Development and validation of a clinical risk calculator for mortality after colectomy for fulminant Clostridium difficile colitis.

BACKGROUND: Clostridium difficile colitis is an increasingly important cause of morbidity and mortality. Fulminant C. difficile colitis (FCDC) is a severe form of the colitis driven by a significant systemic inflammatory response, and managed with a total abdominal colectomy. Despite surgery, postoperative mortality rates remain high. The aim of this study was to develop a bedside calculator to predict the risk of 30-day postoperative mortality for patients with FCDC. METHODS: After institutional review board approval, the American College of Surgeons National Surgical Quality Improvement Program database (2005-2015) was used to include adult patients who underwent emergency surgery for FCDC. A priori preoperative predictors of mortality were selected from the literature: age, immunosuppression, preoperative shock, intubation, and laboratory values. The predictive accuracy of different logistic regression models was measured by calculating the area under the receiver-operating characteristic curve. A cohort of 124 patients from Québec was used to validate the developed mortality calculator. RESULTS: A total of 557 patients met the inclusion criteria, and the overall mortality was 44%. After developing the calculator, no statistically significant differences were found in comparison with the American College of Surgeons National Surgical Quality Improvement Program probability of mortality available in the database (area under the receiver operating curve, 75.61 vs. 75.14; p = 0.79). External validation with the cohort of patients from Quebec showed an area under the curve of 74.0% (95% confidence interval, 65.0-82.9). CONCLUSION: A clinically applicable calculator using preoperative variables to predict postoperative mortality for patients with FCDC was developed and externally validated. This calculator may help guide preoperative decision making. LEVEL OF EVIDENCE: Prognostic and epidemiological study, level III.

Timely Use of Probiotics in Hospitalized Adults Prevents Clostridium difficile Infection: A Systematic Review With Meta-Regression Analysis.

BACKGROUND & AIMS: Systematic reviews have provided evidence for the efficacy of probiotics in preventing Clostridium difficile infection (CDI), but guidelines do not recommend probiotic use for prevention of CDI. We performed an updated systematic review to help guide clinical practice. METHODS: We searched MEDLINE, EMBASE, International Journal of Probiotics and Prebiotics, and The Cochrane Library databases for randomized controlled trials evaluating use of probiotics and CDI in hospitalized adults taking antibiotics. Two reviewers independently extracted data and assessed risk of bias and overall quality of the evidence. Primary and secondary outcomes were incidence of CDI and adverse events, respectively. Secondary analyses examined the effects of probiotic species, dose, timing, formulation, duration, and study quality. RESULTS: We analyzed data from 19 published studies, comprising 6261 subjects. The incidence of CDI in the probiotic cohort, 1.6% (54 of 3277), was lower than of controls, 3.9% (115 of 2984) (P < .001). The pooled relative risk of CDI in probiotic users was 0.42 (95% confidence interval, 0.30-0.57; I2 = 0.0%). Meta-regression analysis demonstrated that probiotics were significantly more effective if given closer to the first antibiotic dose, with a decrement in efficacy for every day of delay in starting probiotics (P = .04); probiotics given within 2 days of antibiotic initiation produced a greater reduction of risk for CDI (relative risk, 0.32; 95% confidence interval, 0.22-0.48; I2 = 0%) than later administration (relative risk, 0.70; 95% confidence interval, 0.40-1.23; I2 = 0%) (P = .02). There was no increased risk for adverse events among patients given probiotics. The overall quality of the evidence was high. CONCLUSIONS: In a systematic review with meta-regression analysis, we found evidence that administration of probiotics closer to the first dose of antibiotic reduces the risk of CDI by >50% in hospitalized adults. Future research should focus on optimal probiotic dose, species, and formulation. Systematic Review Registration: PROSPERO CRD42015016395.

Clostridium difficile Infection in Production Animals and Avian Species: A Review.

Clostridium difficile is the leading cause of antibiotic-associated diarrhea and colitis in hospitalized humans. Recently, C. difficile infection (CDI) has been increasingly recognized as a cause of neonatal enteritis in food animals such as pigs, resulting in stunted growth, delays in weaning, and mortality, as well as colitis in large birds such as ostriches. C. difficile is a strictly anaerobic spore-forming bacterium, which produces two toxins A (TcdA) and B (TcdB) as its main virulence factors. The majority of strains isolated from animals produce an additional binary toxin (C. difficile transferase) that is associated with increased virulence. C. difficile is ubiquitous in the environment and has a wide host range. This review summarizes the epidemiology, clinical presentations, risk factors, and laboratory diagnosis of CDI in animals. Increased awareness by veterinarians and animal owners of the significance of clinical disease caused by C. difficile in livestock and avians is needed. Finally, this review provides an overview on methods for controlling environmental contamination and potential therapeutics available.

