Clostridioides difficile Biofilm.

Clostridioides difficile infection (CDI), previously Clostridium difficile infection, is a symptomatic infection of the large intestine caused by the spore-forming anaerobic, gram-positive bacterium Clostridioides difficile. CDI is an important healthcare-associated disease worldwide, characterized by high levels of recurrence, morbidity, and mortality. CDI is observed at a higher rate in immunocompromised patients after antimicrobial therapy, with antibiotics disrupting the commensal microbiota and promoting C. difficile colonization of the gastrointestinal tract.A rise in clinical isolates resistant to multiple antibiotics and the reduced susceptibility to the most commonly used antibiotic molecules have made the treatment of CDI more complicated, allowing the persistence of C. difficile in the intestinal environment.Gut colonization and biofilm formation have been suggested to contribute to the pathogenesis and persistence of C. difficile. In fact, biofilm growth is considered as a serious threat because of the related antimicrobial tolerance that makes antibiotic therapy often ineffective. This is the reason why the involvement of C. difficile biofilm in the pathogenesis and recurrence of CDI is attracting more and more interest, and the mechanisms underlying biofilm formation of C. difficile as well as the role of biofilm in CDI are increasingly being studied by researchers in the field.Findings on C. difficile biofilm, possible implications in CDI pathogenesis and treatment, efficacy of currently available antibiotics in treating biofilm-forming C. difficile strains, and some antimicrobial alternatives under investigation will be discussed here.

Clostridioides difficile infections; new treatments and future perspectives.

PURPOSE OF REVIEW: As a significant cause of global morbidity and mortality, Clostridioides difficile infections (CDIs) are listed by the Centres for Disease Control and prevention as one of the top 5 urgent threats in the USA. CDI occurs from gut microbiome dysbiosis, typically through antibiotic-mediated disruption; however, antibiotics are the treatment of choice, which can result in recurrent infections. Here, we highlight new treatments available and provide a perspective on different classes of future treatments. RECENT FINDINGS: Due to the reduced risk of disease recurrence, the microbiome-sparing antibiotic Fidaxomicin has been recommended as the first-line treatment for C. difficile infection. Based on the success of faecal microbiota transplantations (FMT) in treating CDI recurrence, defined microbiome biotherapeutics offer a safer and more tightly controlled alterative as an adjunct to antibiotic therapy. Given the association between antibiotic-mediated dysbiosis of the intestinal microbiota and the recurrence of CDI, future prospective therapies aim to reduce the dependence on antibiotics for the treatment of CDI. SUMMARY: With current first-in-line antibiotic therapy options associated with high levels of recurrent CDI, the availability of new generation targeted therapeutics can really impact treatment success. There are still unknowns about the long-term implications of these new CDI therapeutics, but efforts to expand the CDI treatment toolbox can offer multiple solutions for clinicians to treat this multifaceted infectious disease to reduce patient suffering.

MiGut: A scalable in vitro platform for simulating the human gut microbiome-Development, validation and simulation of antibiotic-induced dysbiosis.

In vitro models of the human colon have been used extensively in understanding the human gut microbiome (GM) and evaluating how internal and external factors affect the residing bacterial populations. Such models have been shown to be highly predictive of in vivo outcomes and have a number of advantages over animal models. The complexity required by in vitro models to closely mimic the physiology of the colon poses practical limits on their scalability. The scalable Mini Gut (MiGut) platform presented in this paper allows considerable expansion of model replicates and enables complex study design, without compromising on in vivo reflectiveness as is often the case with other model systems. MiGut has been benchmarked against a validated gut model in a demanding 9-week study. MiGut showed excellent repeatability between model replicates and results were consistent with those of the benchmark system. The novel technology presented in this paper makes it conceivable that tens of models could be run simultaneously, allowing complex microbiome-xenobiotic interactions to be explored in far greater detail, with minimal added resources or complexity. This platform expands the capacity to generate clinically relevant data to support our understanding of the cause-effect relationships that govern the GM.

Transcatheter aortic valve implantation-related infective endocarditis: experience from an Irish tertiary referral centre.

BACKGROUND: Transcatheter aortic valve implantation-related infective endocarditis (TAVI-IE) is a well-recognised and serious complication following TAVI. The purpose of this study was to describe the clinical characteristics, microorganism spectrum, and outcomes of TAVI-IE in an Irish context. METHODS: A prospective registry was used to assess the baseline demographics, procedural variables, and clinical outcomes of patients undergoing TAVI between 2009 and 2020 at two tertiary referral Irish Hospitals. RESULTS: A total of 733 patients underwent TAVI during the study period. During a follow-up duration of 1,949 person-years (median 28 months), TAVI-IE occurred in 17 (2.3%) patients. The overall incidence was 0.87 per 100 person-years and the median time from TAVI to presentation with IE was 7 months [IQR: 5-13 months]. In those who developed TAVI-IE, the mean age was 78.7 years, 70.5% were male, and there was a trend towards more permanent pacemaker implantations post-TAVI (17.6% vs. 5.86%; p = 0.08). The dominant culprit microorganisms were streptococci (41.1%) and four (23.5%) cases were attributed to dental seeding. Major complications of TAVI-IE included one (5.8%) stroke, one (5.8%) in-hospital death, and two (11.7%) urgent surgical aortic valve replacements. The Kaplan-Meier estimate of survival at 1-year was 82% (95% CI = 55-95). CONCLUSIONS: This Irish cohort of TAVI-IE exhibited a similar incidence and time to presentation compared to prior international registries; however, the 1-year mortality rate was comparatively lower. The need for rigorous dental clearance pre-TAVI and maintenance of dental health post-TAVI is underscored by the high prevalence of oral streptococcus species in this cohort.

