scholarly journals Protection from Lethal Clostridioides difficile Infection via Intraspecies Competition for Cogerminant

mBio ◽  
2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Jhansi L. Leslie ◽  
Matthew L. Jenior ◽  
Kimberly C. Vendrov ◽  
Alexandra K. Standke ◽  
Madeline R. Barron ◽  
...  
Keyword(s):  
Virulent Strain ◽  
Single Species ◽  
Multiple Infection ◽  
Life Stages ◽  
Content Type ◽  
Clostridioides Difficile ◽  
Nosocomial Diarrhea ◽  
Clostridioides Difficile Infection ◽  
Intraspecies Competition ◽  
Gut Microbial Community

ABSTRACT Clostridioides difficile, a Gram-positive, spore-forming bacterium, is the primary cause of infectious nosocomial diarrhea. Antibiotics are a major risk factor for C. difficile infection (CDI), as they disrupt the gut microbial community, enabling increased germination of spores and growth of vegetative C. difficile. To date, the only single-species bacterial preparation that has demonstrated efficacy in reducing recurrent CDI in humans is nontoxigenic C. difficile. Using multiple infection models, we determined that precolonization with a less virulent strain is sufficient to protect from challenge with a lethal strain of C. difficile, surprisingly even in the absence of adaptive immunity. Additionally, we showed that protection is dependent on high levels of colonization by the less virulent strain and that it is mediated by exclusion of the invading strain. Our results suggest that reduction of amino acids, specifically glycine following colonization by the first strain of C. difficile, is sufficient to decrease germination of the second strain, thereby limiting colonization by the lethal strain. IMPORTANCE Antibiotic-associated colitis is often caused by infection with the bacterium Clostridioides difficile. In this study, we found that reduction of the amino acid glycine by precolonization with a less virulent strain of C. difficile is sufficient to decrease germination of a second strain. This finding demonstrates that the axis of competition for nutrients can include multiple life stages. This work is important, as it is the first to identify a possible mechanism through which precolonization with C. difficile, a current clinical therapy, provides protection from reinfection. Furthermore, our work suggests that targeting nutrients utilized by all life stages could be an improved strategy for bacterial therapeutics that aim to restore colonization resistance in the gut.

scholarly journals Protection from lethal Clostridioides difficile infection via intraspecies competition for co-germinant

2021 ◽  
Author(s):  
Jhansi L Leslie ◽  
Matthew L Jenior ◽  
Kimberly C Vendrov ◽  
Alex Standke ◽  
Madeline R Barron ◽  
...  
Keyword(s):  
Amino Acids ◽  
Virulent Strain ◽  
Single Species ◽  
Multiple Infection ◽  
Clostridioides Difficile ◽  
Nosocomial Diarrhea ◽  
Infection Models ◽  
Clostridioides Difficile Infection ◽  
Intraspecies Competition ◽  
Gut Microbial Community

Clostridioides difficile, a Gram-positive, spore-forming bacterium, is the primary cause of infectious nosocomial diarrhea. Antibiotics are a major risk factor for C. difficile infection (CDI) as they disrupt the gut microbial community, enabling increased germination of spores and growth of vegetative C. difficile. To date the only single-species bacterial preparation that has demonstrated efficacy in reducing recurrent CDI in humans is non-toxigenic C. difficile. Using multiple infection models we determined that pre-colonization with a less virulent strain is sufficient to protect from challenge with a lethal strain of C. difficile, surprisingly even in the absence of adaptive immunity. Additionally, we showed that protection is dependent on high levels of colonization by the less virulent strain and that it is mediated by exclusion of the invading strain. Our results suggest that reduction of amino acids, specifically glycine following colonization by the first strain of C. difficile is sufficient to decrease germination of the second strain thereby limiting colonization by the lethal strain.

scholarly journals Risk Factors Associated with Recurrent Clostridioides difficile Infection

