[Pharmaceutical system of fecal microbiota transplantation: Heterogeneous practices]. / Circuit pharmaceutique, transplantation de microbiote fécal : Des pratiques hétérogènes.

OBJECTIVE: To describe current pharmaceutical practice in French hospitals regarding fecal microbiota transplantation in terms of prescription, preparation and compounding, as well as local legislation. MATERIAL AND METHODS: A national survey was conducted at 28 French university hospital centers followed by the sending of a GoogleForm® questionnaire from June to August 2018 in the 16 respondent centers either performing or subcontracting fecal microbiota transplant. RESULTS: All hospitals performing or subcontracting fecal transplant (n=16,%57) report prescription indication of recurrent Clostridium difficile infection treatment, and 6 of them also as part of a clinical trial protocol. In hospitals performing fecal transplant themselves (n=11), the number of pre-donation consultations with donors varies from one (n=6) to two (n=5). Fecal sample is collected at the donor's home in 45% of cases. Route of administration for transplant is either naso-gastric administration (n=4), rectal (n=4) or both (n=5). Fecal samples for transplant are compounded either in the hospital pharmacy (n=73%) or in the laboratory (27%). Thawing methods include refrigeration between 2-8°C (50%), room temperature (25%) and water bath (25%). Billing system and reporting to health authorities are highly heterogeneous from one hospital to another. CONCLUSION: This survey shows significant pharmaceutical practice heterogeneity within French hospitals regarding fecal microbiota transplantation despite the existence of national and European recommendations.

[Recommendations from a panel of experts on the usefulness of fidaxomicin for the treatment of infections caused by Clostridium difficile]. / Recomendaciones de un panel de expertos sobre la utilidad de fidaxomicina para el tratamiento de las infecciones causadas por Clostridium difficile.

OBJECTIVE: Clostridium difficile infections have a high recurrence rate, which can complicate the prognosis of affected patients. It is therefore important to establish an early detection and an appropriate therapeutic strategy. The objective of this manuscript was to gather the opinion of an expert group about the predictive factors of poor progression, as well as when to use fidaxomicin in different groups of high-risk patients. METHODS: A scientific committee of three experts in infectious diseases reviewed the most recent literature on the management of C. difficile infections, and the use of fidaxomicin. They developed a questionnaire of 23 items for consensus by 15 specialists in this type of infection using a modified Delphi method. RESULTS: The consensus reached by the panelists was 91.3% in terms of agreement. The most important agreements were: recurrence is a risk criterion per se; fidaxomicin is effective and safe for the treatment of infections caused by C. difficile in critical patients, immunosuppressed patients, or patients with chronic renal failure; fidaxomicin is recommended from the first episode of infection to ensure maximum efficacy in patients with well-contrasted recurrence risk factors. CONCLUSIONS: The experts consulted showed a high degree of agreement on topics related to the selection of patients with poorer prognosis, as well as on the use of fidaxomicin in groups of high-risk patients, either in the first line or in situations of recurrence.

Clostridium difficile co-infection in inflammatory bowel disease is associated with significantly increased in-hospital mortality.

OBJECTIVE: Inflammatory bowel disease (IBD) patients with Clostridium difficile co-infection (CDCI) have an increased risk of morbidity and mortality. We aim to evaluate the impact of CDCI on in-hospital outcomes among adults with IBD hospitalized in the USA. PATIENTS AND METHODS: Using the 2007-2013 Nationwide Inpatient Sample, hospitalizations among US adults with Crohn's disease (CD), ulcerative colitis (UC) and CDCI were identified using ICD-9 coding. Hospital charges, hospital length of stay (LOS), and in-hospital mortality was stratified by CD and UC and compared using χ-testing and Student's t-test. Predictors of hospital charges, LOS, and in-hospital mortality were evaluated with multivariate regression models and were adjusted for age, sex, race/ethnicity, year, insurance status, hospital characteristics, and CDCI. RESULTS: Among 224 500 IBD hospitalizations (174 629 CD and 49 871 UC), overall prevalence of CDCI was 1.22% in CD and 3.41% in UC. On multivariate linear regression, CDCI was associated with longer LOS among CD [coefficient: 5.30, 95% confidence interval (CI): 4.61-5.99, P<0.001] and UC (coefficient 4.08, 95% CI: 3.54-4.62, P<0.001). Higher hospital charges associated with CDCI were seen among CD (coefficient: $35 720, 95% CI: $30 041-$41 399, P<0.001) and UC (coefficient: $26 009, 95% CI: $20 970-$31 046, P<0.001). On multivariate logistic regression, CDCI was associated with greater risk of in-hospital mortality (CD: odds ratio: 2.74, 95% CI: 1.94-3.87, P<0.001; UC: OR: 5.50, 95% CI: 3.83-7.89, P<0.001). CONCLUSION: Among US adults with CD and UC related hospitalizations, CDCI is associated with significantly greater in-hospital mortality and greater healthcare utilization.

