Therapy For Clostridium Difficile Infection Research Articles

Lack of Benefit With Combination Therapy for Clostridium difficile Infection.

Limited data exist regarding combination therapy for Clostridium difficile infection (CDI). After adjusting for confounders in a cohort of patients with CDI and≥1 year old, combination therapy was not associated with significant differences in clinical outcomes, but it was associated with prolonged duration of therapy (1.22 days; 95% confidence interval, 1.03-1.44 days; P=.02). Infect Control Hosp Epidemiol 2017;38:602-605.

Comparative Effectiveness of Vancomycin and Metronidazole for the Prevention of Recurrence and Death in Patients With Clostridium difficile Infection

Metronidazole hydrochloride has historically been considered first-line therapy for patients with mild to moderate Clostridium difficile infection (CDI) but is inferior to vancomycin hydrochloride for clinical cure. The choice of therapy may likewise have substantial consequences on other downstream outcomes, such as recurrence and mortality, although these secondary outcomes have been less studied. To evaluate the risk of recurrence and all-cause 30-day mortality among patients receiving metronidazole or vancomycin for the treatment of mild to moderate and severe CDI. This retrospective, propensity-matched cohort study evaluated patients treated for CDI, defined as a positive laboratory test result for the presence of C difficile toxins or toxin genes in a stool sample, in the US Department of Veterans Affairs health care system from January 1, 2005, through December 31, 2012. Data analysis was performed from February 7, 2015, through November 22, 2016. Treatment with vancomycin or metronidazole. The outcomes of interest in this study were CDI recurrence and all-cause 30-day mortality. Recurrence was defined as a second positive laboratory test result within 8 weeks of the initial CDI diagnosis. All-cause 30-day mortality was defined as death from any cause within 30 days of the initial CDI diagnosis. A total of 47 471 patients (mean [SD] age, 68.8 [13.3] years; 1947 women [4.1%] and 45 524 men [95.9%]) developed CDI, were treated with vancomycin or metronidazole, and met criteria for entry into the study. Of 47 147 eligible first treatment episodes, 2068 (4.4%) were with vancomycin. Those 2068 patients were matched to 8069 patients in the metronidazole group for a total of 10 137 included patients. Subcohorts were constructed that comprised 5452 patients with mild to moderate disease and 3130 patients with severe disease. There were no differences in the risk of recurrence between patients treated with vancomycin vs those treated with metronidazole in any of the disease severity cohorts. Among patients in the any severity cohort, those who were treated with vancomycin were less likely to die (adjusted relative risk, 0.86; 95% CI, 0.74 to 0.98; adjusted risk difference, -0.02; 95% CI, -0.03 to -0.01). No significant difference was found in the risk of mortality between treatment groups among patients with mild to moderate CDI, but vancomycin significantly reduced the risk of all-cause 30-day mortality among patients with severe CDI (adjusted relative risk, 0.79; 95% CI, 0.65 to 0.97; adjusted risk difference, -0.04; 95% CI, -0.07 to -0.01). Recurrence rates were similar among patients treated with vancomycin and metronidazole. However, the risk of 30-day mortality was significantly reduced among patients who received vancomycin. Our findings may further justify the use of vancomycin as initial therapy for severe CDI.

Risks factors and outcomes of Clostridium difficile infection in patients with cancer: a matched case-control study.

