Category Archives: C. diff. Research & Development

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

Abstract

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

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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).

CONCLUSIONS:

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

Acurx Pharmaceuticals LLC Lead Product ACX-362E Has Successfully Completed First-In-Man Phase I Clinical Trial To Treat C.difficile Infection

 Acurx Pharmaceuticals, LLC is, a privately-held, clinical stage, biopharmaceutical company developing new antibiotics for difficult-to-treat bacterial infections, announced that its lead product candidate, ACX-362E, has successfully completed the 32-subject, double-blinded, placebo-controlled, single-ascending dose portion of this first-in-man Phase 1 clinical trial. ACX-362E is a novel, oral antibacterial agent for the treatment of Clostridioides difficile infection (CDI), an acute, serious, potentially life-threatening, intestinal infection.

ACX-362E is Acurx’s lead compound in a pipeline of molecules that target a previously unexploited mechanism of action, namely, inhibition of the bacterial enzyme DNA polymerase IIIC (pol IIIC).  Pol IIIC is required for DNA replication of many Gram-positive pathogens, including not only Clostridioides but also Enterococcus, Staphylococcus, and Streptococcus.  Although the trial data remain blinded, ongoing monitoring of the data show dose levels up to 600mg have been generally well tolerated. Blood levels of ACX-362E show low systemic exposure, as predicted by prior animal studies and desirable in treating CDI.  Additionally, fecal concentrations of ACX-362E at higher dose levels have exceeded the concentrations known to inhibit C. difficile by several hundred-fold.

“We are very encouraged by these initial data which corroborate our nonclinical findings, showing that at well-tolerated doses ACX-362E reaches concentrations in the colon that are projected to be therapeutically relevant for patients with CDI” said Robert J. DeLuccia, Co-Founder and Managing Partner of Acurx.  “This gives us confidence that the ongoing multiple-dose segment of the trial will provide data to guide selection of our Phase 2 dose and improve the probability of success and timeline efficiency of our Phase 2 clinical trial planned to start later this year.”

Dr. Kevin Garey, Professor, University of Houston College of Pharmacy and the Principal Investigator for microbiomic aspects of the Phase 1 clinical trial said: “The emerging fecal concentration data are comparable to those observed with precedent products that have advanced to demonstrate clinical success. I look forward to the multiple-dose safety data and to the results of the microbiomic analyses that our laboratory is performing which will form a template for a new paradigm in microbiome studies associated with drug discovery and development of CDI-directed antibiotics.”

About the Phase 1 Clinical Trial
This Phase 1 trial, conducted in the U.S., is a double-blinded, placebo-controlled study to determine safety, tolerability, pharmacokinetics and fecal concentrations of ACX-362E in healthy volunteers.  It is being conducted in two parts; first, single ascending doses are administered to four cohorts of 8 subjects each, and second, multiple ascending doses are given that simulate the anticipated clinical treatment regimen. Safety information is analyzed through assessment of adverse events and other standard safety measures, while concentrations of ACX-362E are determined in both the blood and the feces, the latter being the critical site of drug delivery for treating CDI.  In addition, Acurx has partnered with the laboratory of Dr. Kevin Garey at the University of Houston to perform state-of-the-art microbiomic testing of gastrointestinal flora in trial subjects.

About ACX-362E, FDA QIDP and Fast Track Designation
FDA Fast Track Designation is a process designed to facilitate the development and expedite the regulatory pathway of new drugs to treat serious or life-threatening conditions and that fill a high unmet medical need. ACX-362E is a novel, first-in-class, orally-administered antibacterial.  It is the first of a novel class of DNA polymerase IIIC inhibitors under development by Acurx to treat bacterial infections. Acurx acquired ACX-362E from GLSynthesis, Inc. in February 2018.

ACX-362E is a Qualified Infectious Disease Product (QIDP) for the treatment of patients with Clostridium difficile infection (CDI).  Under QIDP designation, ACX-362E will now be eligible to benefit from certain incentives for the development of new antibiotics provided under the Generating Antibiotic Incentives Now Act (the GAIN Act). These incentives include Priority Review and eligibility for Fast Track status. Further, if ultimately approved by the FDA, ACX-362E is eligible for an additional five-year extension of Hatch-Waxman marketing exclusivity. ACX-362E is being developed as a targeted, narrow spectrum oral antibiotic for the treatment of patients with CDI.  Acurx anticipates completing the Phase 1 clinical trial in the second quarter of 2019 and is planning to advance ACX-362E into a Phase 2 clinical trial in the fourth quarter of 2019. The CDC (Centers for Disease Control & Prevention) has designated Clostridium difficile bacteria as an urgent threat highlighting the need for new antibiotics to treat CDI.