Risk Factors and Costs Associated With Clostridium difficile Colitis in Patients With Prosthetic Joint Infection Undergoing Revision Total Hip Arthroplasty.

BACKGROUND: With the increased demand for primary total hip arthroplasty (THA) and corresponding rise in revision procedures, it is imperative to understand the factors contributing to the development of Clostridium difficile colitis. We aimed to provide a detailed analysis of: (1) the incidence of; (2) the demographics, lengths of stay, and total costs for; and (3) the risk factors and mortality associated with the development of C. difficile colitis after revision THA. METHODS: The National Inpatient Sample database was queried for all individuals diagnosed with a periprosthetic joint infection and who underwent all-component revision THA between 2009 and 2013 (n = 40,876). Patients who developed C. difficile colitis during their inpatient hospital stay were identified. Multilevel logistic regression analysis was conducted to assess the association between hospital- and patient-specific characteristics and the development of C. difficile colitis. RESULTS: The overall incidence of C. difficile colitis after revision THA was 1.7%. These patients were significantly older (74 vs 65 years), had greater lengths of hospital stay (19 vs 9 days), accumulated greater costs ($51,641 vs $28,282), and were more often treated in an urban hospital compared to their counterparts who did not develop C. difficile colitis (P < .001 for all). Patients with colitis also had a significantly higher in-hospital mortality compared to those without (5.6% vs 1.4%; P < .001). CONCLUSION: While C. difficile colitis infection is an uncommon event following revision THA, it can have potentially devastating consequences. Our analysis demonstrates that this infection is associated with a longer hospital stay, higher costs, and greater in-hospital mortality.

Recurrent Clostridium difficile infection among Medicare patients in nursing homes: A population-based cohort study.

We explored the epidemiology and outcomes of Clostridium difficile infection (CDI) recurrence among Medicare patients in a nursing home (NH) whose CDI originated in acute care hospitals.We conducted a retrospective, population-based matched cohort combining Medicare claims with Minimum Data Set 3.0, including all hospitalized patients age ≥65 years transferred to an NH after hospitalization with CDI 1/2011-11/2012. Incident CDI was defined as ICD-9-CM code 008.45 with no others in prior 60 days. CDI recurrence was defined as (within 60 days of last day of CDI treatment): oral metronidazole, oral vancomycin, or fidaxomicin for ≥3 days in part D file; or an ICD-9-CM code for CDI (008.45) during a rehospitalization. Cox proportional hazards and linear models, adjusted for age, gender, race, and comorbidities, examined mortality within 60 days and excess hospital days and costs, in patients with recurrent CDI compared to those without.Among 14,472 survivors of index CDI hospitalization discharged to an NH, 4775 suffered a recurrence. Demographics and clinical characteristics at baseline were similar, as was the risk of death (24.2% with vs 24.4% without). Median number of hospitalizations was 2 (IQR 1-3) among those with and 0 (IQR 0-1) among those without recurrence. Adjusted excess hospital days per patient were 20.3 (95% CI 19.1-21.4) and Medicare reimbursements $12,043 (95% CI $11,469-$12,617) in the group with a recurrence.Although recurrent CDI did not increase the risk of death, it was associated with a far higher risk of rehospitalization, excess hospital days, and costs to Medicare.

Economic evaluation of fecal microbiota transplantation for the treatment of recurrent Clostridium difficile infection in Australia.

