Tag Archives: Biological Research and Development Clostridium difficile

A Study Shares Predictive Factors of Clostridioides difficile Infection In Hospitalized Patients with New Diarrhea Symptoms

 

 

 

 

Koray K. DemirData curationInvestigationWriting – original draftWriting – review & editing,1 Matthew P. ChengSupervisionWriting – review & editing,2 and Todd C. LeeConceptualizationFormal analysisMethodologySoftwareSupervisionWriting – review & editing2,3,*

Abhishek Deshpande, Editor

Abstract

Introduction and objective

Diagnostic testing for Clostridioides difficile infection (CDI) by nucleic acid amplification test (NAAT) cannot distinguish between colonization and infection.

A positive NAAT may therefore represent a false positive for infection, since diarrhea due to various aetiologies may occur in hospitalized patients.

Our objective was to help answer the question: “does this medical inpatient with diarrhea have CDI?”

Design

We conducted a retrospective cohort study (n = 248) on the Clinical Teaching Units of the Royal Victoria Hospital (Montréal, Canada). Patients were included if they had a NAAT between January 2014 and September 2015 and their admission diagnosis was not CDI. CDI cases and non-CDI cases were compared, and independent predictors of CDI were determined by logistic regression.

Results

Several factors were independently associated with CDI, including: hemodialysis (OR: 13.5, 95% CI: 2.85–63.8), atrial fibrillation (OR: 3.70, 95% CI: 1.52–9.01), whether the patient received empiric treatment (OR: 3.01, 95% CI: 1.04–8.68), systemic antibiotic therapy prior to testing (OR: 4.23, 95% CI: 1.71–10.5), previous positive NAAT (OR: 3.70, 95% CI: 1.41–9.72), and a leukocyte count of 11×109/L or higher (OR: 3.43, 95% CI: 1.42–8.26). The area under the curve was 0.80.

Conclusion

For patients presenting with hospital-onset diarrhea, various parameters can help differentiate between CDI and other causes. A clinical prediction calculator derived from our cohort (http://individual.utoronto.ca/leet/cdiff.html) might assist clinicians in estimating the risk of CDI for inpatients; those with low pre-test probability may not require immediate testing, treatment, nor prolonged isolation.

Introduction

Diarrhea is very common among hospitalized patients. There are many causes, including medications, chronic gastrointestinal diseases, as well as acute viral and bacterial infections. Among the latter group, Clostridioides difficile (the preferred name for the former Clostridium difficile [] is a leading cause of hospital-onset diarrhea. Since a sudden spike in Cdifficile infection (CDI) rates at the turn of the 21st century in both Canadian and American hospitals, it has increased drastically in prevalence across North America [], recently surpassing methicillin-resistant Staphyloccocus aureus (MRSA) as the most common source of nosocomial infection in many American jurisdictions [].

Classically, CDI occurs when exposure to antibiotics alters the gut flora, leading to overgrowth of Cdifficile and severe diarrhea due to Cdifficile toxin. If untreated, infection progresses to pseudomembranous colitis and toxic megacolon, ultimately resulting in shock. In 2011, 500,000 Americans were diagnosed with and 29 000 patients died of CDI, costing an estimated US $4.8 billion in acute treatment alone [].

The diagnosis of CDI remains a matter of scientific debate as there is not yet a universally accepted test or testing algorithm. For example, though stool cultures can sensitively detect the presence of Cdifficile, they require specific laboratory conditions and expertise, as well as prolonged incubation periods, which have resulted in them falling out of favour as first-line diagnostic tests. A modified toxigenic culture, which not only isolates Cdifficile but also confirms the presence of toxin (thereby reducing the possibility of false positive results), is considered the gold standard for diagnosis. However, toxin detection (and the expertise required for these tests) is not yet widely available, so many centres need other rapid tests to rely on.

Since 2009, highly sensitive Cdifficile toxin nucleic acid amplification tests (NAATs) have therefore emerged as a test of choice in many institutions []. These tests primarily detect and amplify the tcdB gene, which is responsible for the expression of toxin B, and are thought to be very highly sensitive[]. However, these assays may also detect the presence of unexpressed tcdB genes in patients who do not have disease[] and may only be asymptomatic carriers of Cdifficile. They must therefore be interpreted in the clinical context, mindful of risk factors like recent antibiotic use, to determine if a patient with a positive assay truly has clinical CDI. Ideally, for diagnostic purposes, they should be sent only in patients with high pre-test probability of CDI.

In particular, for hospitalized patients with multiple comorbidities and concomitant medications, it can be difficult to immediately differentiate CDI from another cause of diarrhea when loose stools develop on the ward. Given the associated costs of the overuse of empiric therapy and challenges due to false-positive testing, we believed that clinicians could benefit from an estimate of the pre-test probability of new onset diarrhea for hospitalized patients being caused by CDI prior to requesting a toxin NAAT.

The objective of our study was therefore to identify clinical and laboratory parameters that were ultimately associated with a confirmed diagnosis of CDI, in order to answer: “does this medical inpatient with healthcare-facility onset diarrhea have Cdifficile infection?”

