Therapy For Clostridium Difficile Infection Research Articles

Nutritional support in the complex therapy of clostridial infection after surgery

This article presents the tactics of nutritional support in a patient with pseudomembranous colitis after repeated consecutive operations on the abdominal organs, which led to significant violations of the nutritional status. Competent, individually selected correction of protein-energy deficiency in patients with pseudomembranous colitis allows achieving an effective treatment result, avoiding severe complications such as perforation, toxic dilatation, and bleeding. The peculiarity of this clinical case is that a patient with perforation of Meckels diverticulum and abdominal abscess developed a complication secondary widespread peritonitis, phlegmon, which required repeated surgical interventions. Surgical treatment and massive antibiotic therapy led to the development of Clostridium difficile infection: during the treatment the patient developed multiple loose stools and C. difficile toxins A and B were detected. Severe pseudomembranous colitis was accompanied by protein-energy deficiency (hypoproteinemia, hypoalbuminemia), severe dehydration, hypokalemia, hyponatremia, and moderately severe anemia of complex genesis. When selecting nutritional support for patients with clostridial infection, it is important to take into account severe systemic inflammation, which affects the absorption and absorption of the intestinal wall, which in turn determines the route of introduction of nutrient substrates. In this case we needed to choose the right method for correcting the patients nutritional status.

Future of Engineered Phage Therapy for Clostridium difficile Infections

Future of Engineered Phage Therapy for Clostridium difficile Infections

Inflammatory bowel disease and Clostridium difficile infection: clinical presentation, diagnosis, and management.

As a frequent complication of inflammatory bowel disease (IBD), Clostridium difficile infection (CDI) was confirmed to not only aggravate the symptoms of IBD but also result in unexpected outcomes, including death. With the increasing prevalence rate of IBD and the updating of CDI diagnosis, the incidence of CDI in IBD patients is also seen rising. Although a detection method consisting of glutamate dehydrogenase immunoassay or nucleic acid amplification test and then toxin A/B enzyme immunoassay was recommended and widely adopted, the diagnosis of CDI in IBD is still a challenge because of the overlap between the symptoms of CDI in IBD and CDI itself. Vancomycin and fidaxomicin are the first-line therapy for CDI in IBD; however, the treatment has different effects due to the complexity of IBD patients' conditions and the choice of different treatment schemes. Although the use of fecal microbial transplantation is now in the ascendant for IBD management, the prospects are still uncertain and the prevention and treatment of the recurrence of CDI in IBD remain a clinical challenge. In this paper, the epidemiology, pathophysiology, clinical manifestation, prevention, and therapy of CDI in IBD were summarized and presented.

Efficacy and safety of fecal microbiota transplant for recurrent Clostridium difficile infection in inflammatory bowel disease: a systematic review and meta-analysis.

the objective of this systematic review and meta-analysis was to evaluate the outcomes of fecal microbiota transplantation (FMT) therapy for recurrent Clostridium difficile infection (CDI) in inflammatory bowel disease (IBD) patients. electronic databases were searched for studies reporting on the efficacy and/or safety of FMT therapy for recurrent CDI in IBD. The meta-prop command of the meta package in R was used to assess efficacy and safety. Subgroup analyses were performed to explore heterogeneity regarding all outcomes. eleven trials were included in the study. A pooled analysis showed that the initial cure rate of recurrent CDI among IBD patients was 80 % (95 % CI, 0.76, 0.84), and the overall cure rate after two or more FMT procedures was 90 % (95 % CI, 0.84, 0.94). The recurrence rate post-FMT therapy was 25 % (95 % CI: 0.20, 0.32). Sub-analyses suggested that the initial cure rate of CDI in ulcerative colitis (UC) patients was higher than in Crohn's disease (CD) patients (85 % vs. 79 %), with no statistically significant differences (p > 0.05). No serious adverse events were noted in any of the patients post-FMT. FMT is an effective and safe treatment for recurrent CDI in patients with IBD. FMT should be considered early in cases of recurrent or refractory CDI. Multiple FMT procedures can improve the cure rate of CDI.

The potential of microbiome replacement therapies for Clostridium difficile infection.