BACKGROUND AND AIM: Clostridium difficile is the most common cause of hospital-acquired diarrhea in Australia. In 2013, a randomized controlled trial demonstrated the effectiveness of fecal microbiota transplantation (FMT) for the treatment of recurrent Clostridium difficile infection (CDI). The aim of this study is to evaluate the cost-effectiveness of fecal microbiota transplantation-via either nasoduodenal or colorectal delivery-compared with vancomycin for the treatment of recurrent CDI in Australia. METHODS: A Markov model was developed to compare the cost-effectiveness of fecal microbiota transplantation compared with standard antibiotic therapy. A literature review of clinical evidence informed the structure of the model and the choice of parameter values. Clinical effectiveness was measured in terms of quality-adjusted life years. Uncertainty in the model was explored using probabilistic sensitivity analysis. RESULTS: Both nasoduodenal and colorectal FMT resulted in improved quality of life and reduced cost compared with vancomycin. The incremental effectiveness of either FMT delivery compared with vancomycin was 1.2 (95% CI: 0.1, 2.3) quality-adjusted life years, or 1.4 (95% CI: 0.4, 2.4) life years saved. Treatment with vancomycin resulted in an increased cost of AU$4094 (95% CI: AU$26, AU$8161) compared with nasoduodenal delivery of FMT and AU$4045 (95% CI: -AU$33, AU$8124) compared with colorectal delivery. The mean difference in cost between colorectal and nasoduodenal FMT was not significant. CONCLUSIONS: If FMT, rather than vancomycin, became standard care for recurrent CDI in Australia, the estimated national healthcare savings would be over AU$4000 per treated person, with a substantial increase in quality of life.

[New methodological advances: algorithm proposal for management of Clostridium difficile infection]. / Nuevos avances metodológicos: propuesta de algoritmo para el manejo de la infección por Clostridium difficile.

INTRODUCTION: Clostridium difficile infection (CDI) is considered the most common cause of health care-associated diarrhea and also is an etiologic agent of community diarrhea. The aim of this study was to assess the potential benefit of a test that detects glutamate dehydrogenase (GDH) antigen and C. difficile toxin A/B, simultaneously, followed by detection of C. difficile toxin B (tcdB) gene by PCR as confirmatory assay on discrepant samples, and to propose an algorithm more efficient. MATERIAL AND METHODS: From June 2012 to January 2013 at Hospital Infantil Universitario Niño Jesús, Madrid, the stool samples were studied for the simultaneous detection of GDH and toxin A/B, and also for detection of toxin A/B alone. When results between GDH and toxin A/B were discordant, a single sample for patient was selected for detection of C. difficile toxin B (tcdB) gene. RESULTS: A total of 116 samples (52 patients) were tested. Four were positive and 75 negative for toxigenic C. difficile (Toxin A/B, alone or combined with GDH). C. difficile was detected in the remaining 37 samples but not toxin A/B, regardless of the method used, except one. Twenty of the 37 specimens were further tested for C. difficile toxin B (tcdB) gene and 7 were positive. DISCUSSION: The simultaneous detection of GDH and toxin A/B combined with PCR recovered undiagnosed cases of CDI. In accordance with our data, we propose a two-step algorithm: detection of GDH and PCR (in samples GDH positive). This algorithm could provide a superior cost-benefit ratio in our population.

[Economic burden of Clostridium difficile enterocolitis in German hospitals based on routine DRG data]. / Ökonomische Auswirkungen einer Clostridium-difficile-Enterokolitis in deutschen Krankenhäusern auf der Basis von DRG-Kostendaten.

BACKGROUND: Clostridium difficile associated diarrhea (CDAD) is not only a increasing medical but also economical problem. METHODS: Data from the DRG project group of the German society for digestive and metabolic diseases (DGVS) were analyzed for CDAD. Out of 430,875 cases from 37 German hospitals 2,767 cases were grouped by having CDAD either as primary (PD) or secondary diagnosis (SD; likely to be from a hospital source) in an initial or recurring hospital stay (RD). For comparison non-CDAD cases from the same hospitals from that year where matched using propensity score matching. As endpoints we defined LOS (length of stay), difference of LOS to national average LOS, total costs per case and difference between costs and revenue for all three groups. RESULTS: Patients from the PD group (n = 817) showed a mean LOS of 11.2 days compared to 8.5 days for the control group, 4,132 € mean cost per case (536 € more than control) and a mean loss of -1,064 € per case compared to -636 €. In the SD group (n = 1,840) patients stayed in the hospital for 28.8 days (control: 18.1 days), had costs of 19,381 € (control: 13,082 €) and a loss of -3,442 € compared to -849 € in the control group. Recurring cases (RD; n = 110) showed a LOS of 37.3 days (control: 21.3 days), had even higher costs (20.755 € vs. 13,101 €) and higher losses (-4,196 € vs. -1,109 €). CONCLUSION: By extrapolating these findings CDAD not only harms patients but generates a yearly cost burden of 464 million € for the German healthcare system including a loss of 197 million € for German hospitals. To the authors' opinion sufficient measures against CDAD should include pre hospital risk reduction programs, introduction of effective therapeutic and hygienic strategies in hospitals as well as improvements in documentation for these cases to support further developments of the German DRG system.