Methods and materials

Patient information was obtained from chart review of patients admitted to the medical clinical teaching units (CTU) at the Royal Victoria Hospital in Montréal, Canada. Data was extracted from January 2014 to September 2015. Patients were included in the study if their admission diagnosis was not Cdifficile and if they were tested for Cdifficile by NAAT during their admission. An episode of CDI was defined as a patient with new diarrhea any time after admission and a positive Cdifficile NAAT who received at least ten days of treatment with either oral vancomycin or metronidazole.

Our cases are described as healthcare-facility onset diarrhea with acquisition of Cdifficile either in community or at the healthcare institution. At our hospital, in the absence of toxic megacolon or shock, a Cdifficile NAAT is sent when there are three or more unformed stools within 24 hours and all cases were confirmed to meet the standard IDSA-SHEA definition [] by trained infection control personnel.

Clinical and laboratory data were extracted from patient records. Clinical data notably included medical comorbidities and previous history of positive Cdifficile toxin NAAT (dating back to June 2010, which is when the test entered use at our institution). We also recorded laxative prescription within the last 48 hours, number of bowel movements within 24 hours, as well as charting of abdominal tenderness and the quality of stool within 24 hours. Our hospital protocol states that NAAT tests are, in general, not sent for fewer than three bowel movements in 24 hours. Therefore, patients who did not have a specific documented number of bowel movements were assumed to have less than five but at minimum three bowel movements. Additionally, when abdominal tenderness was not explicitly mentioned in the chart, it was assumed to be absent.

Although laxatives were often held after diarrhea developed, this variable was included to determine if laxative prescription at time of diarrhea onset influenced pre-test probability for CDI. Fever within 24 hours of diarrhea was included and assessed by charted vital signs, which at our institution are measured every eight hours on the inpatient unit. Antibiotic exposure within the previous 30 days was also recorded and assessed by prescription history within our hospital network, or mention of recent antibiotic exposure in the patient’s chart. Empiric therapy was defined as the initiation of Cdifficile therapy prior to the receipt of NAAT results. At least 10 days of Cdifficile directed therapy was considered to be a full course of CDI therapy. The highest white blood cell (WBC) count on the day of sample procurement as well as in the preceding 72 hours was recorded and leukocytosis was defined as a WBC above 11 × 109/L as this is the cut-off in our laboratory. Creatinine levels on the day of testing were also recorded; acute kidney injury was defined as an increase of 26 μmol/mL from a patient’s baseline, excluding patients with end-stage renal disease on dialysis who were considered separately []. For both WBC and creatinine, if same-date data were not available, data from within 48 hours before or after the specimen procurement was used.

Ethics approval was granted by the McGill University Health Centre Research Ethics Board who waived the requirement for informed consent given the retrospective nature of our study. After data was extracted, all patient data were de-identified and analyzed in an anonymous fashion.

Univariate comparisons were made using chi-square and multivariate comparisons were made using logistic regression, with a P-value of .05 representing significance. To avoid over-representing patients with multiple admissions and multiple NAAT tests sent over the study period, only the first test result per patient was used in the derivation of the regression model. The initial logistic regression model was selected using backwards selection with a goal of maximizing the c-statistic. We initially started will all covariates in the model and worked backwards by removing those with a p-value above 0.05 until we arrived at the final model. We then attempted to build the model using forwards selection involving all covariates which converged on the same result. We then forced potential confounders such as age (which were not independently associated) into this model to determine if the c-statistic improved. Since it did not, and those covariates were not associated with the outcome of interest, we did not include them in our final selected model. This final model was converted into an interactive Microsoft Excel calculator using the co-efficient for each term in the equation for the post-test probability predicted by regression.

Results

Of the 2537 admissions to the CTU within our specified time frame, 319 NAAT tests for Cdifficile were performed. These samples were obtained from 248 unique patients who were admitted in the absence of an admission diagnosis of CDI. 215 of these unique tests were negative (87%), whereas 33 (13%) were positive and were classified as having CDI (see Table 1). 2 (0.8%) patients tested positive but did not receive treatment, were considered asymptomatic carriers by the clinical treating teams, and are therefore not included in Table 1.

Table 1

Demographics of patients included.
Cases of CDI N = 33 (%) Controls N = 215 (%) P-value
Characteristic
Median age (years) (IQR) 76 (63–82) 70 (57–81) 0.07
Female (%) 13 (39%) 113 (53%) 0.14
Comorbid Diagnoses:
    Hypertension 24 (72%) 116 (54%) 0.05
    Diabetes Mellitus 10 (30%) 66 (31%) 0.91
    Coronary Artery Disease 10 (30%) 56 (26%) 0.63
    Atrial Fibrillation 13 (39%) 36 (17%) <0.01
    Congestive Heart Failure 9 (27%) 37 (17%) 0.17
    Solid Organ Transplant 3 (9%) 38 (18%) 0.20
    Solid or Hematologic Cancer 8 (24%) 47 (38%) 0.12
    Cirrhosis 3 (9%) 20 (9%) 1.0
    End-Stage Renal Disease on Dialysis 6 (18%) 4 (2%) <0.01
    HIV Infection 1 (3%) 9 (4%) 0.78
Clinical Features
Antibiotic Exposure in Past 30 Days 16 (48%) 47 (22%) <0.01
Five or more bowel movements 7 (21%) 44 (20%) 0.89
Fever 0 (0%) 0 (0%) 1.0
Abdominal Tenderness 9 (27%) 37 (17%) 0.27
Treated Empirically for CDI 8 (24%) 22 (10%) 0.02
Active Laxative Prescription 8 (24%) 73 (34%) 0.26
Proton Pump Inhibitor Use 19 (57%) 126 (59%) 0.83
Mycophenolate Drugs 2 (6%) 34 (16%) 0.13
Calcineurin Inhibitors 1 (3%) 31 (14%) 0.08
Laboratory Parameters
Previous Positive CDiff NAAT 11 (33%) 27 (13%) 0.02
Leukocytosis > = 11×109 cells/mL 20 (60%) 84 (39%) 0.02
    Median maximal WBC count (x109 cells/mL) (IQR) 12.9 (10.1–19.2) 9.6 (6.8–13.9) 0.01
Acute Kidney Injury1 11 (41%) 69 (33%) 0.41