Evaluation of gastrointestinal leakage using serum (1→3)-ß-D-glucan in a Clostridium difficile murine model.

Gastrointestinal (GI) leakage in Clostridium difficile-associated diarrhea (CDAD) is well known but is not routinely assessed in clinical practice. Serum (1→3)-ß-D-glucan (BG), a fungal cell wall component used as a biomarker for invasive fungal disease, was tested in a CDAD mouse model with and without probiotics. Higher serum fluorescein isothiocyanate-dextran (FITC-dextran) and spontaneous gram-negative bacteremia, GI leakage indicators, were frequently found in CDAD mice, which died compared with those which survived. BG, serum macrophage inflammatory protein-2 and FITC-dextran but not quantitative blood bacterial count differentiated the clinical severity. Interestingly, a specific dose of Lactobacillus rhamnosus L34 attenuated CDAD and decreased serum BG and FITC-dextran, but not other parameters. BG also showed a higher area under the receiver operating characteristic curve for 7-day mortality than FITC-dextran. Fifty-five percent of CDAD mice with BG ≥ 60 pg/ml (the human negative cut-off value for invasive fungal disease) at 1 day after C. difficile gavage died within 7 days. In conclusion, S: erum BG was elevated in mice with severe CDAD, an established model of GI leakage with a strong association with mortality rate. BG monitoring in patients with CDAD is of interest as both a potential prognostic tool and a therapeutic efficacy indicator.

Clostridium difficile colitis: pathogenesis and host defence.

Clostridium difficile is a major cause of intestinal infection and diarrhoea in individuals following antibiotic treatment. Recent studies have begun to elucidate the mechanisms that induce spore formation and germination and have determined the roles of C. difficile toxins in disease pathogenesis. Exciting progress has also been made in defining the role of the microbiome, specific commensal bacterial species and host immunity in defence against infection with C. difficile. This Review will summarize the recent discoveries and developments in our understanding of C. difficile infection and pathogenesis.

[Relationship between Clostridium difficile ITS-PCR Type and Pathogenicity].

Clostridium difficile (C. difficile) causes antibiotic-associated diarrhea and nosocomial infection. The PCR of internal transcribed spacer regions (ITS) is easily conductible in a relatively short time. The purpose of the current study is to classify C. difficile by PCR electrophoresis pattern of ITS (ITS-PCR type) and estimate the relationship of the ITS-PCR type of C. difficile with its pathogenicity. We examined 77 strains which were obtained in our hospital from March 2012 to August 2013. Toxin genes were detected by PCR using toxin gene specific primers. Antimicrobial sensitivities were measured by E-test. Pseudomembrane formation and severity of the illness in clinical patients were investigated based on the medical records. The strains were classified into the 33 ITS-PCR types. Among them, most of strains in 18 PCR types were not associated with any toxin genes. Strains with toxin A(+)/B(+)genes were classified into 14PCR types. The 3 strains with toxin B (+) strains and the two strains with toxin A(+)/B(+)/binary toxin(+) genes were classified into 1 PCR type, type 17, and type 16, respectively. 6 strains in 13 strains of type 33, and 5 strains in 11 strains of type 2 were detected from the same ward, presuming nosocomial infection. Minimum inhibitory concentrations (MICs) of vancomycin and metronidazole were ≤ 2 µg/mL, distribution of MICs were not correlated with ITS-PCR type. The pseudomembrane forming and severity of the illness were not obviously related to ITS-PCR pattern. Thus, the typing of C. difficile by ITS-PCR pattern is considered to be useful for early detection of nosocomial infection, and assessment of toxigenicity.

Predictors of Early Failure After Fecal Microbiota Transplantation for the Therapy of Clostridium Difficile Infection: A Multicenter Study.