There is a paradox when treating Clostridium difficile infection (CDI); treatment antibiotics reduce C. difficile colonization but cause further microbiota disruption and can lead to recurrent disease. The success of faecal microbiota transplants (FMT) in treating CDI has become a new research area in microbiome restorative therapies but are they a viable long-term treatment option? C. difficile displays metabolic flexibility to use different nutritional sources during CDI. Using microbiome therapies for the efficient restoration of bile homeostasis and to reduce the bioavailability of preferential nutrients will target the germination ability of C. difficile spores and the growth rate of vegetative cells. Several biotechnology companies have developed microbiome therapeutics for treating CDI, which are undergoing clinical trials. There is confidence in using restorative microbiome therapies for treating CDI after the demonstrated efficacy of FMT, where several biotechnology companies are aiming to supply what would be a 'first in class' treatment option. Efficient removal of C. difficile from the different intestinal biogeographies should be considered in future microbiome therapies. With the gut microbiota implicated in different diseases, more work is needed to assess the long-term consequences of microbiome therapies.

Fecal Microbiota Transplantation and Medical Therapy for Clostridium difficile Infection : Meta-analysis of Randomized Controlled Trials.

The aim was to assess the effectiveness of fecal microbiota transplantation (FMT) against medical therapy (MT). FMT has shown good outcomes in the treatment of Clostridium difficile infection (CDI). We aimed to conduct a systematic review and meta-analysis to compare the effectiveness of FMT versus MT for CDI. We performed a comprehensive search to identify randomized controlled trials comparing FMT against MT in patients with CDI. Outcomes of interest were clinical cure as determined by the resolution of diarrhea and/or negative C. difficile testing. Primary CDI is defined as the first episode of CDI confirmed endoscopically or by laboratory analysis. Recurrent C. difficile infection (RCDI) is defined as laboratory or endoscopically confirmed episode of CDI after at least 1 course of approved antibiotic regimen. A total of 7 studies with 238 patients were included in meta-analysis. Compared with MT, FMT did not have a statistically significant difference for clinical cure of combined primary and RCDI after first session [risk ratio (RR): 1.52, 95% confidence interval (CI): 0.90, 2.58; P =0.12; I2 =77%] and multiple sessions of FMT (RR: 1.68; CI: 0.96, 2.94; P =0.07; I2 =82%). On subgroup analysis, FMT has statistically higher rate of response than MT (RR: 2.41; CI: 1.20, 4.83; I2 =78%) for RCDI. However, for primary CDI there is no statistically significant difference between FMT and MT (RR: 1.00; CI: 0.72, 1.39; I2 =0%). As per our analysis, FMT should not be utilized for every patient with CDI. It is more effective in RCDI, but the results were not significant in patients with primary CDI.

Intracolonic Administration of Vancomycin in Intensive Care Unit Patients with Severe Clostridium Difficile Colitis.

Background: Clostridium difficile infection (CDI) is a major cause of antibiotic-associated diarrhea worldwide. The incidence of sepsis has been shown to be increasing due to severe or fulminant colitis. Oral vancomycin is the treatment of choice for CDI, but it is often ineffective in patients in the intensive care unit (ICU) due to poor intestinal motility. We present a review of eight cases with severe to fulminant CDI treated with adjunctive intracolonic vancomycin (ICV) administration.Methods: A retrospective chart review identified patients in sepsis with severe colitis and positive Clostridium difficile toxin A or B. Patients who had failed standard therapy for CDI were given adjunctive ICV through an enteric tube, which was inserted via colonoscopy. To indicate the severity of patients, the patients selected had required vasopressor support.Results: Eight patients (37.5% females) received this adjunctive treatment; the mean age was 73.25. The average Acute Physiology and Chronic Health Evaluation (APACHE) 2 score at the time of the procedure was 39. The median length of stay was 5.5 days, with in-hospital mortality of 37.5% and an average time to death of 1.33 days from the day of colonoscopy. Conclusion: Colonoscopic decompression and administration of vancomycin for fulminant CDI using an enteric tube can have favorable outcomes in severely ill patients whose surgical options carry a high risk of mortality. Further larger randomized controlled trials are needed to evaluate its efficacy.

The Trend for Antibiotic Use for Clostridioides (Clostridium) difficile Infection in Japan.