1: patients with end-stage renal disease on hemodialysis were excluded from this measurement.

In our multivariable model, a number of factors were independently associated with CDI in medical inpatients including: receipt of hemodialysis (OR: 13.5, 95% CI: 2.85–63.8), atrial fibrillation (OR: 3.70, 95% CI: 1.52–9.01), whether the patient received empiric treatment (OR: 3.01, 95% CI: 1.04–8.68), receipt of systemic antibiotics in the 30 days prior to the test (OR: 4.23, 95% CI: 1.71–10.5), previous positive NAAT (OR: 3.70, 95% CI: 1.41–9.72), and a leukocyte count of 11×109/L or higher (OR: 3.43, 95% CI: 1.42–8.26) (see Table 2). The presence of fever, abdominal tenderness, acute kidney injury, number of bowel movements, description of the stool and laxative use within 48 hours were not found to be independent predictors of CDI. The area under the receiver-operator curve (c-statistic) for the model was 0.80.

Table 2

Clinical and laboratory factors independently associated with CDI.
Factor Odds ratio 95% Confidence P-value
Dialysis 13.5 2.85 63.8 0.001
Warrants Empiric Therapy 3.01 1.04 8.68 0.042
Atrial Fibrillation 3.70 1.52 9.01 0.004
Antibiotic exposure ≤ 30 days 4.23 1.71 10.45 0.002
Previous positive Cdiff NAAT 3.70 1.41 9.72 0.008
WBC Count ≥ 11 3.43 1.43 8.26 0.006

We used the results of our study to derive a preliminary clinical prediction calculator (accessible at: http://individual.utoronto.ca/leet/cdiff.html), which converts the coefficients of our regression model into a means by which one could estimate the pre-test CDI probability for individual medical patients. Most non-CDI cases of diarrhea in our cohort were ultimately considered to be related to medication side effects although there were likely other infectious illnesses with diarrhea as a component (influenza and viral gastroenteritis). There were no cases of de novo inflammatory bowel disease diagnosed.

Discussion

Our data suggest that a number of clinical or laboratory findings are associated with an increased risk of CDI among hospitalized patients with diarrhea. Unsurprisingly, recent antibiotic exposure (OR: 4.23, 95% CI: 1.71–10.5), a previous positive NAAT (OR: 3.70, 95% CI: 1.41–9.72) and leukocytosis (OR: 3.43, 95% CI: 1.42–8.26) were associated with increased risk of CDI in our model. These findings corroborate the literature as being important and independent markers of disease.

In addition, our results support the concept that clinical judgment as shown by the belief that the patient requires empiric therapy while diagnostic testing results are pending is a reasonable predictor that the patient is more likely to have CDI than another cause of diarrhea (OR: 3.01, 95% CI: 1.04–8.68). Although this concept is subjective, it reflects the many complexities of clinical judgment, which are difficult to precisely quantify but which have been shown in other clinical prediction rules to add discriminative power [].

Our data also suggests that dialyzed patients with diarrhea were significantly more likely (OR: 13.5, 95% CI: 2.85–63.8) than patients not on dialysis to have CDI. In our analysis, AKI and creatinine levels were not correlated with increased probability of CDI, suggesting that renal injury was not the inherent predisposing risk factor. Rather, this finding is more likely explained by the fact that dialyzed patients, whose frequent weekly visits over a long time period cumulate to significant hospital exposure, are more likely to be exposed to and acquire Cdifficile. In addition, although it is possible that these patients’ uniquely thorough medical records may cause misclassification bias, their charts are consolidated upon admission to the inpatient unit, which mitigates this risk. As these patients are also relatively immune suppressed, they may also be more likely to experience disease [].

Atrial fibrillation (OR: 3.70, 95% CI: 1.52–9.01) was also found to increase the likelihood of a patient with diarrhea having CDI. This may be a chance association due to an unmeasured covariate within our cohort or represent an increased risk of CDI due to other metabolic and/or pharmacologic differences for these patients.