Clostridium difficile infection (CDI) is the leading cause of diarrhoea in hospitalised patients. Cancer populations are at high-risk for infection, but comprehensive evaluation in the current era of cancer care has not been performed. The objective of this study was to describe characteristics, risk factors, and outcomes of CDI in cancer patients. Fifty consecutive patients with CDI at a large Australian cancer centre (2013-2015) were identified from the hospital pathology database. Each case was matched by ward and hospital admission date to three controls without toxigenic CDI. Treatment and outcomes of infection were evaluated and potential risk factors were analysed using conditional logistic regression. Patients with CDI had a mean age of 59.7years and 74% had an underlying solid tumour. Healthcare-associated infection comprised 80% of cases. Recurrence occurred in 10, and 12% of cases were admitted to ICU within 30days. Severe or severe-complicated infection was observed in 32%. Independent risk factors for infection included chemotherapy (odds ratio (OR) 3.82, 95% CI 1.67-8.75; p=0.002), gastro-intestinal/abdominal surgery (OR 4.64, 95% CI 1.20-17.91; p=0.03), proton pump inhibitor (PPI) therapy (OR 2.47, 95% CI 1.05-5.80; p=0.04), and days of antibiotic therapy (OR 1.04, 95% CI 1.01-1.08; p=0.02). Severe or complicated infections are frequent in patients with cancer who develop CDI. Receipt of chemotherapy, gastro-intestinal/abdominal surgery, PPI therapy, and antibiotic exposure contribute to infection risk. More effective CDI therapy for cancer patients is required and dedicated antibiotic stewardship programs in high-risk cancer populations are needed to ameliorate infection risk.

DS11960558, A Water Soluble Prodrug of DS-2969b, for Intravenous Treatment of Clostridium difficile Infection

Background Clostridium difficile infection (CDI) is the most common cause of diarrhea in hospitals. The only available intravenous (IV) therapy for CDI is metronidazole, which showed only a 52.4% cure rate in a prospective observational study. DS11960558 is a water-soluble prodrug of DS-2969b, which is a novel GyrB inhibitor in clinical development for oral treatment of CDI and has been found to be safe and tolerable in its phase 1 study. The in vivo efficacy and physicochemical, pharmacokinetic, and toxicological profiles of the prodrug were evaluated in this study.MethodsEfficacy was evaluated in a hamster CDI model. The animals were primed with a single subcutaneous (SC) clindamycin injection. Then, the infection was induced by oral gavage of C. difficile 2009155 (NAP1/027) spores. Treatment was initiated 6 hours post infection and repeated for 5 days. The animals were observed for survival and death once daily for 35 days. The physicochemical, pharmacokinetic, and toxicological profiles were evaluated by standard methods.ResultsSC administration of the prodrug showed comparable and superior efficacy to oral (PO) administration of DS-2969b and the combination of metronidazole (SC) and vancomycin (PO), respectively, in the hamster CDI model (Figure 1). The solubility of DS-2969b was 0.4 mg/mL while that of the prodrug was much higher, >100 mg/mL. The prodrug was converted to DS-2969a (free form of DS-2969b) rapidly after IV administration, and the conversion ratio was >80% (Figure 2). The main metabolites in rat urine and feces were oxidized forms of DS-2969a, and there were no prodrug-specific metabolites. Fecal excretion of DS-2969a was similar between IV administration of the prodrug and PO administration of DS-2969b. Most of the radioactivity was recovered after IV administration of the 14C-labeled prodrug in rats. The radioactivity was distributed widely in most tissues including the intestinal lumen, similar to the distribution of DS-2969b in rats. In safety pharmacology, genotoxicity, and rat 14-day repeated dose toxicity studies, the prodrug as well as DS-2969b did not show any significant findings.ConclusionThese results support development of DS11960558 as an alternative IV treatment option for CDI patients who cannot take medicine orally.Disclosures M. Yamada, Daiichi Sankyo Co., Ltd.: Employee, Salary; M. Uchiyama, Daiichi Sankyo Co., Ltd.: Employee, Salary; S. I. Inoue, Daiichi Sankyo Co., Ltd.: Employee, Salary; T. Deguchi, Daiichi Sankyo Co., Ltd.: Employee, Salary; Y. Furuta, Daiichi Sankyo Co., Ltd.: Employee, Salary; K. Yabe, Daiichi Sankyo Co., Ltd.: Employee, Salary; N. Masuda, Daiichi Sankyo Co., Ltd.: Employee, Salary

New and emerging therapies for Clostridium difficile infection.

