Tag Archives: c diff

On June 13th the U.S. Food and Drug Administration Warned of Infections From Fecal Microbiota Transplantation (FMT) Linked to a Patient’s Death

Dr. Peter Marks, director the Center for Biologics Evaluation and Research at the U.S. Food and Drug Administration stated, “While we support this area of scientific discovery, it’s important to note that fecal microbiota for transplantation does not come without risk,”

Two patients contracted severe infections, and one of them died, from fecal transplants that contained drug-resistant bacteria.

The agency said two patients received donated stool that had not been screened for drug-resistant germs, leading it to halt clinical trials until researchers prove proper testing procedures are in place.

After reports of serious, antibiotic-resistant infections linked to the procedures, the FDA wants “to alert all health care professionals who administer FMT [fecal microbiota transplant] about this potential serious risk so they can inform their patients.” said Dr. Peter Marks, director the Center for Biologics Evaluation and Research at the U.S. Food and Drug Administration.

Other samples from the same donor were tested after the patients got sick. The samples were found to harbor the same dangerous germs found in the patients, known as multi-drug-resistant organisms (MDRO). They were E. coli bacteria that produced an enzyme called extended-spectrum beta-lactamase, which makes them resistant to multiple antibiotics. The stool had not been tested for the germs before being given to the patients.

The F.D.A. on Thursday issued a warning to researchers that stool from donors in studies of fecal transplantation should be screened for drug-resistant microbes, and not used if those were present. It is also warning patients that the procedure can be risky, is not approved by the agency and should be used only as a last resort when C. difficile does not respond to standard treatments.

Dr. Marks said the agency was trying to strike a balance between giving patients who need the treatment access to it while also establishing safeguards to protect them from infection. In a statement, he said, “While we support this area of scientific discovery, it’s important to note that fecal microbiota for transplantation does not come without risk.”

Researchers are also looking into the use of fecal transplants to treat chronic gastrointestinal illnesses such as ulcerative colitis or irritable bowel syndrome.

The patients received treatment as part of a clinical trial, and the researchers conducting the trial reported the cases as adverse events to the F.D.A., which they are required to do. But the rules governing this kind of experiment prohibit the F.D.A. from revealing details about the treatment or who provided it.


SOURCE:  https://www.nytimes.com/2019/06/13/health/fecal-transplant-fda.html

A Systematic Review Evaluates the Diagnostic Accuracy of Laboratory Testing Algorithms that Include Nucleic Acid Amplification Tests (NAATs) to Detect the Presence of C. difficile


The evidence base for the optimal laboratory diagnosis of Clostridioides (Clostridium) difficile in adults is currently unresolved due to the uncertain performance characteristics and various combinations of tests.

This systematic review evaluates the diagnostic accuracy of laboratory testing algorithms that include nucleic acid amplification tests (NAATs) to detect the presence of C. difficile. The systematic review and meta-analysis included eligible studies (those that had PICO [population, intervention, comparison, outcome] elements) that assessed the diagnostic accuracy of NAAT alone or following glutamate dehydrogenase (GDH) enzyme immunoassays (EIAs) or GDH EIAs plus C. difficile toxin EIAs (toxin). The diagnostic yield of NAAT for repeat testing after an initial negative result was also assessed.

Two hundred thirty-eight studies met inclusion criteria. Seventy-two of these studies had sufficient data for meta-analysis. The strength of evidence ranged from high to insufficient. The uses of NAAT only, GDH-positive EIA followed by NAAT, and GDH-positive/toxin-negative EIA followed by NAAT are all recommended as American Society for Microbiology (ASM) best practices for the detection of the C. difficile toxin gene or organism. Meta-analysis of published evidence supports the use of testing algorithms that use NAAT alone or in combination with GDH or GDH plus toxin EIA to detect the presence of C. difficile in adults. There is insufficient evidence to recommend against repeat testing of the sample using NAAT after an initial negative result due to a lack of evidence of harm (i.e., financial, length of stay, or delay of treatment) as specified by the Laboratory Medicine Best Practices (LMBP) systematic review method in making such an assessment. Findings from this systematic review provide clarity to diagnostic testing strategies and highlight gaps, such as low numbers of GDH/toxin/PCR studies, in existing evidence on diagnostic performance, which can be used to guide future clinical research studies.