OBJECTIVES: Fecal microbiota transplant (FMT) is a highly efficacious treatment for recurrent or refractory Clostridium difficile infection (CDI); however, 10-20% of patients fail to achieve cure after a single FMT. The aim of this study was to identify risk factors associated with FMT failure and to develop and validate a prediction model for FMT failure. METHODS: Patient characteristics, CDI history, FMT characteristics, and outcomes data for patients treated between 2011 and 2015 at three academic tertiary referral centers were prospectively collected. Early FMT failure was defined as non-response or recurrence of diarrhea associated with positive stool C. difficile toxin or PCR within 1 month of FMT. Late FMT failure was defined as recurrence of diarrhea associated with positive stool C. difficile toxin or PCR between 1 and 3 months of the FMT. Patient data from two centers were used to determine independent predictors of FMT failure and to build a prediction model. A risk index was constructed based on coefficients of final predictors. The patient cohort from the third center was used to validate the prediction model. RESULTS: Of 328 patients in the developmental cohort, 73.5% (N=241) were females with a mean age of 61.4±19.3 years; 19.2% (N=63) had inflammatory bowel disease (IBD), and 23.5% (N=77) were immunocompromised. The indication for FMT was recurrent CDI in 87.2% (N=286) and severe or severe-complicated in 12.8% (N=42). FMT was performed as an inpatient in 16.7% (N=54). The stool source was patient-directed donors in 40% (N=130) of cases. The early FMT failure rate was 18.6%, and the late failure rate was 2.7%. In the multivariable analysis, predictors of early FMT failure included severe or severe-complicated CDI (odds ratio (OR) 5.95, 95% confidence interval (CI): 2.26-15.62), inpatient status during FMT (OR 3.78, 95% CI: 1.55-9.24), and previous CDI-related hospitalization (OR 1.43, 95% CI: 1.18-1.75); with each additional hospitalization, the odds of failure increased by 43%. Risk scores ranged from 0 to 13, with 0 indicating low risk, 1-2 indicating moderate risk, and ≥3 indicating high risk. In the developmental cohort, early FMT failure rates were 5.6% for low risk, 12.7% for moderate risk, and 41% for high-risk patients. Of 134 patients in the validation cohort, 57% (N=77) were females with a mean age of 66±18.1 years; 9.7% (N=13) had IBD, and 17.9% (N=24) were immunocompromised. The early FMT failure rate at 1 month was 19.4%, with an additional 3% failing by 3 months. In the validation cohort, FMT failure rates were 2.1% for low risk, 16.1% for moderate risk, and 35.7% for high risk patients. The area under the receiver operating characteristic curve (AUROC) for FMT failure was 0.81 in the developmental cohort and 0.84 in the validation cohort. CONCLUSIONS: Severe and severe-complicated indication, inpatient status during FMT, and the number of previous CDI-related hospitalizations are strongly associated with early failure of a single FMT for CDI. The novel prediction model has good discriminative power at identifying individuals who are at high risk of failure after FMT therapy and may assist the treating physician in subsequent management plans.

Colitis pseudomembranosa letal en paciente inmunocompetente / Lethal pseudomembranous colitis in an immunocompetent patient

No disponible

Adverse reactions associated with oral and parenteral use of cephalosporins: A retrospective population-based analysis.

BACKGROUND: Few studies have provided population-based, route-specific data on allergy to cephalosporin or incidence of serious adverse drug reactions (ADRs). OBJECTIVE: We investigated the incidence of new reports of cephalosporin-associated "allergy" and serious ADRs. METHODS: We identified all members of the Kaiser Permanente Southern California health plan given cephalosporins (from January 1, 2010, through December 31, 2012), all new reports of cephalosporin-associated allergy, and all serious ADRs. RESULTS: There were 622,456 health plan members exposed to 901,908 courses of oral cephalosporins and 326,867 members exposed to 487,630 courses of parenteral cephalosporins over the 3-year study period. New reports of allergy to cephalosporin were more frequent among women (0.56%; 95% CI, 0.54% to 0.57%) than among men (0.43%; 95% CI, 0.41% to 0.44%) per course (P < .0001). The most frequent serious cephalosporin-associated ADRs were Clostridium difficile infection within 90 days (0.91%), nephropathy within 30 days (0.15%), and all-cause death within 1 day (0.10%). None correlated with history of drug allergy. Physician-documented cephalosporin-associated anaphylaxis occurred with 5 oral exposures (95% CI, 1/1,428,571-1/96,154) and 8 parenteral exposures (95% CI, 1/200,000-1/35,971) (P = .0761). There were 3 documented cephalosporin-associated serious cutaneous adverse reactions (95% CI, 0-1 in 217,291). All were associated with the use of another antibiotic at the same time as cephalosporin. CONCLUSIONS: Cephalosporins are widely and safely used, even in individuals with a history of penicillin allergy. Physician-documented cephalosporin-associated anaphylaxis and serious cutaneous adverse reactions are rare compared with C difficile infection within 90 days, nephropathy within 30 days, and all-cause death within 1 day.

Impacts of infection with different toxigenic Clostridium difficile strains on faecal microbiota in children.