In Japan, there is no national surveillance study of Clostridioides (Clostridium) difficile infection (CDI), and details about the epidemiology and treatment status of CDI are unknown. Additionally, clinical practice guidelines (CPGs) for CDI are published by four different institutions. All CPGs recommend that the antimicrobials, vancomycin (VCM) and metronidazole (MNZ), should be selected according to disease severity. However, the trends for VCM and MNZ use in Japan remain unclear. Therefore, this study was aimed at clarifying the secular trends for VCM and MNZ use based on sales data from 2006 to 2015 and discussing its impact on CDI status and drug costs. This is the first study to clarify the antibiotic use trends for CDI treatment. We found that the total use increased over time (r = 0.0013, Pfor trend < 0.0001). While VCM use significantly decreased (r = -0.0003, Pfor trend = 0.0002), MNZ use increased (r = 0.0017, Pfor trend < 0.0001). These results show that although treatment for CDI was in line with CPGs, CDI incidence might be on an increasing trend. Additionally, despite the increased total use, the total drug costs decreased by 55% ($ 25 million) from 2006 to 2015. It was also surmised that CDI treatment in compliance with CPGs would lead to a reduction in drug costs. Hence, to understand the epidemiology of CDI, it is important to continuously investigate the use of drugs used for CDI therapy.

LC–MS/MS based observation of Clostridium difficile inhibition by Lactobacillus rhamnosus GG

Clostridium difficile is a spore-forming obligate anaerobe that most commonly causes nosocomial disease, such as diarrhea and colitis. Although antibiotic treatment has been used for Clostridium difficile infection (CDI), its use can also lethally cause antibiotic-associated CDI with the risk of antibiotic resistance. Recently, to avoid these problems, probiotics therapies for CDI have been introduced and studied. However, the molecular mechanisms of C. difficile induced by probiotics, such as Lactobacillus rhamnosus GG (LGG), and associated pathways, have rarely been studied. Here, we co-cultured C. difficile and LGG, which is a promising candidate for treating CDI, in a transwell platform to profile metabolic and proteomic changes of C. difficile with mass spectrometric methods. In the co-cultured condition with LGG, energy generation pathways related to C. difficile growth, such as Stickland reactions and butyrate metabolism, were significantly inhibited, resulting in the decrease of growth rate. In particular, the inhibition of Stickland reactions had a negative effect on the toxin production of C. difficile. In addition, metabolic changes in purine biosynthesis that is known to play an important role in the life of bacteria were observed. Finally, we briefly discussed proteins involved in major iron uptake and electron transfer, as well as the chaperone proteins in bacteria that showed changes by LGG. These results demonstrate that metabolic alterations in C. difficile by LGG caused growth inhibition. Our in vitro co-culture model and multi-omics approach will not only provide better understanding of pathogen-probiotics interaction, but will also contribute to functional study, such as probiotics screening or probiotics engineering, for the therapy of disease caused by pathogenic bacteria.

Clinical practice guidelines for Clostridioides (Clostridium) difficile infection and fecal microbiota transplant protocol - recommendations of the Polish Society od Epidemiology and Infectious Diseases.

Symptomatic Clostridium difficile infection (CDI) is an acute inflammatory disease of the gastrointestinal tract, manifesting in at least 3 unformed stools within 24 hours. Predicting factors for CDI include contact with medical care (mainly hospitalization), antibiotic therapy in the last 12 weeks, use of proton pump inhibitors (PPI), H2 blockers, cancer chemotherapy, especially in the neutropenia stage, gastrointestinal surgery, advanced age and concomitant chronic diseases (renal failure, liver failure, chronic inflammatory bowel disease - especially ulcerative bowel disease, cancer, HIV infection, cachexia and hypoalbuminaemia) and vitamin D deficiency. Clinical classification distinguishes three types of CDI - mild / moderate, severe, and fulminant. The principles of treatment of the first and subsequent CDI incidents depending on the clinical course are based on oral vancomycin. CDI is recurrent. The basis for treating CDI relapses is vancomycin administered orally at a dose of 4x125 mg for 10 days followed by concomitant vancomycin dose reduction therapy. The use of fecal microbiota transfer (FMT) in the treatment of CDI relapses is considered to be the most effective therapy for recurrent CDI. An indication for FMT is antibiotic-resistant C. difficile infection, regardless of the number of incidents CDI. The panel of tests recommended for a bacterial flora donor is presented in the recommendations.