Healthcare ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 352
Author(s):  
Nicoleta Negrut ◽  
Simona Bungau ◽  
Tapan Behl ◽  
Shamim Ahmad Khan ◽  
Cosmin Mihai Vesa ◽  
...  
Keyword(s):  
Treatment Strategies ◽  
First Episode ◽  
Old Patients ◽  
Clostridioides Difficile ◽  
Nosocomial Diarrhea ◽  
Clostridioides Difficile Infection ◽  
Comorbidity Index ◽  
Diarrhea Syndrome ◽  
Multiple Episodes

Clostridioides difficile (CD) is responsible for nosocomial diarrhea syndrome with possible severe progression. Recurrence of the disease induces higher health system costs, as well as exposes patients to additional health risks. Patients with recurrence of this disease are difficult to identify, so the purpose of this study is to quantify various demographic, clinical, and treatment factors that could prevent further progression to recurrence of the disease. In the period 2018–2019, about 195 patients were diagnosed with more than one episode of CDI in the three months following the first episode. The recurrence rate for CDI was 53.84% (60.95% for one episode and 39.05% for multiple episodes). Most commonly afflicted were 60–69-year-old patients, or those with higher Charlson Comorbidity Index (CCI). Multiple analyses associated cardiovascular (odds ratios (OR) = 3.02, 95% confidence intervals (CI) = 1.23–7.39, p = 0.015), digestive (OR = 3.58, 95% CI = 1.01–12.63, p = 0.047), dementia (OR = 3.26, 95% CI = 1.26–8.41, p = 0.014), immunosuppressive (OR = 3.88, 95% CI = 1.34–11.21, p = 0.012) comorbidities with recurrences. Risk factor identification in the first episode of CDI could lead to the implementation of treatment strategies to improve the patients’ quality of life affected by this disease.

scholarly journals Initial vancomycin versus metronidazole for the treatment of first-episode non-severe Clostridioides difficile infection

2021 ◽  
Vol 1 (1) ◽  
Author(s):  
Kevin Zhang ◽  
Patricia Beckett ◽  
Salaheddin Abouanaser ◽  
Marek Smieja
Keyword(s):  
Treatment Guidelines ◽  
Multivariable Analysis ◽  
Current Treatment ◽  
Multivariate Logistic Regression Model ◽  
First Episode ◽  
Study Cohort ◽  
Clostridioides Difficile ◽  
Nosocomial Diarrhea ◽  
Clostridioides Difficile Infection ◽  
Incident Infection

Abstract Objective: Clostridioides difficile infection (CDI) is the leading cause of infectious nosocomial diarrhea. Although initial fidaxomicin or vancomycin treatment is recommended by most major guidelines to treat severe CDI, there exists varied recommendations for first-episode non-severe CDI. Given the discrepancy in current treatment guidelines, we sought to evaluate the use of initial vancomycin versus metronidazole for first-episode non-severe CDI. Methods: We conducted a retrospective cohort study of all adult inpatients with first-episode CDI at our institution from January 2013 to May 2018. The initial vancomycin versus initial metronidazole cohorts were examined using a multivariate logistic regression model. Results: The study cohort of 737 patients had a median age of 72.3 years, and 357 of these patients (48.4%) had hospital-acquired infection. Among 326 patients with non-severe CDI, recurrence, new incident infection, and 30-day mortality rates were 16.2%, 10.9%, and 5.3%, respectively, when treated with initial metronidazole, compared to 20.0%, 1.4%, and 10.0%, respectively, when treated with initial vancomycin. In an adjusted multivariable analysis, the use of initial vancomycin for the treatment of non-severe CDI was associated with a reduction in new incident infection (adjusted odds ratio [ORadj], 0.11; 95% confidence interval [CI], 0.02–0.86; P = .035), compared to initial metronidazole. Conclusions: Initial vancomycin was associated with a reduced rate of new incident infection in the treatment of adult inpatients with first-episode non-severe CDI. These findings support the use of initial vancomycin for all inpatients with CDI, when fidaxomicin is unavailable.