Our work has several limitations. First, our study population was restricted to the inpatient clinical teaching units of one institution and our sample size was relatively small so our findings should be interpreted with caution. We did not have enough of a sample to provide a derivation and validation subset and our model requires validation elsewhere. However, at the time of our study, these units had the highest rate of inpatient CDI at our institution and as it is a general medical unit the patients represent a heterogeneous and diverse population. Secondly, we have relied on charted comorbidities, vital signs (including temperature), physical findings, and stool characteristics which may have introduced information bias in cases where this information was incorrectly documented. Moreover, as we only had access to data from our own hospital network, we lacked comprehensive data on a full history of healthcare exposures, previous positive Cdifficile NAAT assays as well as out-of-centre antibiotic use. Nonetheless, the data available in our chart review was the same information that treating teams used when deciding to test for Cdifficile or to treat a positive result. Furthermore, at our institution, admission comorbidities are reviewed at minimum three times (initially by the emergency room physician, the emergency room internal medicine consultant, as well as on admission to the internal medicine unit). They are therefore highly comprehensive at our centre.

Thirdly, although NAAT tests were sent shortly after the onset of diarrhea due to standard operating procedures in our institution, the exact timing relative to symptom onset could not be ascertained due to the retrospective nature of our study It is also worth noting that patients with previous positive NAAT may be more likely to be tested, which may affect our results. Indeed, if CDI colonization status is known (because of prior NAAT results or previous confirmed infection) there could certainly be a bias towards ordering testing in such patients which may bias the results in these cases. A prospective study with structured data collection, assessing information on other risk factors such as the magnitude of health care contact or Cdifficile exposure/colonization pressure, would lead to a superior tool.

Finally, we only evaluated patients whose stool was tested and not all patients with diarrhea in the hospital. Therefore, we may have under-sampled the group of patients that the treating team felt had the lowest probability of CDI. It is possible that not all cases of CDI were identified in our cohort, such that false negatives may have been considered CDI-negative controls. However, the NAAT employed has sensitivity close to 100% [] and no negative patient was fully treated for CDI.

Our study therefore presents a number of clinical and laboratory findings, outside of the usually well-recognized risk factors, that influence the likelihood of a hospitalized patient with healthcare facility-onset diarrhea having CDI. Importantly, unlike previous work, which compares patients with CDI to those without irrespective of clinical presentation [], we have attempted to determine who has CDI amongst the more relevant subset of patients with diarrhea. Our results encourage diagnostic stewardship by helping to determine the pre-test probability of CDI in patients with healthcare facility-onset diarrhea, to help clinicians evaluate the utility of a toxin NAAT. To translate our data into an actionable clinical tool, we integrated our results into a model that allows clinicians to enter patient information and determine a likelihood of a patient having CDI. It remains to be seen whether such a rule would be valid in a derivation cohort and if the use of these pre-test probabilities might fit into testing and empiric treatment algorithms.

Conclusion

Our cohort is the first to specifically examine the clinical prediction of CDI in the setting of new onset diarrhea in medical inpatients. For this specific population, certain clinical and laboratory parameters may be useful to differentiate between those with CDI and other aetiologies. If validated in a future cohort, this clinical prediction rule may adjust the pre-test probability of CDI for this patient population and inform diagnostic and management approaches.

Acknowledgments

The authors would like to thank Dr. Vivian G. Loo for her review of the manuscript, as well as Kendra Bradshaw, MDCM and Alexandre P. Cheng, B.Eng for their assistance in data collection.

Funding Statement

The authors received no specific funding for this work.

Data Availability

All relevant data underlying our study’s findings can be found within the manuscript.

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2. Loo VG, Poirier L, Miller MA, Oughton M, Libman MD, Michaud S, et al. A predominantly clonal multi-institutional outbreak of Clostridium difficile–associated diarrhea with high morbidity and mortalityNew England Journal of Medicine. 2005;353(23):2442–9. 10.1056/NEJMoa051639 [PubMed[]
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6. Sailhamer EA, Carson K, Chang Y, Zacharias N, Spaniolas K, Tabbara M, et al. Fulminant Clostridium difficile colitis: patterns of care and predictors of mortalityArchives of surgery. 2009;144(5):433–9. 10.1001/archsurg.2009.51 [PubMed[]
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SOURCE:  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6281280/

C Diff Foundation Recognizes Rebiotix CEO Lee Jones with 2019 ‘Above and Beyond’ Award


C Diff Foundation Board presented Rebiotix CEO Lee Jones for Advocacy, Innovation in
C. difficile infection treatment

 

(NEW PORT RICHEY, Fla.) — The C. Diff Foundation Board of Directors announced that the 2019 “Above and Beyond” Award was presented to Rebiotix CEO Lee Jones in Roseville, Minnesota. The award, given to one recipient annually, is given to a person or organization that show extraordinary dedication to C. diff. patient safety, advocacy, and overall drive to improve the lives of those impacted by the infection.

“We are very proud to recognize Ms. Jones with our “Above and Beyond” award,” said C. Diff Foundation Founder and President, Nancy Caralla. “Lee’s dedication to the entire C.diff. community of patients, family members, and physicians hasn’t wavered since the founding of Rebiotix in 2011. She is a true example of what can happen when focusing on patient well-being drives new approaches to healthcare.”

The award was presented by the Foundation’s Vice President, Scott Battles at the Rebiotix office.

 

 

 

 

 

 

“It’s an honor to receive this award from the C. Diff Foundation,” said Ms. Jones. “The purpose of starting Rebiotix was to bring the power of the microbiome to the clinic in a scientifically sound, quality-controlled way to help patients. We stand with the Foundation in believing that patient well-being should be at the core of all that we do, from clinical trials to exploring new scientific landscapes within the microbiome space.”