Fecal microbiota transplantation in children does not significantly alter body mass index

Fecal microbiota transplantation (FMT) is nowadays a promising therapy for Clostridium difficile infection (CDI) and a potential treatment for ulcerative colitis. However, it is still unclear whether the changes in intestinal microbiome will affect energy homeostasis or metabolism. This brings an intriguing question whether FMT from healthy donors affects recipient's body mass index (BMI). In our randomized placebo-controlled study children patients with CDI or ulcerative colitis were randomly divided into control and FMT groups. The change of post-FMT BMI percentile at 1, 3, 6, 12 months was calculated. The age range of CDI cohort was 1 to 17 years, while the range was 8 to 21 years for ulcerative colitis cohort. We found that the BMI percentile was insignificantly changed by ‒0.7%, ‒1.8%, 1.3%, 4.6% in CDI, while by 3.6%, ‒3.3%, 3.7%, 7.1% in ulcerative colitis at 1, 3, 6, 12 months after FMT ("‒" means decrease). We concluded that FMT from healthy donors does not significantly alter BMI in children with CDI and ulcerative colitis over 12 months.

Fecal microbiota transplantation for Clostridium difficile infection in Taiwan: Establishment and implementation.

Clostridium difficile infection (CDI) remains a major public health issue, and fecal microbiota transplantation (FMT) has become one of the standard therapies for recurrent or refractory CDI. When compared to medical therapies, such as metronidazole or vancomycin, FMT has a high rate of treatment response with acceptable safety and efficiency. Following promulgation of the amendments in September 2018 in Taiwan, FMT has been indicated for recurrent or refractory CDI. The Taiwan Microbiota Consortium contributed to the Taiwan FMT Expert Consensus, which established basic norms and stipulated essential principles, including the indications for transplantation, eligible locations and personnel, donor screening policies, fecal sample handling, and post-FMT follow-up. However, establishing an eligible FMT team in a qualified hospital remains a clinical challenge, and the requirement for facilities and well-screened donors impedes the implementation of FMT. In this review, we aim to provide domestic FMT teams with explicit instructions to facilitate realization and increase the practice of FMT. Based on the Taiwan FMT Expert Consensus and current regulations, we performed a literature review and integrated the experiences of Taiwanese multidisciplinary experts into this article. The content intends to offer clinicians up-to-date evidence and highlight the essential points of FMT.

Fecal Microbiota Transplantation: Past, Present and Future

In this review, we have summarized the latest evidence, indications, and methods of fecal microbiota transplantation (FMT), and analyzed the prospects and therapeutic potentials of this procedure. In recent years, FMT has attracted great interest, especially due to the global Clostridium difficile infection (CDI). FMT is now recommended as alternative therapy for recurrent CDI when standard treatment with antibiotics fails. It involves putting suspended biomaterial with intestinal microorganisms of a healthy donor into the intestine of a patient. Although the exact mechanism of action is not entirely clear, it is believed to restore the composition and function of the intestinal microbiota in diseased patients. The efficacy varies depending on the route of administration, quality and volume of donor biomaterial, and treatment before the procedure.

Impact of Clostridium difficile infection on gastrointestinal malignancies.

e15586 Background: According to the Centers for Disease Control and Prevention, there were half a million documented cases with 83,000 re-infections and 29,000 deaths due to Clostridium Difficile Infection(CDI) in the year 2011. The influence of CDI on outcomes in gastrointestinal(GI) malignancies is not well described, although the incidence is known to be higher in this subgroup of patients. Methods: National Inpatient Sample 1999-2014 was analyzed to identify adult admissions (&gt;18 years of age) using ICD-9-CM codes with a primary diagnosis of esophageal(EC), Gastric(GC), Colorectal(CRC), Small intestinal(SIC), Hepatobiliary(HCC) and Pancreatic(PC) cancers. ICD-9 code 00845 was used to stratify these for the presence of CDI. We performed Chi-Square test to determine the in-hospital mortality percentage, and Cox Proportional Hazard model to control for confounders and determine the Hazard Ratio(HR) of death within 30 days of admission during hospitalization in patients with and without CDI. Results: See Table. Conclusions: Despite controlling for potential confounders, patients with GI cancers and CDI are at an increased risk of death compared to those without CDI. Taking the more detrimental effects of CDI in this subgroup of patients into consideration, healthcare professionals should strive to avoid the inordinate use of antibiotics and strictly maintain current guidelines designed to prevent spread. It may be prudent to treat these patients as severe CDI, even if current criteria are not met. More scientific research is warranted in analyzing the specific outcomes of CDI in GI cancer patients and if more aggressive therapy for CDI is warranted, considering the limitations of this study. [Table: see text]

Treatment and Prevention of Recurrent Clostridium difficile Infection with Functionalized Bovine Antibody-Enriched Whey in a Hamster Primary Infection Model.