Increasing evidence suggests that altered intestinal microbial composition and function result in an increased risk of Clostridium difficile-associated diarrhoea (CDAD); however, the specific changes of intestinal microbiota in children suffering from CDAD and their associations with C. difficile strain toxigenicity are poorly understood. High-throughput pyrosequencing showed that reduced faecal bacterial diversity and dramatic shifts of microbial composition were found in children with CDAD. The Firmicutes/Bacteroidetes ratio was increased significantly in patients with CDAD, which indicated that dysbiosis of faecal microbiota was closely associated with CDAD. C. difficile infection resulted in an increase in lactate-producing phylotypes, with a corresponding decrease in butyrate-producing bacteria. The decrease in butyrate and lactate buildup impaired intestinal colonisation resistance, which increased the susceptibility to C. difficile colonisation. Strains of C. difficile which were positive for both toxin A and toxin B reduced faecal bacterial diversity to a greater degree than strains that were only toxin B-positive, and were associated with unusually abundant Enterococcus, which implies that the C. difficile toxins have different impacts on the faecal microbiota of children. Greater understanding of the relationships between disruption of the normal faecal microbiota and colonisation with C. difficile that produces different toxins might lead to improved treatment.

Clostridium difficile enteritis: a new role for an old foe.

BACKGROUND: Small bowel involvement of Clostridium difficile is increasingly encountered. Data on many management aspects are lacking. AIM: To synthesis existing reports and assess the frequency, pathophysiology, outcomes, risk factors, diagnosis and management of C. difficle enteritis. METHODS: A systematic review of the literature was conducted to evaluate evidence regarding frequency, pathophysiology, risk factors, optimal diagnosis, management and outcomes for C. difficle enteritis. Three major databases (PubMed, MEDLINE and the Cochrane Library) were searched. The review included original articles reporting C. difficle enteritis from January 1950 to December 2012. RESULTS: C. difficle enteritis is rare but increasingly encountered. Presentation is variable and distinct predisposing factors include emergency surgery, white race and increased age. Diagnosis generally involves a sensitive but often non specific screening test for C. difficile antigens. Oral metronidazole represents first line therapy and surgery may be required for complications. Outcomes are inconsistent but may be improving. CONCLUSIONS: A high index of clinical suspicion, early diagnosis and treatment are vital. Further prospective studies are needed to determine the significance of asymptomatic small bowel C. difficile infections.

The P2Y6 receptor mediates Clostridium difficile toxin-induced CXCL8/IL-8 production and intestinal epithelial barrier dysfunction.

C. difficile is a Gram-positive spore-forming anaerobic bacterium that is the leading cause of nosocomial diarrhea in the developed world. The pathogenesis of C. difficile infections (CDI) is driven by toxin A (TcdA) and toxin B (TcdB), secreted factors that trigger the release of inflammatory mediators and contribute to disruption of the intestinal epithelial barrier. Neutrophils play a key role in the inflammatory response and the induction of pseudomembranous colitis in CDI. TcdA and TcdB alter cytoskeletal signaling and trigger the release of CXCL8/IL-8, a potent neutrophil chemoattractant, from intestinal epithelial cells; however, little is known about the surface receptor(s) that mediate these events. In the current study, we sought to assess whether toxin-induced CXCL8/IL-8 release and barrier dysfunction are driven by the activation of the P2Y6 receptor following the release of UDP, a danger signal, from intoxicated Caco-2 cells. Caco-2 cells express a functional P2Y6 receptor and release measurable amounts of UDP upon exposure to TcdA/B. Toxin-induced CXCL8/IL-8 production and release were attenuated in the presence of a selective P2Y6 inhibitor (MRS2578). This was associated with inhibition of TcdA/B-induced activation of NFκB. Blockade of the P2Y6 receptor also attenuated toxin-induced barrier dysfunction in polarized Caco-2 cells. Lastly, pretreating mice with the P2Y6 receptor antagonists (MSR2578) attenuated TcdA/B-induced inflammation and intestinal permeability in an intrarectal toxin exposure model. Taken together these data outline a novel role for the P2Y6 receptor in the induction of CXCL8/IL-8 production and barrier dysfunction in response to C. difficile toxin exposure and may provide a new therapeutic target for the treatment of CDI.

The role of flagella in Clostridium difficile pathogenesis: comparison between a non-epidemic and an epidemic strain.