Identification of Recurrent Clostridium difficile Infection Using Administrative Codes: Accuracy and Implications for Surveillance.

OBJECTIVE: To develop an algorithm using administrative codes, laboratory data, and medication data to identify recurrent Clostridium difficile infection (CDI) and to examine the sensitivity, specificity, positive and negative predictive values, and performance of this algorithm. METHODS: We identified all patients with 2 or more International Classification of Diseases, Ninth Edition, Clinical Modification (ICD-9-CM) codes for CDI (008.45) from January 1 through December 31, 2013. Information on number of diagnosis codes, stool toxin assays (enzyme immunoassay or polymerase chain reaction), and unique prescriptions for metronidazole and vancomycin was identified. Logistic regression was used to identify independent predictors of recurrent CDI and a predictive model was developed. RESULTS: A total of 591 patients with at least 2 ICD-9 codes for CDI were included (median age, 66 years). The derivation cohort consisted of 157 patients among whom 43 (27%) had recurrent CDI. Presence of 3 or more ICD-9 codes for CDI (odds ratio, 2.49), 2 or more stool tests (odds ratio, 2.88), and 2 or more prescriptions for vancomycin (odds ratio, 5.87) were independently associated with confirmed recurrent CDI. A classifier incorporating 2 or more prescriptions for vancomycin and either 2 or more stool tests or 3 or more ICD-9-CM codes had a positive predictive value of 41% and negative predictive value of 90%. The area under the receiver operating characteristic curve for this combined classifier was modest (0.69). CONCLUSION: Identification of recurrent episodes of CDI in administrative data poses challenges. Accurate assessment of burden requires individual case review to confirm diagnosis.

Outcomes of Clostridium difficile infection in hospitalized leukemia patients: a nationwide analysis.

BACKGROUND The incidence of Clostridium difficile infection (CDI) has increased among hospitalized patients and is a common complication of leukemia. We investigated the risks for and outcomes of CDI in hospitalized leukemia patients. METHODS Adults with a primary diagnosis of leukemia were extracted from the United States Nationwide Inpatient Sample database, 2005-2011. The primary outcomes of interest were CDI incidence, CDI-associated mortality, length of stay (LOS), and charges. In a secondary analysis, we sought to identify independent risk factors for CDI in leukemia patients. Logistic regression was used to derive odds ratios (ORs) adjusted for potential confounders. RESULTS A total of 1,243,107 leukemia hospitalizations were identified. Overall CDI incidence was 3.4% and increased from 3.0% to 3.5% during the 7-year study period. Leukemia patients had 2.6-fold higher risk for CDI than non-leukemia patients, adjusted for LOS. CDI was associated with a 20% increase in mortality of leukemia patients, as well as 2.6 times prolonged LOS and higher hospital charges. Multivariate analysis revealed that age >65 years (OR, 1.13), male gender (OR, 1.14), prolonged LOS, admission to teaching hospital (OR, 1.16), complications of sepsis (OR, 1.83), neutropenia (OR, 1.35), renal failure (OR, 1.18), and bone marrow or stem cell transplantation (OR, 1.27) were significantly associated with CDI occurrence. CONCLUSIONS Hospitalized leukemia patients have greater than twice the risk of CDI than non-leukemia patients. The incidence of CDI in this population increased 16.7% from 2005 to 2011. Development of CDI in leukemia patients was associated with increased mortality, longer LOS, and higher hospital charges.

Prevalence of Clostridium difficile infection presenting to US EDs.