Toxin-induced Clostridium difficile infection (CDI) is a major disease characterized by severe diarrhea and high morbidity rates. The aim with this study was to develop an alternative drug for the treatment of CDI. Cows were repeatedly immunized to establish specific immunoglobulin G and A titers against toxins A (TcdA) and B (TcdB) and against C. difficile cells in mature milk or colostrum. The effect of three different concentrations of anti-C. difficile whey protein isolates (anti-CD-WPI) and the standard of care antibiotic vancomycin were investigated in an animal model of CD infected hamsters (6 groups, with 10 hamsters each). WPI obtained from the milk of exactly the same cows pre-immunization and a vehicle group served as negative controls. The survival of hamsters receiving anti-CD-WPI was 50, 80 and 100% compared to 10 and 0% for the control groups, respectively. Vancomycin suppressed the growth of C. difficile and thus protected the hamsters at the time of administration, but 90% of these hamsters nevertheless died shortly after discontinuation of treatment. In contrast, the surviving hamsters of the anti-CD-WPI groups survived the entire study period, although they were treated for only 75 h. The specific antibodies not only inactivated the toxins for initial suppression of CDI, but also provoked the inhibition of C. difficile growth after discontinuation, thus preventing recurrence. Oral administration of anti-CD-WPI is a functional therapy of CDI in infected hamsters for both primary treatment and prevention of recurrence. Thus, anti-CD-WPI could address the urgent unmet medical need for treating and preventing recurrent CDI in humans.

Impact of clostridium difficile infection on gastrointestinal malignancies.

170 Background: According to the Centers for Disease Control and Prevention, there were half a million documented cases with 83,000 re-infections and 29,000 deaths due to Clostridium Difficile Infection(CDI) in the year 2011. The influence of CDI on outcomes in gastrointestinal(GI) malignancies is not well described, although the incidence is known to be higher in this subgroup of patients. Methods: National Inpatient Sample 1999-2014 was analyzed to identify adult admissions (&gt;18 years of age) using ICD-9-CM codes with a primary diagnosis of esophageal(EC), Gastric(GC), Colorectal(CRC), Small intestinal(SIC), Hepatobiliary(HCC) and Pancreatic(PC) cancers. ICD-9 code 00845 was used to stratify these for the presence of CDI. We performed Chi-Square test to determine the in-hospital mortality percentage, and Cox Proportional Hazard model to control for confounders and determine the Hazard Ratio(HR) of death within 30 days of admission during hospitalization in patients with and without CDI. Results: See table. Conclusions: Despite controlling for potential confounders, patients with GI cancers and CDI are at an increased risk of death compared to those without CDI. Taking the more detrimental effects of CDI in this subgroup of patients into consideration, healthcare professionals should strive to avoid the inordinate use of antibiotics and strictly maintain current guidelines designed to prevent spread. It may be prudent to treat these patients as severe CDI, even if current criteria are not met. More scientific research is warranted in analyzing the specific outcomes of CDI in GI cancer patients and if more aggressive therapy for CDI is warranted, considering the limitations of this study. [Table: see text]

Risk factors for recurrent Clostridium difficile infection among patients in the Clinical Centre of Vojvodina, Serbia: A retrospective clinical trial