Clostridium difficile infection has attained high prominence given its prevalence and impacts on patients and healthcare institutions. Multiple new approaches to the prevention and treatment of C. difficile infection (CDI) are undergoing clinical trials. Bezlotoxumab is a monoclonal antibody against toxin B that has successfully completed phase III studies, demonstrating a significant reduction in recurrent CDI when given with standard of care antibiotics. Antibiotics under development include cadazolid and ridinilazole, whereas surotomycin has had disappointing phase III results. Multiple live biotherapeutics are being developed, including freeze thawed and encapsulated versions of faecal microbiota transplantation to improve the practicality of treating patients with recurrent CDI. Alternatives to faecal microbiota transplantation, that aim to improve safety, including a microbial suspension, RBX2660, and a complex spore formulation, SER-109, have progressed to phase II studies. A nontoxigenic C. difficile strain has also shown promise to prevent recurrent CDI. In addition, three C. difficile vaccines have progressed to phase II/III clinical trials. The diverse approaches to treating and preventing CDI offer substantial promise that new treatment options will soon emerge, particular ones that reduce the risk of recurrences.

Epidemiology and Recurrence Rates of Clostridium difficile Infections in Germany: A Secondary Data Analysis.

Introduction Clostridium difficile infection (CDI) is the most common cause of health-care-associated infectious diarrhea. Recurrence rates are as high as 20–30% after standard treatment with metronidazole or vancomycin, and appear to be reduced for patients treated with fidaxomicin. According to the literature, the risk of CDI recurrence increases after the second relapse to 30–65%. Accurate data for Germany are not yet available.MethodsBased on the research database of arvato health analytics (Munich, Germany), a secondary data analysis for the incidence, treatment characteristics and course of CDI was performed. The database included high granular accounting information of about 1.46 million medically insured patients covering the period 2006–2013, being representative for Germany. The analysis was based on new-onset CDI in 2012 in patients which either received outpatient antibiotic therapy for CDI or were hospitalized.ResultsThe ICD-10 coded incidence of CDI in 2012 was 83 cases per 100,000 population. Overall mortality rates within the follow-up period of 1 year were 13.5% in inpatients with primary diagnosis of CDI, compared to 24.3% in inpatients with secondary diagnosis of CDI (P < 0.001), and 7.1% in outpatients (P < 0.001). In the median, patients with secondary diagnosis of CDI remained significantly longer hospitalized (24 vs. 9 days, P < 0.001). First recurrence of CDI was observed in 18.2% of cases with index events. There was a significantly increased risk to suffer a second and third recurrence, reaching 28.4% (P < 0.001), and 30.2% (P = 0.017), respectively. Antibiotic therapy of CDI in outpatients was performed mainly with metronidazole (in 90.8% of index events, 60.0% of first recurrences, and 43.5% of second recurrences).ConclusionThe reported incidence of CDI in Germany is higher than noted previously. The recurrence rates do increase with the number of relapses, but are lower than reported in the literature, despite dominance of metronidazole treatment in outpatients.FundingMSD Sharp & Dohme GmbH, Haar, Germany.

Clinical Effectiveness and Safety of Fecal Microbiota Transplantation in Children for Clostridium Difficile infection: Results from 9 Pediatric Centers in the United States: 2016 ACG Presidential Poster Award

Introduction:Clostridium difficile infection (CDI) is a major public health threat and a rising concern among the pediatric population. Fecal microbiota transplantation (FMT) is a cost-effective therapy for recurrent CDI and universal stool banks have emerged to enable safe and seamless access. Although FMT has been reported among children in small case series, a direct donor (e.g. parent) approach has primarily been employed. Accordingly, there is a paucity of pediatric safety and effectiveness data from stool banks. Methods: Quality assurance data on CDI classification, FMT delivery modality and clinical effectiveness was consecutively collected from 9 pediatric healthcare facilities in the United States between January 16, 2014 and June 1, 2016. Patients were treated with 250mL fecal microbiota preparation (FMP) for lower GI delivery or 30mL FMP for upper GI delivery. The primary outcome was physician-reported clinical cure as per standard of care follow-up. Safety data was assessed through mandatory adverse event (AE) reporting and graded according to NIH criteria. Descriptive statistics and Chi-square analysis for binomial variables was conducted. Results: Among consecutively collected reports, complete safety and effectiveness data was returned for 69 patients, which were included in these analyses. Overall, the clinical cure rate from physician-reported data across all delivery modalities and CDI classifications was 85.5%. Across the pediatric cohort, 69.6% (n=48) of patients were treated by lower GI delivery by colonoscopy (n=46) or enema (n=2) with a cure rate of 80.9%. Additionally, 30.4% (n=21) of the cohort was treated by upper GI delivery by nasogastric (n=11), nasoduodenal (n=1), nasojejunal (n=2) and EGD (n=7) with a clinical cure rate of of 87.5%. There was no statistically significant difference in clinical cure between lower and upper GI delivery (p=0.47). Specifically, clinical cure for colonoscopy (85.4%) and nasogastric delivery (85.1%) was not significantly different (p=0.99). On a priori subgroup analysis, there was no significant difference in clinical cure rate by CDI disease classification and FMP preparation type (Table 1). No adverse events were reported to OpenBiome.Figure 1Conclusion: To our knowledge this is the largest pediatric FMT cohort reported to date. This real-world clinical data suggests that FMT in pediatric CDI has a similar safety and effectiveness profile to FMT in adult CDI. Further long-term follow-up is required to evaluate the long-term safety profile.