Clostridium difficile is a major cause of healthcare-associated infection and inflicts a considerable financial burden on healthcare systems worldwide. Disease symptoms range from self-limiting diarrhoea to fatal pseudomembranous colitis. Whilst C. difficile has two major virulence factors, toxin A and B, it is generally accepted that other virulence components of the bacterium contribute to disease. C. difficile colonises the gut of humans and animals and hence the processes of adherence and colonisation are essential for disease onset. Previously it has been suggested that flagella might be implicated in colonisation. Here we tested this hypothesis by comparing flagellated parental strains to strains in which flagella genes were inactivated using ClosTron technology. Our focus was on a UK-outbreak, PCR-ribotype 027 (B1/NAP1) strain, R20291. We compared the flagellated wild-type to a mutant with a paralyzed flagellum and also to mutants (fliC, fliD and flgE) that no longer produce flagella in vitro and in vivo. Our results with R20291 provide the first strong evidence that by disabling the motor of the flagellum, the structural components of the flagellum rather than active motility, is needed for adherence and colonisation of the intestinal epithelium during infection. Comparison to published data on 630Δerm and our own data on that strain revealed major differences between the strains: the R20291 flagellar mutants adhered less than the parental strain in vitro, whereas we saw the opposite in 630Δerm. We also showed that flagella and motility are not needed for successful colonisation in vivo using strain 630Δerm. Finally we demonstrated that in strain R20291, flagella do play a role in colonisation and adherence and that there are striking differences between C. difficile strains. The latter emphasises the overriding need to characterize more than just one strain before drawing general conclusions concerning specific mechanisms of pathogenesis.

Fecal microbiota transplant for recurrent Clostridium difficile infection: Mayo Clinic in Arizona experience.

OBJECTIVE: To report the initial experience of treating recurrent Clostridium difficile infection (CDI) with fecal microbiota transplant (FMT) at Mayo Clinic in Arizona. PATIENTS AND METHODS: The study retrospectively reviewed FMTs performed at Mayo Clinic in Arizona between January 1, 2011, and January 31, 2013. All the recipients had multiple recurrent CDIs unresponsive to traditional antibiotic drug therapy. A standardized protocol was developed to identify patients, screen donors, perform FMT, and determine outcomes via telephone surveys. RESULTS: Thirty-one patients (mean ± SD age, 61.26±19.34 years) underwent FMT. Median time from index infection to FMT was 340 days. Ninety-seven percent (29 of 30) of patients reported substantial improvement or resolution of diarrhea (median time to improvement, 3 days), 74% (17 of 23) reported improvement or resolution of abdominal pain (median time to improvement, 3 days), and 55% (16 of 29) had improvement or resolution of fatigue (median time to improvement, 6 days). Three patients underwent repeated FMT owing to persistent symptoms; 2 reported improvement in diarrhea with the second therapy. No serious adverse events directly related to FMT were reported. CONCLUSION: A standardized regimen of FMT for recurrent CDI is safe, is highly effective, and can be provided using a relatively simple protocol.

Un caso de diarrea por Clostridium difficile / A case of diarrhoea by Clostridium difficile

Presentamos el caso de una paciente que presentó una colitis seudomembranosa por Clostridium difficile con una evolución prolongada, empeoramiento de su cuadro diarreico tras 2 ingresos hospitalarios y mejoría con tratamiento ambulatorio. El primer diagnóstico se realizó en atención primaria. Resumimos las medidas preventivas, exponemos los criterios de gravedad de este cuadro, el fracaso del tratamiento antibiótico con metronidazol y la posibilidad de agravamiento por el uso de otros antibióticos en estos pacientes. Tras un prolongado tratamiento, la paciente logró recuperarse de este proceso diarreico. Con este caso clínico, el médico de familia puede observar que, en ocasiones, tras los ingresos hospitalarios de los pacientes más frágiles, se pueden presentar diarreas producidas por este microorganismo. Un diagnóstico precoz, el tratamiento ambulatorio con los antibióticos adecuados y la puesta en práctica de las medidas preventivas pueden ser utilizadas en el ámbito de atención primaria (AU)

We present a patient who developed a pseudomembranous colitis due to Clostridium difficile with a prolonged course. The diarrhoea symptoms worsened after two hospitalisations, but there was an improvement with outpatient treatment. The first diagnosis was made in Primary Care. We summarise the preventive measures, and present the severity criteria of this condition, as well as the failure antibiotic treatment with metronidazole and the possible aggravation by the use of other antibiotics in these patients. The patient recovered from the diarrhoea episodes after prolonged treatment. As with this case, the family doctor should note that, sometimes after hospital admissions of frail patients, there may be diarrhoea caused by this microorganism. An early diagnosis, outpatient treatment with appropriate antibiotics, and the implementation of preventive measures can be used in the Primary Care setting (AU)