scholarly journals Evaluation of Cycle Threshold, Toxin Concentration, and Clinical Characteristics of Clostridioides difficile Infection in Patients with Discordant Diagnostic Test Results

2020 ◽  
Vol 58 (5) ◽  
Author(s):  
Megan D. Shah ◽  
Joan-Miquel Balada-Llasat ◽  
Kelci Coe ◽  
Erica Reed ◽  
Johanna Sandlund ◽  
...  
Keyword(s):  
Clinical Characteristics ◽  
Laboratory Data ◽  
Antibiotic Use ◽  
Neutralization Assay ◽  
Test Results ◽  
Toxin Concentration ◽  
Content Type ◽  
Cycle Threshold ◽  
Clostridioides Difficile ◽  
Clostridioides Difficile Infection

ABSTRACT Clostridioides difficile infection (CDI) is one of the most common health care-associated infections that can cause significant morbidity and mortality. CDI diagnosis involves laboratory testing in conjunction with clinical assessment. The objective of this study was to assess the performance of various C. difficile tests and to compare clinical characteristics, Xpert C. difficile/Epi (PCR) cycle threshold (CT), and Singulex Clarity C. diff toxins A/B (Clarity) concentrations between groups with discordant test results. Unformed stool specimens from 200 hospitalized adults (100 PCR positive and 100 negative) were tested by cell cytotoxicity neutralization assay (CCNA), C. diff Quik Chek Complete (Quik Chek), Premier Toxins A and B, and Clarity. Clinical data, including CDI severity and CDI risk factors, were compared between discordant test results. Compared to CCNA, PCR had the highest sensitivity at 100% and Quik Chek had the highest specificity at 100%. Among clinical and laboratory data studied, prevalences of leukocytosis, prior antibiotic use, and hospitalizations were consistently higher across all subgroups in comparisons of toxin-positive to toxin-negative patients. Among PCR-positive samples, the median CT was lower in toxin-positive samples than in toxin-negative samples; however, CT ranges overlapped. Among Clarity-positive samples, the quantitative toxin concentration was significantly higher in toxin-positive samples than in toxin-negative samples as determined by CCNA and Quik Chek Toxin A and B. Laboratory tests for CDI vary in sensitivity and specificity. The quantitative toxin concentration may offer value in guiding CDI diagnosis and treatment. The presence of leukocytosis, prior antibiotic use, and previous hospitalizations may assist with CDI diagnosis, while other clinical parameters may not be consistently reliable.

scholarly journals 2423. Cost-effectiveness of core and emerging infection control interventions to reduce hospital-onset Clostridioides difficile infection: An agent-based simulation modeling approach

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S837-S837
Author(s):  
Oguzhan Alagoz ◽  
Anna K Barker ◽  
Elizabeth Scaria ◽  
Nasia Safdar
Keyword(s):  
Cost Effectiveness ◽  
Hand Hygiene ◽  
Infection Control ◽  
Hospital Setting ◽  
Multiple Infection ◽  
Agent Based ◽  
Emerging Infection ◽  
Clostridioides Difficile ◽  
Clostridioides Difficile Infection ◽  
The Cost