Fecal Microbiota Transplant as a Bridge to Organ Transplant: An Alternative Indication for Treatment of C. difficile in a Critically Ill Patient

Clostridium difficile infection (CDI) is a major cause of morbidity and mortality especially in the healthcare setting. Fecal microbiota transplant (FMT) is an emerging treatment for CDI, namely for recurrent or refractory disease. A 57 year old Caucasian male with history of chronic idiopathic pulmonary fibrosis was transferred to our institution for lung transplant evaluation due to worsening oxygen requirement. His course was complicated by respiratory failure requiring mechanical intubation and later veno-venous extracorporeal membrane oxygenation. He required tracheostomy for prolonged mechanical ventilation dependence, and his transplant evaluation was expedited. Seventeen days into his course, he developed severe diarrhea with leukocytosis to 13.1. CDI was confirmed by stool PCR and oral vancomycin with intravenous metronidazole was initiated. Active listing for transplant was put on hold as a result. Our team was consulted for consideration of FMT given that his clinical status and requirement for lung transplant might not allow him to survive a full course of standard CDI therapy despite the fact he did not meet previously suggested criteria for FMT. The patient was subsequently rapidly prepped with 8L of polyethylene glycol solution via nasogastric tube, and CDI treatment was held the evening prior to the procedure. A bedside colonoscopy with FMT was performed in the ICU. Afterwards, the patient was given 4mg of loperamide, and all antibiotics were held. Twenty-four hours later, the patient's leukocytosis decreased to 8.3, and after consultation with the infectious disease service, he was reactivated on the lung transplant list. Six days later, the patient underwent successful double lung transplant. He was empirically treated with a fourteen day course of metronidazole following his operation. The patient continued to clinically improve, and one month after his CDI treatment with FMT, he was discharged to an acute rehabilitation facility. Nine months post-lung transplant, the patient remains free of CDI recurrence despite the need for antibiotics for a subsequent pneumonia and continued immunosuppressive agents. This case was the first at our institution where FMT was used outside of the previously established criteria and suggests a need to include the use of FMT in the critically ill patient in whom active CDI precludes their candidacy for a potentially life-saving intervention.

'Get in Early'; Biofilm and Wax Moth (Galleria mellonella) Models Reveal New Insights into the Therapeutic Potential of Clostridium difficile Bacteriophages.

Clostridium difficile infection (CDI) is a global health threat associated with high rates of morbidity and mortality. Conventional antibiotic CDI therapy can result in treatment failure and recurrent infection. C. difficile produces biofilms which contribute to its virulence and impair antimicrobial activity. Some bacteriophages (phages) can penetrate biofilms and thus could be developed to either replace or supplement antibiotics. Here, we determined the impact of a previously optimized 4-phage cocktail on C. difficile ribotype 014/020 biofilms, and additionally as adjunct to vancomycin treatment in Galleria mellonella larva CDI model. The phages were applied before or after biofilm establishment in vitro, and the impact was analyzed according to turbidity, viability counts and topography as observed using scanning electron and confocal microscopy. The infectivity profiles and efficacies of orally administered phages and/or vancomycin were ascertained by monitoring colonization levels and larval survival rates. Phages prevented biofilm formation, and penetrated established biofilms. A single phage application reduced colonization causing extended longevity in the remedial treatment and prevented disease in the prophylaxis group. Multiple phage doses significantly improved the larval remedial regimen, and this treatment is comparable to vancomycin and the combined treatments. Taken together, our data suggest that the phages significantly reduce C. difficile biofilms, and prevent colonization in the G. mellonella model when used alone or in combination with vancomycin. The phages appear to be highly promising therapeutics in the targeted eradication of CDI and the use of these models has revealed that prophylactic use could be a propitious therapeutic option.