OBJECTIVE: The objective of the study is to determine the prevalence of Clostridium difficile infection (CDI) presenting to emergency departments (EDs) in the United States. Secondary objectives included defining the burden of CDI. METHODS: This is a retrospective, observational cohort study of 2006-2010 Nationwide Emergency Department Sample database of 980 US hospital EDs in 29 states. Prevalence, mortality rate, length of stay, hospital charges, and endemicity were measured. RESULTS: A total of 474513 patients with CDI-related ED visits were identified. From 2006 to 2010, the prevalence of CDI increased from 26.2 to 33.1 per 100,000 population (P<.001). The number of CDI-related ED cases increased 26.1% (P<.001) over the study period: 18.6% from 2006 to 2007 (P<.001), 4.3% from 2007 to 2008 (P=.46), 1.8% from 2008 to 2009 (P=.73), and 0.13% from 2009 to 2010 (P=.95). Emergency department visits occurred more frequently with individuals 85 years or older (relative risk [RR], 13.74; P<.001), females (RR, 1.77; P<.001) and in the northeast United States (RR, 1.42; P<.001). From 2009 to 2010, the mortality rate decreased 17.9% (P=.01). CONCLUSIONS: The prevalence of CDI presenting to EDs increased each year from 2006 to 2010; however, the rate of increase slowed from each year to the next. The mortality rate increased from 2006 to 2009 and decreased significantly from 2009 to 2010. C difficile infection visits presenting to EDs occurred more frequently with older individuals, females, and in the northeast.

Attributable inpatient costs of recurrent Clostridium difficile infections.

OBJECTIVE: To determine the attributable inpatient costs of recurrent Clostridium difficile infections (CDIs). DESIGN: Retrospective cohort study. SETTING: Academic, urban, tertiary care hospital. PATIENTS: A total of 3,958 patients aged 18 years or more who developed an initial CDI episode from 2003 through 2009. METHODS: Data were collected electronically from hospital administrative databases and were supplemented with chart review. Patients with an index CDI episode during the study period were followed up for 180 days from the end of their index hospitalization or the end of their index CDI antibiotic treatment (whichever occurred later). Total hospital costs during the outcome period for patients with recurrent versus a single episode of CDI were analyzed using zero-inflated lognormal models. RESULTS: There were 421 persons with recurrent CDI (recurrence rate, 10.6%). Recurrent CDI case patients were significantly more likely than persons without recurrence to have any hospital costs during the outcome period (P < .001). The estimated attributable cost of recurrent CDI was $11,631 (95% confidence interval, $8,937-$14,588). CONCLUSIONS: The attributable costs of recurrent CDI are considerable. Patients with recurrent CDI are significantly more likely to have inpatient hospital costs than patients who do not develop recurrences. Better strategies to predict and prevent CDI recurrences are needed.

Clostridium difficile infection after colorectal surgery: a rare but costly complication.

BACKGROUND: The incidence and virulence of Clostridium difficile infection (CDI) are on the rise. The characteristics of patients who develop CDI following colorectal resection have been infrequently studied. MATERIALS AND METHODS: We utilized the University HealthSystem Consortium database to identify adult patients undergoing colorectal surgery between 2008 and 2012. We examined the patient-related risk factors for CDI and 30-day outcomes related to its occurrence. RESULTS: A total of 84,648 patients met our inclusion criteria, of which the average age was 60 years and 50% were female. CDI occurred in 1,266 (1.5%) patients during the years under study. The strongest predictors of CDI were emergent procedure, inflammatory bowel disease (IBD), and major/extreme APR-DRG severity of illness score. CDI was associated with a higher rate of complications, intensive care unit (ICU) admission, longer preoperative inpatient stay, 30-day readmission rate, and death within 30 days compared to non-CDI patients. Cost of the index stay was, on average, $14,130 higher for CDI patients compared with non-CDI patients. CONCLUSION: Emergent procedures, higher severity of illness, and inflammatory bowel disease are significant risk factors for postoperative CDI in patients undergoing colorectal surgery. Once established, CDI is associated with worse outcomes and higher costs. The poor outcomes of these patients and increased costs highlight the importance of prevention strategies targeting high-risk patients.

A review of the economics of treating Clostridium difficile infection.

