosporins and amoxicillin/clavulanate) and narrow-spectrum antibiotics for increase (benzyl penicillin, amoxicillin and trimethoprim). Changes in the use of targeted antibiotics (intervention group) were compared with those of untargeted antibiotics (control group) using segmented regression analysis. Changes in CDI rates were examined by the Poisson regression model. Methicillin-resistant Staphylococcus aureus (MRSA) acquisition rates acted as an additional control., Results: There was a reduction in the use of all targeted broad-spectrum antibiotics and an increase in all targeted narrow-spectrum antibiotics, statistically significant for sudden change and/or linear trend. All other antibiotic use remained unchanged. CDI rates fell with incidence rate ratios of 0.35 (0.17, 0.73) (P=0.009). MRSA incidence did not change [0.79 (0.49, 1.28); P=0.32]., Conclusions: This is the first controlled prospective ITS study to use feedback to reinforce antibiotic policy and reduce CDI. Multicentre ITS or cluster randomized trials of this and other methods need to be undertaken to establish the most effective means of optimizing antibiotic use and reducing CDI.

Clostridium difficile should be suspected in patients who present with nosocomial diarrhoea. It is more common in the elderly or in patients with a debilitating underlying condition who have received antimicrobial agents, and up to 20-25% of patients may experience a relapse. The reference method for diagnosis is the cell culture cytotoxin test which detects the presence of toxin B in a cellular culture of human fibroblasts, but recovering C. difficile in culture allows the performance of a ''second-look" cell culture assay that enhances the potential for diagnosis. Oral metronidazole (500 mg tid or 250 mg every 6 hrs) and oral vancomycin (125 mg every 6 hrs) administered for 1014 days have similar therapeutic efficacy, with response rates near 90-97%. C. difficile strains resistant to metronidazole and with intermediate resistance to vancomycin have been described. The administration of probiotics such as Saccharomyces boulardii, Lactobacillus sp. or brewer's yeast for prophylaxis of CDAD remains controversial.

Clostridium difficile is responsible for 10-25% of cases of antibiotic-associated diarrhea (AAD) and for virtually all cases of antibiotic-associated pseudo-membranous colitis (PMC). This anaerobic spore-forming bacterium has been identified as the leading cause of nosocomial infectious diarrhea in adults. Pathogenesis relies on a disruption of the normal bacterial flora of the colon, a colonization by C. difficile and the release of toxins A and B that cause mucosal damage and inflammation. Incidence of C. difficile intestinal disorders usually varies from one to 40 per thousand patient admissions. Risk factors for C. difficile-associated diarrhea include antimicrobial therapy, older age (> 65 years), antineoplastic chemotherapy, and length of hospital stay. Nosocomial transmission of C. difficile via oro-fecal route occurs in 3-30% of total patient admissions but it remains asymptomatic in more than 66% of cases. Persistent environmental contamination and carrying of the organism on the hands of hospital staff are common. Measures that are effective in reducing cross-infection consist of an accurate and rapid diagnosis, an appropriate treatment, an implementation of enteric precautions for symptomatic patients, a reinforcement of hand-washing and a daily environmental disinfection. C. difficile is a common cause of infectious diarrhea and should be therefore systematically investigated in patients with nosocomial diarrhea.

Objective: To compare the efficacy of vancomycin and metronidazole for eradication of asymptomatic Clostridium difficile fecal excretion as a means of controlling nosocomial outbreaks of C. difficile diarrhea., Design: Randomized, placebo-controlled, non-blinded trial., Setting: Six hundred-bed regional referral Veterans Affairs Medical Center., Patients: Thirty patients excreting C. difficile without diarrhea or abdominal symptoms., Interventions: All patients were randomized to receive 10 days of oral vancomycin, 125 mg four times daily; metronidazole, 500 mg twice daily; or placebo, three times daily., Measurements: Stool cultures were obtained during treatment and for 2 months after treatment. All C. difficile isolates were typed by restriction endonuclease analysis (REA)., Results: Clostridium difficile organisms were not detected during and immediately after treatment in 9 of 10 patients treated with vancomycin compared with 3 of 10 patients treated with metronidazole (P = 0.02) and 2 of 10 patients in the placebo group (P = 0.005). The fecal vancomycin concentration was 1406 +/- 1164 micrograms/g feces, but metronidazole was not detectable in 9 of 10 patients. Eight of the nine evaluable patients who had negative stool cultures after treatment with vancomycin began to excrete C. difficile again 20 +/- 8 days after completing treatment. Three of these patients received additional antibiotics before C. difficile excretion recurred, and five acquired new C. difficile REA strains. Four of six patients who received only vancomycin before C. difficile excretion recurred were culture-positive at the end of the study compared with one of nine patients who received only placebo (P = 0.047)., Conclusions: Asymptomatic fecal excretion of C. difficile is transient in most patients, and treatment with metronidazole is not effective. Although treatment with vancomycin is temporarily effective, it is associated with a significantly higher rate of C. difficile carriage 2 months after treatment and is not recommended.