SOURCE:  To Learn More:  https://cmr.asm.org/content/32/3/e00032-18.long?utm_source=dlvr.it&utm_medium=twitter


Clostridioides (Clostridium) difficile infection (CDI) is the leading cause of health care-associated infections in the United States (1, 2). It accounts for 15% to 25% of health care-associated diarrhea cases in all health care settings, with 453,000 documented cases of CDI and 29,000 deaths in the United States in 2015 (3). Acquisition of C. difficile as a health care-associated infection (HAI) is associated with increased morbidity and mortality. This adds a significant burden to the health care system by increasing the length of hospital stay and readmission rates, with significant financial implications. The cost of hospital-associated CDI ranges from $10,000 to $20,000 per case (47) and $500 million to $1.5 billion per year nationally (1, 4, 5, 810).

Accurate diagnosis of CDI is critical for effective patient management and implementation of infection control measures to prevent transmission (11). The diagnosis of CDI requires the combination of appropriate test ordering and accurate laboratory testing to differentiate CDI from non-CDI diarrheal cases, including non-CDI diarrhea in a C. difficile-colonized patient (8). Accurate diagnosis of CDI is critical for appropriate patient management and reduction of harms that may arise from diagnostic error (12) and is critical for implementation of infection control measures to prevent transmission (11). Consequently, among patients presenting with diarrhea, there is significant potential for underdiagnosis or overdiagnosis as can arise from incorrect diagnostic workups (13).

Quality Gap: Factors Associated with the Laboratory Diagnosis of C. difficile

Best practices for laboratory diagnosis of CDI remain controversial (14). Current laboratory practice is not standardized, with wide variation in test methods and diagnostic algorithms. Several laboratory assays are available to support CDI diagnosis in combination with clinical presentation. These include toxigenic culture (TC); the cell cytotoxicity neutralization assay (CCNA); enzyme immunoassays (EIAs) and immunochromatographic assays for the detection of glutamate dehydrogenase (GDH), toxin A or B, or both toxins; and, within the last 10 years, nucleic acid amplification tests (NAATs). Currently, two tests, TC and the CCNA, serve as reference methods for the diagnosis of C. difficile infection (15). The principle of the TC test is to detect strains of C. difficile that produce a toxin(s) following culture on an appropriate medium. CCNA detects fecal protein toxins contained within the stool and is often referred to as fecal toxin detection (16). Unfortunately, both tests are slow and labor-intensive.

Commercially available NAATs for C. difficile detection include those based on PCR or loop-mediated or helicase-dependent isothermal amplification (1720). The performance of NAATs and non-NAAT tests is commonly assessed using diagnostic accuracy measures for the presence of the organism (e.g., diagnostic sensitivity, diagnostic specificity, positive predictive value [PPV], and negative predictive value [NPV]). However, these measures may not directly link to the clinical definition of CDI or clinical outcomes, and some measures (e.g., PPV and NPV) are dependent on disease prevalence in the patient population being tested (8, 17, 19, 20). Finally, in addition to diagnostic sensitivity and specificity, other factors influence the choice of testing strategy, such as cost and turnaround time.

The diagnostic accuracies of current commercially available assays (GDH EIAs, toxin A/B EIAs, and NAATs) are based on comparison with one or both of the currently accepted reference methods (TC and CCNA) for the detection of toxigenic C. difficile, and these comparisons are generally made to inform potential replacement of these reference methods. Although a definitive reference “gold standard” is lacking, both TC and CCNA are regarded as acceptable reference methods (15). However, some view the gold standard to be TC of a stool specimen combined with colonic histopathology of pseudomembranous colitis in patients with symptoms, but it is known that there is a spectrum of disease wherein not all patients with C. difficile infection have pseudomembranes (21). Finally, less frequently, colonoscopic or histopathologic findings demonstrating pseudomembranous colitis can be used in diagnostic workups to increase the diagnostic specificity for CDI diagnosis (14).

In contrasting the two reference methods (TC and CCNA), TC, while infrequently performed in clinical laboratories, is regarded as being more analytically sensitive than CCNA for detecting C. difficile in fecal specimens but may have lower diagnostic specificity (and, therefore, a greater likelihood of false-positive [FP] test results). CCNA has been shown to have high diagnostic sensitivity, ranging from 80 to 100%. In addition, CCNA has high diagnostic specificity and positive predictive values as well as having greater clinical utility based upon clinical outcomes (2226). Furthermore, each reference method differs by the target detected: TC detects the presence of C. difficile strains that produce toxins A and/or B in vitro to confirm a toxigenic strain, whereas CCNA detects the presence of free toxin A or B in clinical specimens. Given these contrasting characteristics, there is potential for diagnostic discrepancy between the reference standards. Therefore, observed diagnostic performance may vary according to which reference standard is used.