About Rebiotix Inc.:

Rebiotix Inc., part of the Ferring Pharmaceuticals Group, is a late-stage clinical microbiome company focused on harnessing the power of the human microbiome to revolutionize the treatment of debilitating diseases. Rebiotix possesses a deep and diverse clinical pipeline, with its lead drug candidate, RBX2660, in Phase 3 clinical development for the prevention of recurrent Clostridium difficile (C. diff) infection. RBX2660 has been granted Fast Track, Orphan and Breakthrough Therapy designation from the FDA for its potential to prevent recurrent C. diff infection.

Rebiotix’s clinical pipeline also features RBX7455, a lyophilized, room temperature stable oral capsule formulation. Rebiotix is also targeting several other disease states with drug products built on its pioneering Microbiota Restoration Therapy(tm) platform. For more information on Rebiotix and its pipeline of human microbiome-directed therapies, visit https://www.rebiotix.com/

 

Highlights Of the Latest Advances In the Battle Against the Deadly Pathogen – Dale Gerding, MD

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In September, researchers, health care workers, and industry and patient advocates convened for the 4th Annual International Raising C. diff Awareness Conference and Health Expo in Atlanta.

Clifford McDonald, MD, Associate Director for Science in the Division of Healthcare Quality Promotion at the Centers for Disease Control and Prevention (CDC), chaired the conference. In his role at the CDC, McDonald’s at the forefront of efforts to prevent and treat the infection – one the CDC has declared among the most urgent drug-resistant threats that we currently face.

“It’s my firm belief that we are on the threshold of a new era in better diagnosis, treatment, and prevention approaches. At the CDC, we deal with statistics, but there are faces behind those numbers. At the heart of every infection is a patient who deserves our competence, our empathy, and our passion,” said McDonald.

One of those faces, Roy Poole, is a volunteer patient advocate for the  C Diff Foundation. After retiring from a career in the Air Force, Poole led a healthy, active lifestyle as an avid outdoors-man in Colorado before antibiotics prescribed for a routine dental procedure set the stage for CDI. In the medical community, his symptoms were met with disbelief and inappropriate treatment.

“Three weeks after leaving the hospital, I walked into my (previous) primary care physician, and asked for an order to have a stool sample taken to determine if Toxins A or B were present. His response was, ‘Are you still having problems with that?’ Clearly, there is a need for more education about C. diff among physicians,” said Poole.

CDI is a formidable opponent. However, with the newly focused attention on discovering ways to disable the bacteria and cohesive public health approaches aimed at prevention, presenters from government, academia and industry offered five key reasons we can win the battle against C. diff:

Antibiotic stewardship efforts are gaining a foothold.
Statistics present a chilling picture: 453,000 new cases and an estimated 30,000 deaths each year. It’s likely that those numbers grossly underestimate the true impact of CDI, since it’s what we know from death certificate reporting.

However, we are seeing that rates may have peaked after a long plateau. Mark Wilcox, MD, Head of Microbiology at Leeds Teaching Hospital, Professor of Medical Microbiology at University of Leeds, and the lead on Clostridium difficile for Public Health England in the United Kingdom, has demonstrated a 70% reduction in cases in England in just 7 years. This was after a concerted effort that Wilcox spearheaded surrounding antibiotic stewardship, specifically addressing a reduction in unnecessary prescribing of fluoroquinolones and cephalosporin antibiotics.

Commonly prescribed antibiotics disrupt the protective microbiota (the normal bacteria of the gut) and leave it vulnerable for C. diff colonization. “There was a concerted effort that went beyond lip service and truly embraced the principles of improved surveillance, more accurate diagnostics, enhanced infection prevention measures to use antibiotics more wisely and to limit transmission and careful treatment,” said Wilcox.

High rates of CDI are always associated with the use of certain antibiotics: clindamycin, cephalosporin, and fluoroquinolones. Research has shown that lower respiratory tract infections and urinary tract infections account for more than 50% of all in-patient antibiotics use. But are these really necessary?

“We know that antibiotics are overused and misused across every healthcare setting. At least 30% of antibiotic prescriptions are unnecessary – and this equates to 47 million unnecessary antibiotic prescriptions per year written in doctors’ offices, hospital outpatient departments, and emergency departments. We have a lot of work to do, and CDC is actively working to reduce unnecessary antibiotic use,” said Arjun Srinivasan, MD at the CDC. “Stopping unnecessary antibiotics is the single most effective thing we can do to curb C. diff infections in the United States. This is something that we can do today.”

Srinivasan acknowledged that telling patients that they can’t have a prescription for an antibiotic might result in some pushback. “Patient satisfaction scores are a very real concern. When someone is sick and takes a day off work, they’re not leaving without a prescription – especially when the last provider wrote one for their same symptoms,” he said. “But this is a new day, and it’s up to the physician to educate their patients and stay strong.”

Hospitalists have access to accurate, inexpensive and quick diagnostic tests that can lead to targeted, effective treatment. This can arm the treating physician and patient with information that can put patients on a path to recovery without feeling like they are being dismissed.

Emerging guidance reflects important advances in research and development.