A multi-center study of fidaxomicin use for Clostridium difficile infection.

PurposeFidaxomicin use in real-world clinical practice, especially for severe Clostridium difficile infection (CDI), is mainly based on single-center observational studies. The purpose of this pharmacoepidemiology study was to assess outcomes of patients given fidaxomicin based on episode number and use of concomitant antibiotics.MethodsFidaxomicin use over time across included hospitals in the United States was assessed using a large inpatient drug utilization database. A multicenter retrospective chart review was also conducted of hospitalized patients with CDI that received fidaxomicin between 2011 and 2013. Fidaxomicin utilization and clinical outcomes were stratified by use of fidaxomicin for first or second episode (early episodes) versus greater than or equal to episodes (later episodes).ResultsThe overall fidaxomicin use rate was 2.16 % which increased from 0.22 % in the last two quarters of 2011 to 3.16 % in the first two quarters of 2013. A total of 102 hospitalized patients that received fidaxomicin from 11 hospitals were identified in the multicenter study. Sixty-nine patients received fidaxomicin for early (68 % with severe CDI) and 33 received for later episodes. The majority of patients received other CDI therapy including 61 patients (88 %) for early episodes and 27 (82 %) for later episodes. Concomitant non-CDI antibiotics were received by 48 patients (47 %). Rates of clinical outcomes were similar regardless of CDI episode.ConclusionThis study demonstrated a slow but steady increase in fidaxomicin utilization over time; most of which was combined with other systemic antibiotics. Antimicrobial stewardship teams should provide guidance on appropriate use of fidaxomicin to optimize therapy and assess the need to continue other antibiotics during CDI treatment.

Can we improve the therapy of Clostridium difficile infection in elderly patients?

Clostridium difficile infection (CDI) is becoming aserious problem predominantly in geriatric patients, who are asignificant risk group. The goal of this study was to evaluate the risk factors for mortality in CDI patients and to construct abinary logistic regression model that describes the probability of mortality in geriatric patients suffering from CDI. In this retrospective study, we evaluated agroup of 235 patients over 65 years of age with confirmed diagnoses of CDI, hospitalized at the Department of Internal Medicine, Geriatrics and General Practice, Brno, from January 2008 to December 2013. The examined group comprised 148 women (63 %) and 87 men (37 %). For the diagnosis of CDI, confirmation of A and B toxins in the patients' stool or an autopsy confirmation was crucial. The impact of antibiotic therapy on the increased incidence of CDI was clearly confirmed in our study group when examining patients' histories. Other risk factors included cerebrovascular disease, dementia, the presence of pressure ulcers, and immobility. Our new model consisted of acombination of the following parameters: the number of antibiotics used (from patients' history), nutritional status (Mini Nutritional Assessment short-form test), presence of pressure ulcers, and occurrence of fever. Our logistic regression model may predict mortality in geriatric patients suffering from CDI. This could help improve the therapeutic process.

Bacterial and Fungal Microbiota Changes Distinguish C. difficile Infection from Other Forms of Diarrhea: Results of a Prospective Inpatient Study.