Given the variety of test methods and diagnostic algorithms, there is disagreement in the laboratory community on whether best practices for the diagnosis of CDI consist of NAAT only or algorithmic testing that includes NAAT (GDH EIA followed by NAAT [GDH/NAAT] or GDH and toxin EIAs followed by NAAT [GDH/toxin/NAAT]) (20). At the initiation of these guidelines, this was the clinical quandary facing individuals who decide on a C. difficile testing strategy for their health care system, particularly as there is limited high-quality evidence to support which diagnostic testing strategy best supports the laboratory diagnosis of CDI (8, 22). Additionally, it remains to be determined if the potential differences in the accuracy of NAAT only or an algorithmic strategy would impact patient management or patient outcomes (27). There are few studies that encompass the nuances of laboratory CDI diagnosis as it occurs in the clinical context, for example, that evaluate the effect of preanalytic testing considerations on outcomes, to include clinical outcomes. This limitation is evident from the recent Infectious Diseases Society of America (IDSA)/Society for Healthcare Epidemiology of America (SHEA) systematic review, which included only studies that encompassed C. difficile testing within its clinical context, including preanalytic and postanalytic aspects (11).

Given these practice issues, and related diagnostic quality and patient safety concerns, the goal of this systematic review was to determine which laboratory testing strategies, with the inclusion of NAAT, had the best diagnostic accuracy for CDI. While it is clear that laboratory testing alone without taking into consideration the entire clinical picture is not appropriate for the diagnosis of CDI, the available literature has limited evidence linking laboratory diagnosis with clinical outcomes. Therefore, the questions for this systematic review were refined to be based only on the intermediate outcome of diagnostic accuracy for detecting the presence of the C. difficile organism or toxin. Although the reference standard in these studies defines what is meant by the target condition, this systematic review compares the diagnostic accuracies of these tests, including GDH detection by EIA, toxin detection by EIA, and NAAT, to those of CCNA and TC. It has been clear that preanalytical factors are crucial for NAAT specifically, and many of the studies did not include a preanalytical component, which limits whether this review can answer the question, Does this patient have C. difficile infection?

The questions that guided this systematic review were the following: (i) What is the diagnostic accuracy of NAAT only versus either TC or CCNA for detection of the C. difficile toxin gene?, (ii) What is the diagnostic accuracy of a GDH-positive EIA followed by NAAT versus either TC or CCNA for detection of the C. difficile organism/toxin gene?, (iii) What is the diagnostic accuracy of a GDH-positive/toxin-negative EIA followed by NAAT versus either TC or CCNA for detection of the C. difficile organism/toxin/toxin gene?, and (iv) What is the increased diagnostic yield of repeat testing using NAAT after an initial negative result for C. difficile detection of the toxin gene?

The goals of analysis based on these questions were specifically to evaluate the effectiveness of the following: (i) the diagnostic accuracies of NAAT-only and algorithmic (“two-step” or “three-step”) testing strategies, including detection of toxin or GDH in addition to NAAT, and (ii) the diagnostic yield of repeat testing after an initial negative NAAT result. The evidence supporting these two important issues was evaluated by applying the Centers for Disease Control and Prevention (CDC) Laboratory Medicine Best Practices (LMBP) Initiative’s systematic review method for translating results into evidence-based recommendations (28). The method has recently been used to evaluate practices for improving blood culture contamination (29), blood sample hemolysis (30), urine culture sample quality (31), timeliness of providing targeted therapy for bloodstream infections (32), and laboratory test utilization (33), in addition to others, and can be found at the CDC LMBP website (https://www.cdc.gov/labbestpractices/our-findings.html).

National and State Healthcare-associated Infection (HAI) Progress Report from the CDC 2019

Between 2016 and 2017, healthcare-associated infections decreased in the United States, according to the most recent National and State HAI Progress Report   from the CDC.

The report includes a summary of rates for select HAIs across four settings: acute care hospitals, critical access hospitals, inpatient rehabilitation facilities and long-term acute care hospitals.

Key findings from the report include:

1. Central line-associated bloodstream infections saw a 9 percent decrease, with the largest decrease occurring in hospital wards.

2. Catheter-associated urinary tract infections dropped by 5 percent, with ICUs showing the largest decrease of 8 percent.

3. Methicillin-resistant Staphylococcus aureus bacteremia declined by 8 percent and Clostridioides difficile events reduced by 13 percent.

4. Ventilator-associated events and surgical site infections both decreased, by 3 percent and 1 percent respectively. The decrease in SSIs was related to 10 procedures tracked in the report.