Most recently published in 2010, the Society for Healthcare Epidemiology of America (SHEA) and Infectious Diseases Society of America (IDSA) Clinical Practice Guidelines for C. diff are currently under review. This is critical because of the number of physicians still treating with metronidazole first, despite the fact that the largest randomized controlled clinical trial has shown that vancomycin is more effective.

“Since 2010, the landscape has changed dramatically,” said Stuart B. Johnson, MD, Professor, Department of Medicine, Loyola University, and Researcher at the Hines VA Hospital in Chicago.

“The past few years have ushered in a new age of understanding how and where C. diff colonizes, and the damaging toxins A and B that it produces.”

Considering that 25-30% of patients experience a CDI recurrence, it’s evident that metronidazole unnecessarily contributes to the failed treatment outcomes for patients. Metronidazole is less expensive, but has more side effects than oral vancomycin and is less effective in treating CDI.

Johnson provided an overview of the dramatic advances this space has seen in just the past few years.

Limitations of current guidelines include:
•       No mention of fidaxomicin, a narrow-spectrum antibiotic, which in 2011 was the first medication approved in 25 years for the treatment of C. diff associated diarrhea
•       Limited evidence for recommendations to treat severe, complicated CDI
•       Limited evidence for recommendations on recurrent CDI
•       Little mention of Fecal Microbiota Transplant (FMT)

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5.  Patient advocacy and awareness efforts can alter the course of CDI.
CDI survivors shared their experiences along their emotional journey – fear, disbelief, isolation, and depression. They also expressed gratitude at the validation, information and support they received from the patient advocacy community. Perhaps the greatest gift they have received is the empowerment to question their physicians about the necessity of antibiotics they have been prescribed in terms of risk of CDI.

“The hospital where I was treated initially seemed eager to have me leave. They offered no additional help. The C diff Foundation has been my greatest source of help. In turn, I feel I help myself cope best, when I help others to cope with the disease,” said Poole.

TO READ THIS ARTICLE IN ITS ENTIRETY AS PUBLISHED IN THE MD MAGAZINE 

PLEASE CLICK ON THE FOLLOWING LINK TO BE REDIRECTED —- THANK YOU

http://www.mdmag.com/medical-news/c-diff-foundation-highlights-latest-advances-in-the-battle-against-the-deadly-pathogen

 

Dale Gerding, MD, FACP, FIDSA, is Professor of Medicine at Loyola University Chicago, Research Physician at the Edward Hines Jr. VA Hospital. Additionally, Gerding is an infectious disease specialist and hospital epidemiologist, past president of the Society for Healthcare Epidemiology of America and past chair of the antibiotic resistance committee of SHEA. He is a fellow of the Infectious Diseases Society of America and past chair of the National and Global Public Health Committee and the Antibiotic Resistance Subcommittee of IDSA. His research interests include the epidemiology and prevention of Clostridium difficile, antimicrobial resistance, and antimicrobial distribution and kinetics.

The paper, “Burden of Clostridium difficile Infection in the United States,” was published in the New England Journal of Medicine.

The study, “Changing epidemiology of Clostridium difficile infection following the intriduction of a national ribotyping-based surveillance scheme in England,” was published in the journal Clinical Infectious Diseases.

The study, “Prevalence of antimicrobial use in US acute care hospitals,” was published in JAMA.

The paper, “Vancomycin, metronidazole, or toleyamer for Clostridium difficile infection: results from two multinaionalm randomized, controlled trials,” was published in Clinical Infectious Diseases.

The study, “A Randomized Placebo-controlled Trial of Saccharomyces boulardii in Combination with Standard Antibiotics for Clostridium difficile disease,” was published in JAMA.

Synthetic Biologics SYN-004 (ribaxamase) Achieves Primary Endpoint in Phase 2b Trial for C. difficile Infection

SyntheticBiologics2016LOGO

Synthetic Biologics’ SYN-004 (ribaxamase) Achieves Primary Endpoint
in Phase 2b Trial for C. difficile Infection (CDI)

 

Synthetic Biologics, Inc. a late-stage clinical company developing therapeutics
that preserve the microbiome to protect and restore the health of patients, today
announced positive topline data from its Phase 2b clinical trial for SYN-004 (ribaxamase),
the Company’s first-in-class oral enzyme designed to protect the gut microbiome
from disruption caused by certain intravenous (IV) beta-lactam antibiotics.

The study, a randomized, double-blind, placebo controlled trial of 412 patients, met its primary endpoint of significantly reducing C. difficile Infection (CDI). Preliminary analysis of the data indicated seven confirmed cases of CDI in the placebo group compared to two cases in the ribaxamase treatment group. Patients receiving ribaxamase achieved a 71.4% relative risk reduction (p-value=0.045) in CDI rates compared to patients receiving placebo. Adverse events reported during this trial were comparable between treatment and placebo arms.

Synthetic Biologics is also in the process of analyzing data from several exploratory endpoints that were designed to evaluate ribaxamase’s ability to protect the gut microbiome from colonization by opportunistic bacteria such as C. difficile and other antibiotic-resistant pathogens. Preliminary analysis of the data demonstrated a significant reduction in new colonization by vancomycin-resistant enterococci (VRE) for patients receiving ribaxamase compared to placebo (p-value=0.0002). With agreement from the FDA, the study included a secondary endpoint to assess ribaxamase’s capacity to decrease the incidence of antibiotic-associated diarrhea from all causes. Preliminary analysis of the data suggested a trend towards such a reduction (p-value=0.13), which was due, for the most part, to the reduction of CDI.