This study sought to characterize the bacterial and fungal microbiota changes associated with Clostridium difficile infection (CDI) among inpatients with diarrhea, in order to further explain the pathogenesis of this infection as well as to potentially guide new CDI therapies. Twenty-four inpatients with diarrhea were enrolled, 12 of whom had CDI. Each patient underwent stool testing for CDI prior to being treated with difficile-directed antibiotics, when appropriate. Clinical data was obtained from the medical record, while each stool sample underwent 16S rRNA and ITS sequencing for bacterial and fungal elements. An analysis of microbial community structures distinct to the CDI population was also performed. The results demonstrated no difference between the CDI and non-CDI cohorts with respect to any previously reported CDI risk factors. Butyrogenic bacteria were enriched in both CDI and non-CDI patients. A previously unreported finding of increased numbers of Akkermansia muciniphila in CDI patients was observed, an organism which degrades mucin and which therefore may provide a selective advantage toward CDI. Fungal elements of the genus Penicillium were predominant in CDI; these organisms produce antibacterial chemicals which may resist recovery of healthy microbiota. The most frequent CDI microbial community networks involved Peptostreptococcaceae and Enterococcus, with decreased population density of Bacteroides. These results suggest that the development of CDI is associated with microbiota changes which are consistently associated with CDI in human subjects. These gut taxa contribute to the intestinal dysbiosis associated with C. difficile infection.

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

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. 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. 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. 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.

Physician Prescribing Behavior in Suspected Clostridium difficile Infection

Background Empirical antibiotic therapy for Clostridium difficile infection (CDI) is associated with adverse effects. We sought to describe physician prescribing behavior with regard to empirical CDI therapy and hypothesized that delays in stool testing results may lead to increased use of empirical therapy. Methods A sample of 100 patients was selected from the population of patients with stool specimens submitted for C difficile enzyme immunoassay testing over a 6-month period. The time between order placement and result posting was compared between patients who received empirical CDI therapy and patients who did not receive empirical therapy. A chart review was conducted to assess for other factors driving physician prescribing behavior. Results The mean time between order submission and result posting was 16.7 hours in the group receiving empirical therapy and 17.6 hours in the group receiving test-guided therapy, with no statistically significant difference between the 2 groups. In univariate analysis, significant factors associated with empirical therapy included leukocytosis (16.5 vs. 10.7), bandemia (7.1% vs. 1.9%), higher Hines Veterans Administration score (1.8 vs. 1.1), diarrhea present on admission (relative risk, 2.3), and ordering of abdominal imaging (relative risk, 2.9). On multivariate regression, leukocytosis and ordering of abdominal imaging remained significant. Conclusions Use of empirical therapy for CDI was not associated with time to stool test results. The decision to use empirical therapy seems to be most related to the presence of leukocytosis and the physician's decision to order abdominal imaging. The pattern of findings suggests a potential component of diagnostic uncertainty driving prescribing behavior.

Impact of Evidence-Based Guidelines on Outcomes of Hospitalized Patients With Clostridium difficile Infection

Clostridium difficile infection (CDI) is the most common healthcare-associated infection in the United States. Clinical practice guidelines for the treatment of CDI were updated in 2010 by the Society for Healthcare Epidemiology of America and the Infectious Diseases Society of America. An institutional guideline for the classification and management of CDI in accordance with the 2010 Society for Healthcare Epidemiology of America/Infectious Diseases Society of America guideline was developed and provided to attending physicians and medical residents in multiple formats. We sought to determine the impact of an evidence-based guideline for the treatment of CDI at a community teaching hospital. A retrospective chart review was conducted to identify length of stay (LOS), readmission rates, direct cost, mortality, and physician adherence to guidelines in patients with International Classification of Diseases, Ninth Edition codes and laboratory confirmation of CDI between February 1, 2013 and January 31, 2014. Endpoints included LOS after diagnosis of CDI, 30-day readmission rates, direct cost after diagnosis of CDI, and mortality. A total of 351 patient encounters were included in the study. Although not statistically significant, it was found that guideline-based therapy (n = 131) was associated with a lower median LOS (6 days vs 8 days; P = 0.06). Thirty-day hospital readmission (25.2% vs 29.5%; P = 0.39) and median cost after diagnosis of CDI ($7238.48 vs $8794.81; P = 0.10) also were lower but not statistically significant. Patients with mild-to-moderate infection were found to have a significantly lower median LOS (5 days vs 7 days; P = 0.03) and median cost after diagnosis ($5257.85 vs $7680.56; P = 0.03) when treated with guideline-based therapy. Overall physician adherence to guidelines was low, at 38%. Treatment with guideline-based therapy for CDI was associated with a trend toward a significantly lower LOS and cost. Barriers to physician adherence to guidelines still exist, despite education and guideline availability. Electronic health record-based order sets or clinical decision tools may improve recognition of and adherence to guidelines.