RESOURCE:  https://www.acurxpharma.com/news-media/press-releases/detail/8/acurx-announces-first-in-man-clinical-trial-data-of

 

 

First Time Clostridioides difficile Infection Study Reveals Correlation Between Antibiotic Use and CDI Utilizing Data From 2006-2012

ABSTRACT :   Association between Antibiotic Use and Hospital-Onset Clostridioides difficile Infection in U.S. Acute Care Hospitals, 2006-2012: an Ecologic Analysis

“> Sophia V Kazakova, M.D., M.P.H, Ph.D James Baggs, Ph.D L Clifford McDonald, M.D Sarah H Yi, Ph.D Kelly M Hatfield, M.S.P.H Alice Guh, M.D., M.P.H Sujan C Reddy, M.D., M.Sc John A Jernigan, M.D., M.S

Clinical Infectious Diseases, ciz169, https://doi.org/10.1093/cid/ciz169
Published:
01 March 2019
Article history

Abstract

Background

Unnecessary antibiotic use (AU) contributes to increased rates of Clostridioides difficile Infection (CDI). The impact of antibiotic restriction on hospital-onset CDI (HO-CDI) has not been assessed in a large group of U.S. acute care hospitals (ACHs).

Methods

We examined cross-sectional and temporal associations between rates of hospital-level AU and HO-CDI using data from 549 ACHs. HO-CDI, a discharge with a secondary ICD-9-CM for CDI (008.45) and treatment with metronidazole or oral vancomycin ≥ 3 days after admission. Analyses were performed using multivariable generalized estimating equation models adjusting for patient and hospital characteristics.

Results

During 2006-2012, the unadjusted annual rates of HO-CDI and total AU were 7.3 per 10,000 patient-days (PD) (95% CI: 7.1-7.5) and 811 days of therapy (DOT)/1,000 PD (95% CI: 803-820), respectively. In the cross-sectional analysis, for every 50 DOT/1,000 PD increase in total AU, there was a 4.4% increase in HO-CDI.

For every 10 DOT/1,000 PD increase in use of third- and fourth-generation cephalosporins or carbapenems there was a 2.1% and 2.9% increase in HO-CDI, respectively. In the time-series analysis, the 6 ACHs with a ≥ 30% decrease in total AU had a 33% decrease in HO-CDI (rate ratio, 0.67; 95% CI, 0.47-0.96); ACHs with a ≥ 20% decrease in fluoroquinolone or third- and fourth-generation cephalosporin use had a corresponding decrease in HO-CDI of 8% and 13%, respectively.

Conclusions

At an ecologic level, reductions in total AU, use of fluoroquinolones and third- and fourth-generation cephalosporins were each associated with decreased HO-CDI rates.

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https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciz169/5367464?fbclid=IwAR0S6XfRWoKTJNmBoZLQicy2BqzuOOyRF9dx2ctQGRn0K9K0m79cr7Or7pQ

Researchers Find Gut Microbes Linked to Depression

Mice experiments and small studies of people with depression have suggested the involvement of the gut microbiome in both behavior and depression, respectively. However, human research addressing how gut microorganisms might contribute to depression—in large samples and considering confounding factors that can affect the microbiota—is lacking.

A new study of two large groups of Europeans, led by Dr. Sara Vieira-Silva and Dr. Jeroen Raes from the Catholic University of Leuven (Belgium), has found new links between gut microbes and depression.

The researchers used 16S ribosomal ribonucleic acid (rRNA) gene sequencing to analyze the fecal microbiota of 1,054 Belgians enrolled in the Flemish Gut Flora Project, aimed at studying gut microbiome variation at population level. Furthermore, microbial taxa were correlated with the participants’ quality of life and incidence of depression, using a self-reported quality of life questionnaire and general practitioner-supplied diagnoses of the latter. The researchers also validated the associations in an independent cohort of 1,063 individuals from the Netherlands’ LifeLines DEEP (LLD) project.

Ten genus abundances were correlated with quality of life scores, including both mental and physical scores. Among these bacterial genera, Faecalibacterium, Coprococcus, Dialister, Butyrivibrio, Gemmiger, Fusicatenibacter and Prevotella were consistently associated with higher quality of life scores, whereas Parabacteroides, Streptococcus and Flavonifractor showed negative associations. After controlling for a wealth of confounding factors, the authors validated some of these associations in the LLD cohort.

The researchers found that Dialister and Coprococcus genera were reduced in people with depression, after taking into account antidepressant drugs as confounders. Furthermore, the authors described an association between enterotype distribution in relation to quality of life scores and diagnosis of depression in the Flemish cohort. For instance, a higher prevalence of Bacteroides enterotype 2 was linked to lower quality of life and depression.

Finally, the authors dug through metagenomic data to create a catalogue describing the gut microbiota’s ability to synthetize or degrade molecules that can cross-talk with the human nervous system. With this aim, Raes and colleagues assessed the distribution of 56 compounds that play an important role in proper nervous system function, which gut microbes either synthesize or metabolize, in human gut-associated microbial genomes (n=532).

Certain neuroactive compounds might explain the beneficial relationship between gut microbes and quality of life. The researchers found, for example, that GABA and tryptophan metabolism pathways were expressed in human gut-associated microorganisms.

Furthermore, some positive correlations were also observed between quality of life and the potential ability of the gut microbiome to produce 3,4-dihydroxyphenyalcetic acid -a breakdown product of the neurotransmitter dopamine-, isovaleric acid and histamine. Of these, the association between 3,4-dihydroxyphenylacetic acid and quality of life was also replicated in the LLD cohort. As neurotransmitters and neuroactive compounds can also have an impact on bacterial growth, further research is needed to disentangle the contribution of microbe-derived neuroactive molecules to a person’s behavior.

This is the first approach to build a database for studying the gut microbiome’s neuroactive potential and it will help future research to interpret microbiome-gut-mental axis research in a clearer way, supporting the translation of such complex research from the bench to the clinic.

Although these new findings do not prove cause and effect due to the observational design of the study, this research contributes to mounting evidence about mechanisms by which the “microbiome-gut-brain axis” is involved in the development of depression. Further options to experimentally prove the association between the gut microbiota and depression might include rodent models and large studies with enough follow-up periods that explore the role of probiotics, prebiotics, a healthy diet and fecal microbiota transplantation for recovering microbiota, considering the confounding effects of microbiome covariates.

On the whole, this new study strengthens the link between gut bacteria and depression. This is a first step towards understanding how the gut microbiome and its metabolites might affect mood in humans

To read the article in its entirety please click on the following link:

https://www.gutmicrobiotaforhealth.com/en/a-large-study-of-belgian-and-dutch-people-finds-new-associations-between-gut-microbes-and-depression/

Researchers at Chinese University of Hong Kong Develop Fluorescent Microrobots to Detect C.diff.

Researchers at Chinese University of Hong Kong (CUHK) have developed fluorescent microrobots that can spot C. diff in a stool sample within a matter of minutes without relying on expensive laboratory equipment.

The technology relies on fungi spore-inspired microrobots that feature fluorescent functionalised carbon nanodots. When the microrobots encounter toxins produced by C. diff, the brightness of the fluorescence changes, something that can be detected with digital photo equipment.

The process is accelerated by the shape and structure of the microrobots, which spread throughout a diluted stool sample and quickly come in contact with as much as the present toxins as possible. This “active” process also helps to detect low concentrations of toxins, according to the researchers.

Additionally, because the microrobots have iron-based nanoparticles in their structure, they can be manipulated by an external magnetic field and gathered together for best visualization.

Study in journal Science Advances: Real-time tracking of fluorescent magnetic spore–based microrobots for remote detection of C. diff toxins

 

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https://www.medgadget.com/2019/02/microrobots-take-minutes-to-detect-c-diff-in-stool-samples.html

Multidisciplinary Program Duke University Medical Center Included UVC Disinfection Technology To Reduce Hospital-Acquired Infections Including CDI

IN THE NEWS………………..

A new manuscript has been accepted by the Journal of the American College of Surgeons which examines C. diff in adult surgical patients. The paper, “Multidisciplinary Approach and Clostridium difficile Infection in Adult Surgical Patients,” discusses the multidisciplinary program that Duke University Medical Center implemented to reduce its C. diff rate.

In 2017, Duke University Medical Center was identified as a “High Outlier” for postoperative C. diff infections in the American College of Surgeons NSQIP semi-annual report with .4 percent cases per year with an increased risk in morbidity and mortality. To address the issue,

“The Department of Surgery initiated a CDI Task Force with representation from Surgery, Infectious Disease, Pharmacy and Performance Services to analyze available data, identify opportunities for improvement and implement strategies to reduce CDI,” the manuscript states.

Strategies to reduce CDI included antimicrobial stewardship optimization, increased use of Tru-D SmartUVC for terminal cleaning of CDI patient rooms, increased hand hygiene and PPE signage as well as monitoring in high-risk CDI areas, improved diagnostic stewardship by an electronic best practice advisory to reduce inappropriate CDI testing, education through surgical grand rounds and routine data feedback via NSQIP and NHSN CDI reports.

Using these strategies, observed rate of C. diff decreased from 1.27 percent in 2016 to 0.91 percent in 2017, a 28 percent decrease.

“Reducing hospital-acquired infections, especially C. diff, takes a multidisciplinary approach and a commitment to numerous infection prevention protocols,” Alice Brewer, MPH, CIC, Director of Clinical Affairs for Tru-D SmartUVC, said.

As one of the strategies, “We reviewed the terminal cleaning policies for rooms occupied by patients with known CDI once they were discharged from the hospital,” the authors stated. “Additionally, the success at eliminating C. difficile through the established terminal cleans was verified through an auditing process. However, the audit demonstrated that there was variability and ineffective cleaning practices within the hospital system. These deficiencies were largely due to lack of Environmental Services staff and staff trained in Tru-D technology.”

The conclusion provided a basis for requesting the hiring and training of additional Environmental Services staff and “expanded training for terminal cleans was used for the Tru-D technology system, a system which uses an ultraviolet light cleaning system to denature the spores of C. difficile. This provided more effective terminal cleaning.”

By training five additional Tru-D operators, the facility went from using Tru-D on 30 percent of C. diff rooms to 100 percent of C. diff rooms. “Appropriately trained Tru-D technicians increased in number following the initiative from two in 2017 to seven in 2019.

This increase in technicians allowed for an increase in terminal cleans by Tru-D Ultraviolet therapy from 30 percent in March 2017 to 100 percent in September 2018,” the manuscript states.

Validated by multiple studies including the only randomized clinical trial on UVC disinfection, Tru-D has been proven to be a chemical-free and environmentally-friendly way of providing thorough room disinfection. UVC is a type of energy that is invisible to the human eye. Its wavelengths are between 200 and 300 nanometers, making them germicidal – meaning they are capable of inactivating microorganisms, such as bacteria, viruses and protozoa.

“It has been proven that increased utilization of Tru-D and UVC disinfection technology correlates to a reduction in hospital-acquired infections, including C. diff,” Brewer said. “By training additional staff in the operation of Tru-D, Duke was able to achieve 100 percent utilization, which helped to contribute to the 28 percent reduction in C. diff infections.”

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https://www.prnewswire.com/news-releases/duke-university-medical-center-reduces-postoperative-c-diff-rates-with-bundled-approach-300800682.html

Deinove Phase II DNV3837 for C.difficile Infection Clinical Trial To Begin Mid 2019

Deinove is preparing initiation of Phase II for DNV3837 in Clostridium difficile infections, with a key partner

  • The test design has been improved for a better assessment of DNV3837 effectiveness in treating Clostridium difficile infections,
  • This will be a multicenter trial, taking place mostly in the United States, where the prevalence of the disease is high,
  • DEINOVE has chosen Medpace as its Clinical Research Organization (CRO)1 to prepare and oversee the trial, notably because of their experience with the target disease,
  • The trial is scheduled to begin mid-2019,
  • This clinical program will be the focal point of DEINOVE’s antibiotic strategy in the coming months, as the Company has decided not to exercise its option on the NBTI program.

DEINOVE (Euronext Growth Paris: ALDEI), a French biotech company that uses a disruptive approach to develop innovative antibiotics and bio-based active ingredients for cosmetics and nutrition, is preparing the Phase II study that will test DNV3837, its most advanced antibiotic candidate, for use against Clostridium difficile infections (CDI). DEINOVE has chosen Medpace (NASDAQ: MEPD) to act as its CRO and to oversee the clinical trial scheduled to begin in 2019.

DNV3837 is a first-in-class antibiotic candidate targeting the treatment of Clostridium difficile infections (CDIs), a disease classified as a priority by the WHO and one of the leading causes of healthcare-associated infections2. DNV3837 has demonstrated a promising efficacy profile and acceptable tolerance in Phase I trials. The FDA3 has already approved the start of a Phase II study and has granted the DNV3837 program the Qualified Infectious Disease Product (QIDP) designation and Fast Track status4 for accelerated product development.

DEINOVE acquired the DNV3837 program in the 1st half of 2018. Since then, their clinical development team has worked with a group of healthcare experts in CDI to prepare for the start of a Phase II clinical trial whose purpose is to demonstrate the efficacy of DNV3837 in patients suffering from CDI. Several aspects of the trial design, which had been presented to the FDA prior to the acquisition, have been improved:

  • the target patient population was expanded and now covers moderate to severe CDIs for greater progressiveness in treatment assessment;
  • it will be a multicenter trial with a major part taking place in the United States, where there is greater prevalence and the regulatory authorities are looking for new treatment options.

The design of the trial has now been finalized for submission of the updated version to the FDA. The selection process of clinical investigation centers is underway. The trial is scheduled to begin mid-year.

DEINOVE has chosen Medpace to oversee the trial. Medpace is an internationally-recognized full-service CRO that notably has a great deal of experience in infectious diseases, especially gastrointestinal infections like CDIs.

Its mission includes support for the clinical trial’s design and set-up (protocol review, contacting the clinical investigation centers, etc.), gathering and analyzing data, and interacting with the FDA.

Georges Gaudriault, Scientific Director at DEINOVE, said: “Preparations for the Phase II clinical trial for DNV3837 are moving forward as planned and we are delighted to have executed such an agreement with Medpace for this trial’s oversight. Their experience in both the pathology and American regulatory procedures will help us to secure and maximize this trial’s progress.”

The DNV3837 program is followed by the AGIR program (backed by Bpifrance), whose aim is to add to the portfolio of new molecules from DEINOVE’s biodiversity. The option on the NBTI5 program will indeed not be exercised, as the data gathered during the assessment phase were not considered to be in line with DEINOVE’s expectations for pursuing the program.

Emmanuel Petiot, CEO of DEINOVE, added: “The antibiotics field is a priority for DEINOVE and the DNV3837 program is our spearhead. Furthermore, we have decided not to exercise our option on the NBTI program with REDX Pharma, insofar as our teams’ assessment showed obstacles to its development without further optimization. We want to respond quickly and effectively to the health emergency and the lack of innovative antibiotics, and we are focusing our efforts on those programs with the highest possible probability of success.”

 

DNV3837 – a prodrug of the DNV3681 molecule (also known as MCB3681) – is a narrow-spectrum, hybrid oxazolidinone-quinolone synthetic antibiotic, targeting only Gram-positive bacteria. It is developed as a highly active 1st line treatment targeting Clostridium difficile.

It has demonstrated significant efficacy and superiority to reference treatments (fidaxomicin in particular) against isolates of C. diff., regardless of their virulence (including the hyper virulent strain NAP1).

DNV3837 is administered intravenously and is able to cross the gastrointestinal barrier, allowing it to precisely target the infection site. Several Phase I trials (on approx. one hundred healthy volunteers) have shown a high concentration of the antibiotic in stools, a strong marker of its presence in the intestine. It has also demonstrated its ability to eliminate C. diff. bacteria without altering the gut microbiota in the long term, a definite advantage for patient prognosis. It has also shown an acceptable tolerance profile.

FDA granted the DNV3837 program with Qualified Infectious Disease Product (QIDP) designation and Fast Track status.

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https://globenewswire.com/news-release/2019/01/31/1708049/0/en/Deinove-is-preparing-initiation-of-Phase-II-for-DNV3837-in-Clostridium-difficile-infections-with-a-key-partner.html