Clostridium difficile infection (CDI) is a costly result of antibiotic use, responsible for an estimated 14,000 deaths annually in the USA according to the Centers for Disease Control and Prevention. Annual costs attributable to CDI are in excess of $US 1 billion. This review summarizes appropriate utilization of prevention and treatment methods for CDI that have the potential to reduce the economic and humanistic costs of the disease. Some cost-effective strategies to prevent CDI include screening and isolation of hospital admissions based on C. difficile carriage to reduce transmission in the inpatient setting, and probiotics, which are potentially efficacious in preventing CDI in the appropriate patient population. The most extensively studied agents for treatment of CDI are metronidazole, vancomycin, and fidaxomicin. Most economic comparisons between metronidazole and vancomycin favor vancomycin, especially with the emergence of metronidazole-resistant C. difficile strains. Metronidazole can only be recommended for mild disease. Moderate to severe CDI should be treated with vancomycin, preferably the compounded oral solution, which provides the most cost-effective therapeutic option. Fidaxomicin offers a clinically effective and potentially cost-effective alternative for treating moderate CDI in patients who do not have the NAP1/BI/027 strain of C. difficile. Probiotics and fecal microbiota transplant have variable efficacy and the US FDA does not currently regulate the content; the potential economic advantages of these treatment modalities are currently unknown.

Validation of the 3-day rule for stool bacterial tests in Japan.

OBJECTIVE: Stool cultures are expensive and time consuming, and the positive rate of enteric pathogens in cases of nosocomial diarrhea is low. The 3-day rule, whereby clinicians order a Clostridium difficile (CD) toxin test rather than a stool culture for inpatients developing diarrhea >3 days after admission, has been well studied in Western countries. The present study sought to validate the 3-day rule in an acute care hospital setting in Japan. METHODS: Stool bacterial and CD toxin test results for adult patients hospitalized in an acute care hospital in 2008 were retrospectively analyzed. Specimens collected after an initial positive test were excluded. The positive rate and cost-effectiveness of the tests were compared among three patient groups. PATIENTS: The adult patients were divided into three groups for comparison: outpatients, patients hospitalized for ≤3 days and patients hospitalized for ≥4 days. RESULTS: Over the 12-month period, 1,597 stool cultures were obtained from 992 patients, and 880 CD toxin tests were performed in 529 patients. In the outpatient, inpatient ≤3 days and inpatient ≥4 days groups, the rate of positive stool cultures was 14.2%, 3.6% and 1.3% and that of positive CD toxin tests was 1.9%, 7.1% and 8.5%, respectively. The medical costs required to obtain one positive result were 9,181, 36,075 and 103,600 JPY and 43,200, 11,333 and 9,410 JPY, respectively. CONCLUSION: The 3-day rule was validated for the first time in a setting other than a Western country. Our results revealed that the "3-day rule" is also useful and cost-effective in Japan.

Active surveillance for carbapenem-resistant Enterobacteriaceae using stool specimens submitted for testing for Clostridium difficile.

Active surveillance to identify asymptomatic carriers of carbapenem-resistant Enterobacteriaceae (CRE) is a recommended strategy for CRE control in healthcare facilities. Active surveillance using stool specimens tested for Clostridium difficile is a relatively low-cost strategy to detect CRE carriers. Further evaluation of this and other risk factor-based active surveillance strategies is warranted.

A simulation-based assessment of strategies to control Clostridium difficile transmission and infection.

BACKGROUND: Clostridium difficile is one of the most common and important nosocomial pathogens, causing severe gastrointestinal disease in hospitalized patients. Although "bundled" interventions have been proposed and promoted, optimal control strategies remain unknown. METHODS: We designed an agent-based computer simulation of nosocomial C. difficile transmission and infection, which included components such as: patients and health care workers, and their interactions; room contamination via C. difficile shedding; C. difficile hand carriage and removal via hand hygiene; patient acquisition of C. difficile via contact with contaminated rooms or health care workers; and patient antimicrobial use. We then introduced six interventions, alone and "bundled" together: aggressive C. difficile testing; empiric isolation and treatment of symptomatic patients; improved adherence to hand hygiene and contact precautions; improved use of soap and water for hand hygiene; and improved environmental cleaning. All interventions were tested using values representing base-case, typical intervention, and optimal intervention scenarios. FINDINGS: In the base-case scenario, C. difficile infection rates ranged from 8-21 cases/10,000 patient-days, with a case detection fraction between 32%-50%. Implementing the "bundle" at typical intervention levels had a large impact on C. difficile acquisition and infection rates, although intensifying the intervention to optimal levels had much less additional impact. Most of the impact came from improved hand hygiene and empiric isolation and treatment of suspected C. difficile cases. CONCLUSION: A "bundled" intervention is likely to reduce nosocomial C. difficile infection rates, even under typical implementation conditions. Real-world implementation of the "bundle" should focus on those components of the intervention that are likely to produce the greatest impact on C. difficile infection rates, such as hand hygiene and empiric isolation and treatment of suspected cases.