The recognition of a cluster of antibiotic-associated nosocomial Clostridium difficile disease (NCDD) caused by serotype C in a surgical ward led to a hospital-wide NCDD surveillance and control program. The initial step included: (a) gas-liquid chromatography screening of inpatients' diarrheal stools; (b) enteric isolation precautions, cohorting and terminal room disinfection in wards with a cluster of two or more NCDD cases per month. During a 12-month period, the quarterly incidence of NCDD remained unchanged and six new clusters of serotype C, K, and H infections occurred, giving a global incidence of 1.5/1,000 admissions. C. difficile spores were recovered from 36.7% surfaces of case patient rooms versus 6.7% in control rooms. More intensive control measures were evaluated: (a) culture screening of inpatients' diarrheal stools; (b) early therapy, enteric isolation precautions, and daily meticulous room disinfection for each sporadic NCDD case. Surface disinfection reduced the contamination level four-fold (p = 0.04). In the following 12 months, no cluster occurred and the incidence of NCDD fell to 0.3/1,000 admission (protective efficacy 73%, 95% confidence interval: 46-87%). These observations suggest that early therapy, isolation precautions, and surface disinfection, focused on patients with sporadic NCDD detected by active surveillance, can prevent nosocomial transmission of C. difficile.

Clostridium difficile has recently become recognized as an important nosocomial pathogen. This review summarizes what is known about the isolation of the organism, the spectrum of clinical disease, virulence factors, treatments, and methods of prevention. Risk factors for C. difficile disease are also discussed. The most important risk factor is the use of certain antibiotics (ampicillin, cephalosporins, and clindamycin). C. difficile is associated with 96% to 100% of cases of pseudomembraneous colitis, 60% to 75% of antibiotic-associated cases of colitis, and 11% to 33% of antibiotic-associated cases of diarrhea. Other risk factors include gastrointestinal manipulations, advanced age, female sex, inflammatory bowel disease, cancer chemotherapy, and renal disorders. Hospital outbreaks of C. difficile disease are examined. Data from nosocomial outbreaks support transmission of C. difficile by contaminated fomites and hand carriage by hospital personnel.

The administration of clindamycin to hamsters induces a lethal enterocolitis as a consequence of toxins produced in the alimentary tract by Clostridium difficile. The lethal and cytopathic effects of C. difficile toxins are neutralized in vitro by C. sordellii antitoxin and hamsters may be protected against clindamycin induction of caecitis by passive immunization using C. sordellii antitoxin. To examine active immunization using C. difficile and C. sordellii toxoids, groups of male and female Syrian hamsters were immunized on two occasions and challenged by parenteral clindamycin. A concentrated C. difficile toxoid protected 90% of females and 78% of males; the degree of protection per group decreased with dilution of the toxoid used for immunization. A similar degree of protection was observed in female hamsters immunized with a bivalent vaccine prepared from the partially purified toxins A and B of C. difficile. Immunization using a C. sordellii toxoid protected between 100 and 25% of females per group and between 50 and 12.5% of males per group.

Pigbel has been recognised as a major cause of mortality and morbidity in the Papua New Guinea Highlands for over 20 years. The clinical features, epidemiology and pathogenesis of this disease have been elucidated, leading to the development of an effective vaccine (Clostridium perfringens type C beta toxoid) for the prevention of pigbel.