Background/Aim. In the last two decades the incidence of recurrent Clostridium difficile infection (CDI) has risen. The aim of this study was to determine the risk factors for the recurrent CDI among patients hospitalized with the initial CDI. Methods. We conducted a retrospective clinical trial at the Clinic for Infectious Diseases, Clinical Center of Vojvodina, Serbia, between January 2010 and January 2016. We enrolled 488 patients with the initial CDI who were treated with oral vancomycin (125 mg, 4 times per day) or oral metronidazole (400 mg, 3 times per day) for 10 days. After the completion of therapy, there was 60 days of the follow-up period for the assessment of the rates of relapse. To determine the risk factors for the CDI relapse, we compared the demographics, clinical and laboratory characteristics of the patients who had a relapse with the patients who had a stable clinical response. Results. Of the 488 cases, 29.09% recurred. The relapse occured in 22.72% patients who received vancomycin and in 36.60% patients treated with metronidazole (p = 0.038). A statistically significant effect on the CDI relapse had the comorbidities such as a malignancies (19.52% vs 8.82%, p = 0.023) and the postoperative CDI (25.67% vs 10.29%, p = 0.035), hipoalbuminemia (&lt; 25 g/L) (70.27% vs 41.94%; p = 0.034) and the concomitant antibiotic therapy (50.67% vs 20.29%; p = 0.031). The persistence of C. difficile toxin in the stool at the end of treatment was registered in 22.32% of patients treated with metronidazole vs 9.09% of patients given vancomycin (p = 0.03). Conclusion. Our data suggest that the important risk factors for the CDI relapse are comorbidities (surgery within a month before developing CDI and malignancy), hipoalbuminemia (&lt; 25g/L) and concomitant non-CDI antibiotics therapy. Vancomycin is more effective than metronidazole in the elimination of C. difficile toxins. The presence of C. difficile toxins in the stool after the successful completion of the initial CDI therapy does not affect significantly the occurrence of relapse.

2367. Infection Incidence and Utilization of Antimicrobials in Physician Office Infusion Centers (POICs)

BackgroundPOICs offer a controlled setting for safe and effective outpatient treatment of moderate to severe infections with intravenous antimicrobial agents (IVAA) and agents used in treatment of Clostridium difficile infection (CDI). These therapies are provided via in-office or home administration. This study provides an overview of nationwide incidence of outpatient infections and utilization of IVAAs through POICs.MethodsA retrospective review of our centralized database was conducted of patient infections and therapy courses provided in POICs nationally that included complete data for 2017. All patients receiving IVAAs and drugs for CDI were included, along with dose, frequency, duration and method of administration. Descriptive measures were used to analyze data.ResultsA total of 12,930 infections were treated in 10,136 patients during 2017 among 77 POICs. Of those, 41% were treated directly from the community setting, avoiding hospitalization. Age distribution was <18 years <1%, 18–65 years 63% and >65 years 36%. Infections comprised 11 major diagnostic groups, with 47 subgroups. The most common diagnoses treated were bone and joint (37%), skin and skin structure (23%), genitourinary (14%) and bacteremia/septicemia (8%). 101 patients (1%) were treated for CDI. Geographical distribution occurred in the Midwest, Northeast, South, and West portion of the United States, where diagnoses were similar for all areas except the Northeast. This area had a significantly lower incidence of bone and joint infections (P < 0.0001) and a higher incidence of genitourinary infections (P < 0.0001). Overall utilization included 52 different agents, with 98.5% antimicrobials, 1% antifungals and 0.5% antivirals. Ceftriaxone was the most frequently used antimicrobial representing 16% of the total use, followed by vancomycin (14.5%), daptomycin (14.2%) and ertapenem (11%). The most prevalent infections and utilization of respective drug therapy is noted in the table. ConclusionThis study provides an annual overview of outpatient infection incidence with the utilization of IVAAs and therapy for CDI. A wide range of moderate to severe infections were treated, often avoiding hospitalization. Treatment regimens were broad, utilizing a wide variety of drugs and enabling extensive patient management in the POIC setting.Disclosures L. J. Van Anglen, Merck & Co.: Grant Investigator, Research grant.

1361. Pharmacokinetics and Safety of Ridinilazole (RDZ), a Potential New Therapy for Clostridium difficile Infection (CDI): From Animal Models to Patients