Breakthroughs in the treatment and prevention of Clostridium difficile infection.

This Review summarizes the latest advances in the treatment and prevention of Clostridium difficile infection (CDI), which is now the most common health-care-associated infection in the USA. As traditional, standard CDI antibiotic therapies (metronidazole and vancomycin) are limited by their broad spectrum and further perturbation of the intestinal microbiota, which result in unacceptably high recurrence rates, novel therapeutic strategies for CDI are needed. Emerging CDI therapies are focused on limiting further perturbation of the intestinal microbiota and/or restoring the microbiota to its pre-morbid state, reducing colonization of the intestinal tract by toxigenic strains of C. difficile and bolstering the host immune response against C. difficile toxins. Fidaxomicin is associated with reduced CDI recurrences, and other emerging narrow-spectrum CDI antibiotic therapies might eventually demonstrate a similar benefit. Prevention of intestinal colonization of toxigenic strains of C. difficile can be achieved through restoration of the intestinal microbiota with faecal microbiota transplantation, as well as by colonizing the gut with nontoxigenic C. difficile strains. Finally, emerging immunological therapies, including monoclonal antibodies and vaccines against C. difficile toxins, might protect against CDI and subsequent CDI recurrences. The available clinical data for these emerging therapies, and their relative advantages and disadvantages, are described.

A Novel Microbiome Therapeutic Increases Gut Microbial Diversity and Prevents Recurrent Clostridium difficile Infection.

Patients with recurrent Clostridium difficile infection (CDI) have a ≥60% risk of relapse, as conventional therapies do not address the underlying gastrointestinal dysbiosis. This exploratory study evaluated the safety and efficacy of bacterial spores for preventing recurrent CDI. Stool specimens from healthy donors were treated with ethanol to eliminate pathogens. The resulting spores were fractionated and encapsulated for oral delivery as SER-109. Following their response to standard-of-care antibiotics, patients in cohort 1 were treated with SER-109 on 2 consecutive days (geometric mean dose, 1.7 × 10(9) spores), and those in cohort 2 were treated on 1 day (geometric mean dose, 1.1 × 10(8) spores). The primary efficacy end point was absence of C. difficile-positive diarrhea during an 8-week follow-up period. Microbiome alterations were assessed. Thirty patients (median age, 66.5 years; 67% female) were enrolled, and 26 (86.7%) met the primary efficacy end point. Three patients with early, self-limiting C. difficile-positive diarrhea did not require antibiotics and tested negative for C. difficile at 8 weeks; thus, 96.7% (29 of 30) achieved clinical resolution. In parallel, gut microbiota rapidly diversified, with durable engraftment of spores and no outgrowth of non-spore-forming bacteria found after SER-109 treatment. Adverse events included mild diarrhea, abdominal pain, and nausea. SER-109 successfully prevented CDI and had a favorable safety profile, supporting a novel microbiome-based intervention as a potential therapy for recurrent CDI.

Effect of an antimicrobial stewardship bundle for patients with Clostridium difficile infection.