These data are consistent with ribaxamase’s mechanism of action designed to protect and preserve the natural balance of the gut microbiome from the unintended effects of IV antibiotic use. The Company expects to share additional results from these exploratory endpoints as they become available later this year, including results focused on ribaxamase’s ability to prevent the emergence of antimicrobial resistance in the gut microbiome.

“These trial results provide a compelling demonstration of the potential of ribaxamase to help address the serious health impacts associated with CDI and infections from other opportunistic bacteria resulting from dysbiosis of the gut microbiome,” said Joseph Sliman, MD, SVP, Clinical and Regulatory Affairs. “More than 453,0001 patients are diagnosed with CDI annually in the U.S., resulting in approximately 29,0001 deaths as well as significant and sometimes prolonged illness. Ribaxamase has the potential to shorten hospital stays, diminish morbidity and mortality and reduce the emergence of antibiotic-resistant organisms in the gut microbiome by protecting patients from primary C. difficile infection resulting from IV antibiotic use.”

In addition to causing significant suffering and mortality, CDI adds an estimated economic burden of nearly $1.5 billion1 to the healthcare system each year, which could potentially be reduced with an effective therapeutic.

“The reduction in the relative risk of CDI represents a significant milestone in the clinical development of ribaxamase and we believe provides further validation for our approach to advancing cutting edge microbiome science,” said Jeffrey Riley, President and Chief Executive Officer. “These findings also help further our goals to bring the first ever microbiome-focused therapeutic to patients and to help illuminate the potential of this drug class to address serious diseases and public health concerns. We expect to share additional data from exploratory endpoints in the coming months and look forward to continuing ongoing and productive discussions with both the FDA and CDC on the protocol for Phase 3 pivotal trials for ribaxamase.”

Synthetic Biologics is also continuing to prepare for the initiation of pivotal Phase 2b/3 clinical trials for SYN-010, the Company’s proprietary, modified-release formulation of lovastatin lactone designed to treat the underlying cause of irritable bowel syndrome with constipation (IBS-C).

Presentation Planned for Biotech Showcase 2017 Conference

Date: Monday, January 9, 2017
Time: 9:30 a.m. (PT) / 12:30 p.m. (ET)
Location: Hilton San Francisco Union Square, San Francisco, CA

A live webcast of Synthetic Biologics’ presentation may be accessed by logging onto the internet at https://event.webcasts.com/viewer/event.jsp?ei=1130367. After the presentation, a replay will be archived and accessible for 90 days at the same website.

About SYN-004 (ribaxamase) and the Phase 2b Study

SYN-004 (ribaxamase) is a first-in-class oral enzyme designed to degrade certain IV beta-lactam antibiotics within the GI tract and maintain the natural balance of the gut microbiome for the prevention of CDI, AAD and the emergence of antibiotic-resistant organisms. The Phase 2b proof-of-concept clinical trial is intended to evaluate the effectiveness of ribaxamase to prevent the onset of primary C. difficile infection (CDI), antibiotic-associated diarrhea (AAD) and the emergence of antibiotic-resistant organisms in patients hospitalized with a lower respiratory infection and receiving IV ceftriaxone. A total of 412 subjects were randomized in a 1:1 ratio receiving either 150 mg dose strength of SYN-004 (ribaxamase) or placebo orally QID from Day 1 and until 72 hours following their last treatment of IV ceftriaxone. The sample size was determined to provide 80% power to detect the treatment effect with a one-sided alpha of 0.05. P-values were determined based on a 1-sided z-test for the comparison of the treatment difference as pre-specified in the statistical analysis plan. To access the ribaxamase mechanism of action video on Synthetic Biologics’ website, please click here.

About Synthetic Biologics, Inc.

Synthetic Biologics, Inc. (NYSE MKT: SYN) is a late-stage clinical company developing therapeutics that preserve the microbiome to protect and restore the health of patients. The Company’s lead candidates poised for Phase 3 development are: (1) SYN-010 which is intended to reduce the impact of methane producing organisms in the gut microbiome to treat an underlying cause of irritable bowel syndrome with constipation (IBS-C), and (2) SYN-004 (ribaxamase) which is designed to protect the gut microbiome from the effects of certain commonly used intravenous (IV) beta-lactam antibiotics for the prevention of C. difficile infection, antibiotic-associated diarrhea (AAD) and the emergence of antibiotic-resistant organisms. The Company is also developing preclinical stage monoclonal antibody therapies for the prevention and treatment of pertussis and novel discovery stage biotherapeutics for the treatment of phenylketonuria (PKU). For more information, please visit Synthetic Biologics’ website at www.syntheticbiologics.com.