Abstract Background Multiple infection control interventions have been recommended to reduce hospital-onset Clostridioides difficile infection (C. difficile; HO-CDI), including contact isolation, environmental disinfection, and hand hygiene. These interventions have differential effects on reducing HO-CDI that change for each hospital setting. In the context of today’s constrained resources, with trade-offs a necessary part of any prevention plan, infection control personnel need information regarding intervention cost-effectiveness that is tailored to their unique hospital setting. Methods We evaluated the cost-effectiveness of nine infection control interventions and eight multiple-intervention bundles using our group’s agent-based model of C. difficile transmission. This previously developed model represents a general 200-bed acute-care adult hospital. Effectiveness was measured from the hospital perspective in terms of both quality-adjusted life years (QALYs) and HO-CDIs. Results Six interventions reduced cost while increasing QALYs and averting HO-CDI, compared with baseline standard hospital practices: daily cleaning (saved an average of $407,854 and 36.8 QALYs annually in a 200-bed hospital), HCW hand hygiene ($181,767; 17.7 QALYs), patient hand hygiene ($25,700; 6.3 QALYs), terminal cleaning ($64,986; 12.8 QALYs), screening at admission ($9,083; 18.5 QALYs), and reducing patient transfers ($27,514; 3.1 QALYs). Adding patient hand hygiene to the HCW hand hygiene intervention was cost saving. When screening, HCW hand hygiene, and patient hand hygiene interventions were sequentially added to daily cleaning to form two, three, and four-pronged bundles, the incremental cost-effectiveness ratios for these additions were $26,588, $44,173, and $123,379 per QALY, respectively. Conclusion Using cost-effectiveness data, institutions may consider streamlining their infection control initiatives and prioritizing a smaller number of highly effective interventions. Our model could be used to evaluate the cost-effectiveness of existing core and emerging infection control interventions for specific hospital settings. Disclosures All authors: No reported disclosures.

scholarly journals Identification of Simplified Microbial Communities That Inhibit Clostridioides difficile Infection through Dilution/Extinction

mSphere ◽  
2020 ◽  
Vol 5 (4) ◽  
Author(s):  
Jennifer M. Auchtung ◽  
Eva C. Preisner ◽  
James Collins ◽  
Armando I. Lerma ◽  
Robert A. Britton
Keyword(s):  
Fecal Microbiota Transplantation ◽  
Gastrointestinal Diseases ◽  
Fecal Microbiota ◽  
Content Type ◽  
Susceptibility To Infection ◽  
Clostridioides Difficile ◽  
Fold Reduction ◽  
Clostridioides Difficile Infection ◽  
Community Types

ABSTRACT The gastrointestinal microbiome plays an important role in limiting susceptibility to infection with Clostridioides difficile. To better understand the ecology of bacteria important for C. difficile colonization resistance, we developed an experimental platform to simplify complex communities of fecal bacteria through dilution and rapidly screen for their ability to resist C. difficile colonization after challenge, as measured by >100-fold reduction in levels of C. difficile in challenged communities. We screened 76 simplified communities diluted from cultures of six fecal donors and identified 24 simplified communities that inhibited C. difficile colonization in vitro. Sequencing revealed that simplified communities were composed of 19 to 67 operational taxonomic units (OTUs) and could be partitioned into four distinct community types. One simplified community could be further simplified from 56 to 28 OTUs through dilution and retain the ability to inhibit C. difficile. We tested the efficacy of seven simplified communities in a humanized microbiota mouse model. We found that four communities were able to significantly reduce the severity of the initial C. difficile infection and limit susceptibility to disease relapse. Analysis of fecal microbiomes from treated mice demonstrated that simplified communities accelerated recovery of indigenous bacteria and led to stable engraftment of 19 to 22 OTUs from simplified communities. Overall, the insights gained through the identification and characterization of these simplified communities increase our understanding of the microbial dynamics of C. difficile infection and recovery. IMPORTANCE Clostridioides difficile is the leading cause of antibiotic-associated diarrhea and a significant health care burden. Fecal microbiota transplantation is highly effective at treating recurrent C. difficile disease; however, uncertainties about the undefined composition of fecal material and potential long-term unintended health consequences remain. These concerns have motivated studies to identify new communities of microbes with a simpler composition that will be effective at treating disease. This work describes a platform for rapidly identifying and screening new simplified communities for efficacy in treating C. difficile infection. Four new simplified communities of microbes with potential for development of new therapies to treat C. difficile disease are identified. While this platform was developed and validated to model infection with C. difficile, the underlying principles described in the paper could be easily modified to develop therapeutics to treat other gastrointestinal diseases.

scholarly journals The Clostridioides difficile Cysteine-Rich Exosporium Morphogenetic Protein, CdeC, Exhibits Self-Assembly Properties That Lead to Organized Inclusion Bodies in Escherichia coli

mSphere ◽  
2020 ◽  
Vol 5 (6) ◽  
Author(s):  
A. Romero-Rodríguez ◽  
S. Troncoso-Cotal ◽  
E. Guerrero-Araya ◽  
D. Paredes-Sabja
Keyword(s):  
Escherichia Coli ◽  
Recombinant Proteins ◽  
Self Assembly ◽  
Inclusion Bodies ◽  
Content Type ◽  
Clostridioides Difficile ◽  
Nosocomial Diarrhea ◽  
Morphogenetic Protein ◽  
Underlying Mechanisms

ABSTRACT Clostridioides difficile is an obligately anaerobic, spore-forming, Gram-positive pathogenic bacterium that is considered the leading cause of nosocomial diarrhea worldwide. Recent studies have attempted to understand the biology of the outermost layer of C. difficile spores, the exosporium, which is believed to contribute to early interactions with the host. The fundamental role of the cysteine-rich proteins CdeC and CdeM has been described. However, the molecular details behind the mechanism of exosporium assembly are missing. The underlying mechanisms that govern exosporium assembly in C. difficile remain poorly studied, in part due to difficulties in obtaining pure soluble recombinant proteins of the C. difficile exosporium. In this work, we observed that CdeC was able to form organized inclusion bodies (IBs) in Escherichia coli filled with lamella-like structures separated by an interspace of 5 to 15 nm; however, CdeC expression in an E. coli strain with a more oxidative environment led to the loss of the lamella-like organization of CdeC IBs. Additionally, dithiothreitol (DTT) treatment of CdeC inclusion bodies released monomeric soluble forms of CdeC. Deletions in different portions of CdeC did not affect CdeC’s ability to aggregate and form oligomers stable under denaturation conditions but affected CdeC’s self-assembly properties. Overall, these observations have important implications in further studies elucidating the role of CdeC in the exosporium assembly of C. difficile spores. IMPORTANCE The endospore of Clostridioides difficile is the vehicle for transmission and persistence of the pathogen, and, specifically, the exosporium is the first contact between the host and the spore. The underlying mechanisms that govern exosporium assembly in C. difficile remain understudied, in part due to difficulties in obtaining pure soluble recombinant proteins of the C. difficile exosporium. Understanding the exosporium assembly’s molecular bases may be essential to developing new therapies against C. difficile infection.

scholarly journals Neonatal Piglets Are Protected from Clostridioides difficile Infection by Age-Dependent Increase in Intestinal Microbial Diversity

2021 ◽  
Author(s):  
Alexandra Proctor ◽  
Nancy A. Cornick ◽  
Chong Wang ◽  
Shankumar Mooyottu ◽  
Paulo A. Arruda ◽  
...  
Keyword(s):  
Bacterial Pathogen ◽  
The United States ◽  
Significant Morbidity ◽  
Common Cause ◽  
Content Type ◽  
Neonatal Piglets ◽  
Neonatal Pigs ◽  
Clostridioides Difficile ◽  
Age Dependent ◽  
Clostridioides Difficile Infection

C. difficile is an important bacterial pathogen that is the most common cause of infections associated with health care in the United States. It also causes significant morbidity and mortality in neonatal pigs, and currently there are no preventative treatments available to livestock producers.

scholarly journals Antibiotic Exposure and Risk for Hospital-Associated Clostridioides difficile Infection

2020 ◽  
Vol 64 (4) ◽  
Author(s):  
Brandon J. Webb ◽  
Aruna Subramanian ◽  
Bert Lopansri ◽  
Bruce Goodman ◽  
Peter Bjorn Jones ◽  
...  
Keyword(s):  
Health Care ◽  
Care Facility ◽  
Health Care Facility ◽  
Antibiotic Use ◽  
Antibiotic Exposure ◽  
Content Type ◽  
Clostridioides Difficile ◽  
Clostridioides Difficile Infection ◽  
Intermountain Healthcare ◽  
Health Care Associated Infection

ABSTRACT Clostridioides difficile infection (CDI) is a health care-associated infection associated with significant morbidity and cost, with highly varied risk across populations. More effective, risk-based prevention strategies are needed. Here, we investigate risk factors for hospital-associated CDI in a large integrated health system. In a retrospective cohort of all adult admissions to 21 Intermountain Healthcare hospitals from 2006 to 2012, we identified all symptomatic (i) hospital-onset and (ii) health care-facility-associated, community-onset CDI. We then evaluated the risk associated with antibiotic exposure, including that of specific agents, using multivariable logistic regression. A total of 2,356 cases of CDI among 506,068 admissions were identified (incidence, 46.6 per 10,000). Prior antibiotic use was the dominant risk factor, where for every antibiotic day of therapy prior to the index admission, the odds of subsequent CDI increased by 12.8% (95% confidence interval [CI], 12.2 to 13.4%; P < 0.0001). This was a much stronger association than was inpatient antibiotic exposure (odds ratio [OR], 1.007 [95% CI, 1.005 to 1.009]; P < 0.0001). The highest-risk antibiotics included second-generation and later cephalosporins (especially oral), carbapenems, fluoroquinolones, and clindamycin, while doxycycline and daptomycin were associated with a lower CDI risk. We concluded that cumulative antibiotic exposure prior to admission is the greatest contributor to the risk of subsequent CDI. Most classes of antibiotics carry some risk, which varies by drug and route. This information may be useful for antimicrobial stewardship efforts.

scholarly journals Dissecting Individual Interactions between Pathogenic and Commensal Bacteria within a Multispecies Gut Microbial Community

mSphere ◽  
2021 ◽  
Vol 6 (2) ◽  
Author(s):  
Jack Hassall ◽  
Jeffrey K. J. Cheng ◽  
Meera Unnikrishnan
Keyword(s):  
Gut Microbiota ◽  
Bacterial Species ◽  
Single Species ◽  
Commensal Bacteria ◽  
Individual Species ◽  
Human Gut ◽  
Content Type ◽  
Clostridioides Difficile ◽  
Gut Pathogen

ABSTRACT Interactions of commensal bacteria within the gut microbiota and with invading pathogens are critical in determining the outcome of an infection. While murine studies have been valuable, we lack in vitro models to monitor community responses to pathogens at a single-species level. We have developed a multispecies community of nine representative gut species cultured together as a mixed biofilm and tracked numbers of individual species over time using a quantitative PCR (qPCR)-based approach. Introduction of the major nosocomial gut pathogen, Clostridioides difficile, to this community resulted in increased adhesion of commensals and inhibition of C. difficile multiplication. Interestingly, we observed an increase in individual Bacteroides species accompanying the inhibition of C. difficile. Furthermore, Bacteroides dorei reduced C. difficile growth within biofilms, suggesting a role for Bacteroides spp. in prevention of C. difficile colonization. We report here an in vitro tool with excellent applications for investigating bacterial interactions within a complex community. IMPORTANCE Studying interactions between bacterial species that reside in the human gut is crucial for gaining a better insight into how they provide protection from pathogen colonization. In vitro models of multispecies bacterial communities wherein behaviors of single species can be accurately tracked are key to such studies. Here, we have developed a synthetic, trackable, gut microbiota community which reduces growth of the human gut pathogen Clostridioides difficile. We report that Bacteroides spp. within this community respond by multiplying in the presence of this pathogen, resulting in reduction of C. difficile growth. Defined in vitro communities that can be tailored to include different species are well suited to functional genomic approaches and are valuable tools for understanding interbacterial interactions.

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