BackgroundCDI is the leading cause of nosocomial diarrhea associated with 29,000 deaths p.a. in the United States. RDZ is a novel oral drug highly selective for C. difficile limiting collateral damage to the gut microbiota. Here we present a combined analysis of all pharmacokinetic (PK) and tolerability data obtained throughout the development of RDZ from animal models to Phase 2, including new human PK data.MethodsRDZ levels were measured in plasma and in the GI tract of infected hamster after a single oral dose at 25 mg/kg. Quantitative whole-body autoradiography (QWBA) and excretion mass balance studies were performed in rats following a single 50 mg/kg oral dose of 14C RDZ. In GLP toxicology studies, RDZ was administered orally for 28 days to dogs and rats at 1,000 mg/kg/day. Toxicokinetic, clinical pathology, and histopathology analysis were performed. The Phase 1 study enrolled 56 healthy male subjects receiving single ascending doses from 2 to 2,000 mg, or, 200 or 500 mg BID for 10 days. The Phase 2 enrolled 100 patients assigned 1:1 to 10 days oral RDZ 200 mg BID or VAN 125 mg QID treatment. Both clinical trials quantified RDZ in plasma and feces, and assessed safety and tolerability.ResultsIn all animal studies, plasma levels of RDZ were below or at the limit of quantification (LOQ, 1.0 ng/mL). In the GI tract of hamsters, RDZ levels were highest in the colon. QWBA and excretion studies showed RDZ accumulated in the cecum and colon, the site of infection; >99% of radioactivity was excreted in feces and no radioactivity was detected systemically. 28 days repeat dosing in dog and rat resulted in no observations from treatment, histopathology or in-life parameters. In Phase 1 and 2 studies, RDZ plasma levels were generally near or below the LOQ (0.1 ng/mL). Concomitant medications, CDI severity, and age had no impact on exposure. In Phase 1, AEs were mild with no dose-dependent relationship, occurring and at a similar incidence to placebo. No significant findings from clinical laboratory, ECGs or other assessment were observed. RDZ was well tolerated in Phase 2 with the incidence of AEs and SAEs similar in both RDZ and VAN groups.ConclusionIn both clinical and nonclinical studies to date, RDZ has been well tolerated and associated with low systemic absorption. Further assessment of safety, tolerability, and PK in Phase 3 studies is warranted.Disclosures E. Duperchy, Summit Therapeutics: Employee, Salary. S. Chowdhury, Summit Therapeutics Inc.: Employee and Shareholder, Salary and Shareholder. R. Vickers, Summit Therapeutics: Employee, Salary and Stock options. N. Robinson, Summit Therapeutics: Consultant, Consulting fee.

178. Impact of a Best Practice Alert Linking Clostridium difficile Infection Test Results to a Severity-Based Treatment Order Set

BackgroundAdherence to practice guidelines for the treatment of Clostridium difficile infection (CDI) has been associated with improved patient outcomes. In March 2014, the hospital’s Antimicrobial Stewardship Program (ASP) implemented a best practice alert (BPA) in the electronic medical record linking a positive test result to guideline-based CDI orders for those not on CDI therapy. We sought to assess provider adherence to practice guidelines before and after implementation of this clinical decision support tool.MethodsIn this quasi-experimental study, a retrospective chart review was conducted on inpatients diagnosed with CDI, defined using a tiered testing algorithm. Those diagnosed with CDI in 2013 served as controls before BPA implementation and patients from 2016 served as cases. Antibiotic prescribing was assessed and guideline compliance evaluated based on institutional guidelines for CDI treatment. Secondary endpoints were resolution of diarrhea, length of stay, in-hospital mortality, 30-day recurrence, and readmission rate. Continuous variables were analyzed using a two-tailed Student’s t-test, or for non-normally distributed data, Mann–Whitney U test. Categorical variables were analyzed using chi-square.ResultsBased on power analysis, 131 CDI cases were randomly selected, 66 in 2013 and 65 in 2016, which accounts for 23.7% (66/278) and 15.9% (65/409) of total inpatient CDI cases, respectively. Mean age was 55.0 ± 19.3 years pre-BPA/Order set and 58.5 ± 14.1 in the post-group. Immuncompormise was present in 53% of the pre-group when compared with 32.3% in the post-group. The majority of patients in both the pre-BPA/Order set group and post-group received metronidazole as initial therapy with 69.7% and 75.4%, respectively. The BPA was opened in 54% (28/57) of triggered encounters and led to signed orders in 82% (23/28) of those patients. Guideline-based prescribing increased from 39.4% in 2013 to 67.7% overall in 2016 (P = 0.014). Secondary endpoints were not significantly different between groups.ConclusionAfter implementation of the BPA linked to a severity-based treatment order set, there was an increase in guideline-compliant prescribing for CDI. Developing a better understanding of how to optimize guideline adherence using BPAs will aid ASPs in determining future improvement efforts.Disclosures S. Bergman, Merck: Grant Investigator, Grant recipient.