This release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. In some cases, forward-looking statements can be identified by terminology such as “may,” “should,” “potential,” “continue,” “expects,” “anticipates,” “intends,” “plans,” “believes,” “estimates” and similar expressions and include statements regarding the potential of ribaxamase to help address the serious health impacts associated with CDI and infections from other opportunistic bacteria resulting from dysbiosis of the gut microbiome, the industry data regarding the expected incidence and economic burden of CDI, the potential of ribaxamase to shorten hospital stays, diminish morbidity and mortality and reduce the emergence of antibiotic resistant organisms in the gut microbiome by protecting patients from primary C. difficile infection resulting from IV antibiotic use, the potential to reduce the economic burden to the healthcare system from an effective therapeutic, the suggested trend toward a reduction of incidence of antibiotic-associated diarrhea from all causes, the expected timing of data release of exploratory endpoints of the trial focused on the ability of ribaxamase to prevent the emergence of antibiotic-resistant organisms in the gut microbiome, the continued ongoing discussions with the FDA and CDC, validation for our approach to advancing cutting edge microbiome science, the continued preparation  for the initiation of pivotal Phase 2b/3 clinical trials for SYN-010, the potential of the drug class to address serious diseases and public health concerns, the ability of SYN-004 to protect the gut microbiome from the effects of certain commonly used IV beta-lactam antibiotics for the prevention of  C. difficile infection, antibiotic-associated diarrhea (AAD) and the emergence of antibiotic-resistant organisms. These forward-looking statements are based on management’s expectations and assumptions as of the date of this press release and are subject to a number of risks and uncertainties that could cause actual results to differ materially from those set forth or implied by any forward-looking statements. Important factors that could cause actual results to differ materially from current expectations include, among others, Synthetic Biologics’ product candidates demonstrating safety and effectiveness, as well as results that are consistent with prior results, Synthetic Biologics’ ability to initiate clinical trials and if initiated, to complete them on time and achieve desired results and benefits, Synthetic Biologics’ clinical trials continuing enrollment as expected, Synthetic Biologics’ ability to obtain regulatory approvals for commercialization of product candidates or to comply with ongoing regulatory requirements, regulatory limitations relating to Synthetic Biologics’ ability to promote or commercialize its product candidates for specific indications, acceptance of its product candidates in the marketplace and the successful development, marketing or sale of Synthetic Biologics’ products by competitors that render Synthetic Biologics’ products obsolete or non-competitive, Synthetic Biologics’ ability to maintain its license agreements, the continued maintenance and growth of Synthetic Biologics’ patent estate, Synthetic Biologics becoming and remaining profitable, Synthetic Biologics’ ability to establish and maintain collaborations, Synthetic Biologics’ ability to obtain or maintain the capital or grants necessary to fund its research and development activities, a loss of any of Synthetic Biologics’ key scientists or management personnel, and other factors described in Synthetic Biologics’ Annual Report on Form 10-K for the year ended December 31, 2015 and its other filings with the SEC, including subsequent periodic reports on Forms 10-Q and 8-K.The information in this release is provided only as of the date of this release, and Synthetic Biologics undertakes no obligation to update any forward-looking statements contained in this release on account of new information, future events, or otherwise, except as required by law.

1: Leffler DA et al. N Engl J Med 2015; 372: 1539-1548

To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/synthetic-biologics-syn-004-ribaxamase-achieves-primary-endpoint-in-phase-2b-trial-for-c-difficile-infection-cdi-300386140.html

SOURCE Synthetic Biologics, Inc.

Fecal Microbiota Transplantation (FMT) A Promising Treatment And Recurrent C diff Infections

NurseCadeceus

The media and publications are raising
FMT awareness .

The positive effects are being
noted as FMT’s hold a promising treatment option and success is being witnessed in patients suffering
through C. diff. infections.

Being treated  by a physician with a Fecal Microbiota Transplantation, to treat recurrent Clostridium difficile infections, is resolving the pain and torment being experienced by patients.

What is a Fecal Microbiota Transplant (FMT)?

Fecal microbiota transplants (FMTs) are exactly what they sound like.
They involve taking feces from a healthy person and putting them into the body
of a sick patient to strengthen the community of bacteria that live in the patient’s gut.
FMTs are very effective at curing stubborn infections with Clostridium difficile (C. diff).

The deadly bacteria cause 500,000 illnesses and 14,000 deaths each year in the United States. Small studies have shown that FMTs can cure about 90 percent of serious C. diff infections. They have been so successful that scientists are testing the transplants for other conditions, such as irritable bowel syndrome. (1)

However; this treatment – in any form – has not yet been approved by the
U.S. Food and Drug Administration (FDA).

Clinical data is pending and FMT remains investigational at this time.

Below is the link to the FDA website and the March 2014 document regarding
Fecal Microbiota Transplantation (FMT) for the general public:

III.  When FDA Intends to Exercise Enforcement Discretion 

FDA does not intend to exercise enforcement discretion for the use of an FMT product when the FMT product is manufactured from the stool of a donor who is not known by either the patient or the licensed health care provider treating the patient, or when the donor and donor stool are not qualified under the direction of the treating licensed health care provider.
FDA will continue to evaluate its enforcement policy.
Furthermore, during the period of enforcement discretion, FDA will continue to work with sponsors who intend to submit INDs for use of FMT to treat C. difficile infection not responding to standard therapies.
This enforcement discretion policy does not extend to other uses of FMT.  Data related to the use and study of FMT to treat diseases or conditions other than C. difficile infection are  more limited, and study of FMT for these other uses is not included in this enforcement policy.  (2)
* Also, click on the link below to view the US Food and Drug Administration (FDA)
Upcoming Workshop Information:
**  Always discuss treatment options available with a Healthcare provider
and review/discuss clinical studies in progress.
Resources: