Category Archives: C. diff. Research & Development

Researchers Share Risk Factors for Recurrence of Clostridioides difficile (formally known as Clostridium difficile) Infection In Japan Real-World Analysis

 

 

 

 

Author information

Abstract

OBJECTIVE:

Recurrent Clostridioides (Clostridium) difficile infection (rCDI) is common and increases healthcare resource utilization. In this study, we assessed rCDI risk factors using an up-to-date, Japanese national hospital-based database.

METHODS:

C. difficile infection (CDI) episodes, occurring July 2014-June 2017, in patients aged ≥18 years were extracted from the database and a nested case-control analysis was performed. Cases were defined as rCDI episodes which required re-initiation of oral vancomycin or oral/intravenous metronidazole treatment within 8 weeks from the start of initial treatment. Cases were matched to 4 non-rCDI episodes at the timing of rCDI occurrence. Adjusted odds ratios (ORs) were estimated using multivariate conditional logistic regression model.

RESULTS:

Of 18,246 initial CDI episodes, 3250 (17.8%) had at least one rCDI. Approximately 90% of episodes occurred in inpatients and 65% were treated with metronidazole. Older age (<75 years vs 75-84 years and vs 85 + years) was associated with higher risk of rCDI (OR = 1.27, 95% confidence interval [1.15, 1.41] and 1.45 [1.30, 1.61], respectively). Use of systemic antibiotics (3.16 [2.90, 3.44]), probiotics (2.53 [2.32, 2.77]), chemotherapy (1.28 [1.08, 1.53]), or proton pump inhibitors (PPIs) (1.17 [1.07, 1.28]), and prior CDI history (1.22 [1.03, 1.43]) were also identified as rCDI risk factors. Vancomycin reduced the risk of rCDI compared with metronidazole treatment (0.83 [0.76, 0.91]).

CONCLUSION:

This large, multicenter, nationwide study confirmed that older age, PPIs, antibiotics, probiotics, chemotherapy, and prior CDI history are risk factors for rCDI in Japan. There was a 17% decrease of rCDI risk with vancomycin vs metronidazole treatment.

CLINICAL TRIAL REGISTRATION NUMBER:N/A.

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University of Virginia School of Medicine Researchers Find Why Certain Patients Are Highly Susceptible to C.diff. Infections

The new finding from the University of Virginia School of Medicine (UVA) explains why certain patients are highly susceptible

to C. diff infections, provides doctors with a way to predict disease severity and points to a new way to treat the often-deadly condition.

The UVA researchers found that the immune response to C. diff causes tissue damage and even death through a type of immune cell called Th17. This solves a longstanding mystery about why disease severity does not correlate with the amount of bacteria in the body but, instead, to the magnitude of the immune response. It also explains why patients with inflammatory bowel disease are more likely to suffer severe C. diff infections and more likely to die from them.

Lingering Effects

The bowel condition colitis, the researchers determined, has a lingering effect on the immune system, priming the patient for a worse C. diff infection.

While scientists have known that C. diff and other bacteria produce toxins that are harmful to the body, they assumed this was a simple matter: more toxin, more sickness.

But UVA’s research reveals that the truth is far more complex. Oftentimes, the type of immune response generated by the body can dictate the outcome of disease independent of bacterial toxin.

“When we, as a lab, started working on this, we were actively discouraged from working

on C. difficile because [some] people in the field thought, ‘Oh, this is a toxin-mediated disease. You don’t need to understand anything more than the fact that the bacteria make toxins,’” UVA’s Dr. William A. Petri Jr. said. “So, it’s been a wonderful opportunity for us because we went in and we sort of countered the prevailing wisdom. Yes, the toxins are important, but the toxins are important because they affect the immune system in dramatic ways.”

Inflammatory Bowel Disease

Seeking to understand why patients with inflammatory bowel disease are so susceptible to C. diff, researcher Mahmoud Saleh created a mouse model of colitis, one of the common forms of inflammatory bowel disease. He was able to determine that mice that recovered from colitis actually had changes in their immune system – an adaptive immune response. Immune cells known as Th17 cells had become hyper-charged, primed to cause a severe reaction to subsequent C. difficile infection. Even the same amount of the bacteria would now cause a dangerous, outsized response. “If we infect a month later, we see that these [T helper cells] alone can cause severe infection,” Saleh said. “So, these cells are sufficient for that increased severity of C. difficile infection.”

The researchers then looked at human samples to determine if their finding would hold true. It did, and they were able to use substances in the blood, including a protein known as interleukin 6 (IL-6), to predict disease severity. Patients with high amounts of IL-6 were almost eight times more likely to die from C. difficile than those with low levels.

Petri, of UVA’s Division of Infectious Diseases and International Health, explained: “Now we know from Mahmoud’s work that if I, as a physician, measure IL-6 in one of my patients with inflammatory bowel disease, I’ll be able to know how severe disease will be in that person and I can make the decision about whether the person needs to be admitted to the hospital … or even go to the intensive care unit.”

Preventing C. diff

The research also suggests a potential new way to treat or prevent severe C. difficile relapses. “We know that in mice by targeting T cells we protect from disease, and that leads to the question, could we do something similar and people to provide better therapy?” Petri said. “It is an interesting and terrible situation right now that C. diff is not resistant to antibiotics, but is resistant to treatment. And so even though we have very, very good antibiotics for this, the [body’s] response is so severe that even though we’re killing the bacteria with the antibiotics, patients are suffering from their own immune response.”

While more research will need to be done to create such a treatment, Petri and Saleh are proud to have solved a big mystery about C. difficile. “When you look at how much bacteria are growing or how much toxin is being produced, a lot of time there is no direct correlation,” Saleh said. “Now we know that what’s making that difference is this immune response.”

Findings Published

The researchers have published their findings in the scientific journal Cell Host & Microbe. The research team consisted of Saleh, Alyse L. Frisbee, Jhansi L. Leslie, Erica L. Buonomo, Carrie A Cowardin, Jennie Z. Ma, Morgan E. Simpson, Kenneth W. Scully, Mayuresh M. Abhyankar and Petri.

The research was supported by the National Institutes of Health, grants T32GM008715, T32AI007496, T32AI007496, T32AI07496, 5F31AI114203, 1R21AI114734 and 1R01AI124214; and the UVA Wagner Fellowship.

 

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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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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

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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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