5. There were no significant decreases or increases in abdominal hysterectomy SSIs and colon surgery SSIs.


Source:  https://www.beckershospitalreview.com/quality/hais-decreased-in-2017-c-diff-down-13-mrsa-down-8.html

C Diff Foundation Welcomes Dr. Sahil Khanna, M.B.B.S.

We are pleased to welcome Dr. Sahil Khanna
as a Member of the C Diff Foundation and Medical Advisory Board.

Dr. Sahil Khanna is an Associate Professor of Medicine in the Division of Gastroenterology and Hepatology at Mayo Clinic, Rochester, MN. He is directing the Comprehensive Gastroenterology Interest group,
C. difficile Clinic, Fecal Microbiota Transplantation program and
C. difficile related Clinical Trials at Mayo Clinic, Rochester, MN.

He completed Medical School at the All India Institute of Medical Sciences, New Delhi; followed by Post Doctoral Research at University of California San Diego, CA; residency in Internal Medicine and Fellowship in Gastroenterology and Hepatology at Mayo Clinic, Rochester, MN before joining the Faculty. He also completed Masters in Clinical and Translational Sciences during his fellowship. His research and clinical interests include Epidemiology, Outcomes and Emerging Therapeutics for Clostridium difficile infection, an arena in which he has had numerous publications and presentations.

Dr. Khanna has over 100 peer-reviewed publications and serves as reviewer and on the editorial board of several journals. He has won numerous awards including the Miles and Shirley Fiterman Award, Mayo Brothers Distinguished Fellowship Award, Donald C. Balfour Mayo Clinic Alumni Association Research Award, Hartz Foundation Young Investigators’ Scholarship and the Most Distinguished Resident Physician Award from the American Association of Physicians of Indian Origin.

First Isolation of C.diff. PCR Ribotype 027 and Epidemiological Research of CDI in Hospitalized Adults In Tongji Hospital, Central China


Author Information: Zhou Y1, Mao L2, Yu J2, Lin Q2, Luo Y2, Zhu X3, Sun Z4.


Clostridium difficile infection (CDI) is an emerging healthcare problem in the world. The purpose of this study was to perform a systematic epidemiological research of CDI in Tongji hospital, the central of China.


Stool samples from hospitalized adults suspected of CDI were enrolled. The diagnosis of CDI were based on the combination of clinical symptoms and laboratory results. Clinical features of CDI and non-CDI patients were compared by appropriate statistical tests to determine the risk factors of CDI. Multilocus sequence typing (MLST) was employed for molecular epidemiological analysis. Susceptibility testing and relevant antimicrobial agent resistance genes were performed as well.


From June 2016 to September 2017, 839 hospitalized adults were enrolled. Among them, 107 (12.8%, 107/839) patients were C. difficile culture positive, and 73 (8.7%, 73/839) were infected with toxigenic C. difficile (TCD), with tcdA + tcdB+ strains accounting for 90.4% (66/73) and tcdA-tcdB+ for 9.6% (7/73). Meanwhile, two TCD strains were binary toxin positive and one of them was finally identified as CD027. Severe symptoms were observed in these two cases. Multivariate analysis indicated antibiotic exposure (p = 0.001, OR = 5.035) and kidney disease (p = 0.015, OR = 8.329) significantly increased the risk of CDI. Phylogenetic tree analysis demonstrated 21 different STs, including one new ST (ST467); and the most dominant type was ST54 (35.6%, 26/73). Multidrug-resistant (MDR) TCD were 53.4% (39/73); resistance to ciprofloxacin, erythromycin, and clindamycin were > 50%. Other antibiotics showed relative efficiency and all strains were susceptible to metronidazole and vancomycin. All moxifloxacin-resistant isolates carried a mutation in GyrA (Thr82 → Ile), with one both having mutation in GyrB (Ser366 → Ala).


Knowledge of epidemiological information for CDI is limited in China. Our finding indicated tcdA + tcdB+ C. difficile strains were the dominant for CDI in our hospital. Significant risk factors for CDI in our setting appeared to be antibiotic exposure and kidney disease. Metronidazole and vancomycin were still effective for CDI. Although no outbreak was observed, the first isolation of CD027 in center China implied the potential spread of this hypervirulent clone. Further studies are needed to enhance our understanding of the epidemiology of CDI in China.

Source:  https://www.ncbi.nlm.nih.gov/pubmed/30845918?dopt=Abstract&utm_source=dlvr.it&utm_medium=twitter