The study objective was to determine whether there was an improvement in compliance with recommended Clostridium difficile infection (CDI) treatment after introduction of an institutional CDI bundle with daily antimicrobial stewardship assessment. This was a single-centre, quasi-experimental study evaluating compliance with an antimicrobial stewardship team-implemented care bundle in patients with CDI compared with historical controls. The primary outcome, compliance with overall bundle elements, was achieved when the following measures were accomplished: (i) appropriate CDI antimicrobial therapy based on the institutional treatment algorithm; (ii) discontinuation of acid-suppressant therapy in the absence of a pre-specified indication; and (iii) discontinuation of unnecessary antimicrobials. Secondary objectives were to evaluate the extent to which antimicrobial stewardship involvement affected treatment compliance and to assess trends in CDI clinical outcomes, such as mortality and readmission. One-hundred-and-sixty-nine patients were evaluated; 83 after implementation of the care bundle (bundle group) and 89 prior to bundle implementation (historical control group). Compliance with overall bundle endpoints was significantly higher in the bundle group versus the control group (81% versus 45%, P < 0.001). Individual bundle components that were significantly improved in the bundle group were discontinuation of non-essential acid suppressants (90% versus 18%, P < 0.001) and administration of appropriate CDI therapy (82% versus 64%, P < 0.009). No significant differences were observed in overall or CDI-related mortality or readmissions, durations of therapy or reduction of non-essential concomitant antimicrobials. Introduction of an antimicrobial stewardship bundle for CDI significantly improved adherence to institutional treatment recommendations and overall management of patients with CDI.

The Long-term Efficacy and Safety of Fecal Microbiota Transplant for Recurrent, Severe, and Complicated Clostridium difficile Infection in 146 Elderly Individuals.

Clostridium difficile infection (CDI) in the elderly has a higher prevalence, greater morbidity and mortality, and lower response to conventional treatment than the general population. Fecal microbiota transplant (FMT) is highly effective therapy for CDI but has not been studied specifically in the elderly. This study aims to determine the long-term efficacy and safety of FMT for recurrent (RCDI), severe (SCDI), and complicated (CCDI) CDI in elderly patients. A multicenter, long-term follow-up study was performed with demographic, pre-FMT, and post-FMT data collected from elderly patients with RCDI, SCDI, and CCDI, through a 47-item questionnaire. Outcome measures included primary and secondary cure rates, early (<12 wk) and late (≥12 wk) recurrence rates, and adverse events (AEs), including post-FMT diagnoses. Of 168 eligible patients, 146 patients met the inclusion criteria. Of these, 68.5% were women. The mean (range) age was 78.6 (65 to 97) years and the follow-up period was 12.3 (1 to 48) months. FMT was performed for RCDI in 89 (61%), SCDI in 45 (30.8%), and CCDI in 12 (8.2%) patients. The primary and secondary cure rates were 82.9% and 95.9%, respectively. Early and late recurrences occurred in 25 and 6 patients, respectively. AEs included CDI-negative diarrhea in 7 (4.8%) and constipation in 4 (2.7%) patients. Serious AEs, recorded in 6 patients, were hospital admissions for CDI-related diarrhea, one of which culminated in death. New diagnoses post-FMT included microscopic colitis (2), Sjogren syndrome (1), follicular lymphoma (1), contact dermatitis and idiopathic Bence-Jones proteinuria (1), and laryngeal carcinoma (1)-all, however, were associated with predisposing factors. FMT is a safe and effective treatment option for RCDI, SCDI, and CCDI in elderly patients.

Clostridium difficile infection in patients with liver disease: a review.

Over the past two decades, there has been a dramatic worldwide increase in both the incidence and severity of Clostridium difficile infection (CDI). Paralleling the increased incidence of CDI in the general population, there has been increased interest in CDI among patients with liver disease, particularly in those with liver cirrhosis and post liver transplantation. MEDLINE and several other electronic databases from January 1995 to December 2014 were searched in order to identify potentially relevant literature. Patients with cirrhosis and liver transplant recipients are at high risk for the development CDI because of antibiotics and proton pump inhibitors use, frequent and prolonged hospitalization, immunosuppressant therapy, and multiple comorbidities. Enzyme immunoassay to detect C. difficile toxins A and B in stool remains the most widely used test for CDI diagnosis, although, more recently, polymerase chain reaction (PCR)-based assays have become the preferred diagnostic test in many laboratories. Metronidazole and vancomycin, given orally, have proved to be effective in the treatment of CDI. Both cirrhotic patients and liver transplant recipients with CDI have longer length of hospital stay, increased mortality, and higher healthcare costs than those without CDI. A rapid diagnosis and adequate therapy of CDI are of paramount importance to improve liver disease patients' outcome. The aim of this review is to provide up-to-date information on the epidemiology, risk factors, pathogenesis, treatment, and outcomes in liver disease patients with CDI.