Intravascular lithotripsy-assisted PCI for severely calcified coronary lesions: evaluating the impact on quality of life and outcomes.

BACKGROUND: Despite the increased uptake of intravascular lithotripsy (IVL) for treating severely calcified coronary lesions, there is limited patient-level data examining the effect of IVL on quality of life, symptomatology, and outcomes beyond 30 days. We sought to assess demographics, procedural characteristics, outcomes, and impact of IVL on patient-reported angina after a minimum of 6 months follow-up. METHODS: A retrospective single-center study was conducted of patients treated with coronary IVL between January and October 2020. Baseline demographics were obtained from electronic patient records and SYNTAX scores were calculated from index coronary angiograms. Technical success and complications were assessed along with clinical outcomes, which included all-cause mortality, myocardial infarction (MI), target lesion revascularization (TLR), and MACE (composite of death, stroke, MI, and TLR). Canadian Cardiovascular Society (CCS) angina classification was assessed at virtual clinical follow-up. RESULTS: Forty-seven consecutive patients were included. At a mean follow-up of 306 ± 74 days, the mean CCS angina score was reduced by 53% post-IVL-assisted PCI (2.9 vs 1.4, p < 0.001). Technical and procedural success were high (94% and 92%, respectively). One patient (2%) met the pre-specified criteria for in-hospital MACE and 4 (9%) met pre-specified MACE at follow-up, including 2 deaths and 2 TLR. Procedural complications included coronary dissection (11%) and coronary perforation (6%) and were managed either conservatively or with PCI. CONCLUSIONS: Coronary IVL is a safe and effective adjunctive therapy for treating heavily calcified coronary lesions. This cohort shows high procedural success and a significant reduction in CCS angina at follow-up.

Total ischaemic time in STEMI: factors influencing systemic delay.

Total ischaemic time in ST-elevation myocardial infarction (STEMI) has been shown to be a predictor of mortality. The aim of this study was to assess the total ischaemic time of STEMIs in an Irish primary percutaneous coronary intervention (pPCI) centre. A single-centre prospective observational study was conducted of all STEMIs referred for pPCI from October 2017 until January 2019. There were 213 patients with a mean age 63.9 years (range 29-96 years). The mean ischaemic time was 387 ± 451.7 mins. The mean time before call for help (patient delay) was 207.02 ± 396.8 mins, comprising the majority of total ischaemic time. Following diagnostic electrocardiogram (ECG), 46.5% of patients had ECG-to-wire cross under 90 mins as per guidelines; 73.9% were within 120 mins and 93.4% were within 180 mins. Increasing age correlated with longer patient delay (Pearson's r=0.2181, p=0.0066). Women exhibited longer ischaemic time compared with men (508.96 vs. 363.33 mins, respectively, p=0.03515), driven by a longer time from first medical contact (FMC) to ECG (104 vs. 34 mins, p=0.0021). The majority of total ischaemic time is due to patient delay, and this increases as age increases. Women had longer ischaemic time compared with men and longer wait from FMC until diagnostic ECG. This study suggests that improved awareness for patients and healthcare staff will be paramount in reducing ischaemic time.

Acute Deep Vein Thrombosis in a Cyclist With Iliac Vein Compression From Psoas Muscle Hypertrophy.

A 22-year-old avid cyclist presented with 1 month of right lower extremity pain and associated swelling. Subsequent imaging demonstrated an extensive acute deep vein thrombosis (DVT) in the setting of right iliac vein compression from psoas muscle hypertrophy. We present an unusual risk factor for DVT among cyclists. (Level of Difficulty: Intermediate.).

Profiling the Effects of Systemic Antibiotics for Acne, Including the Narrow-Spectrum Antibiotic Sarecycline, on the Human Gut Microbiota.

Treatment for moderate-to-severe acne vulgaris relies on prolonged use of oral tetracycline-class antibiotics; however, these broad-spectrum antibiotics are often associated with off-target effects and negative gastrointestinal sequelae. Sarecycline is a narrow-spectrum antibiotic treatment option. Here, we investigated the effect of prolonged sarecycline exposure, compared with broad-spectrum tetracyclines (doxycycline and minocycline) upon the colonic microbiota. Three in vitro models of the human colon were instilled with either minocycline, doxycycline or sarecycline, and we measured microbiota abundance and diversity changes during and after antibiotic exposure. Significant reductions in microbial diversity were observed following minocycline and doxycycline exposure, which failed to recover post antibiotic withdrawal. Specifically, minocycline caused a ~10% decline in Lactobacillaceae and Bifidobacteriaceae abundances, while doxycycline caused a ~7% decline in Lactobacillaceae and Bacteroidaceae abundances. Both minocycline and doxycycline were associated with a large expansion (>10%) of Enterobacteriaceae. Sarecycline caused a slight decline in bacterial diversity at the start of treatment, but abundances of most families remained stable during treatment. Ruminococcaceae and Desulfovibrionaceae decreased 9% and 4%, respectively, and a transient increased in Enterobacteriaceae abundance was observed during sarecycline administration. All populations recovered to pre-antibiotic levels after sarecycline exposure. Overall, sarecycline had minimal and transient impact on the gut microbiota composition and diversity, when compared to minocycline and doxycycline.

Peak troponin T in STEMI: a predictor of all-cause mortality and left ventricular function.

BACKGROUND: The clinical significance of peak troponin levels following ST-elevation myocardial infarction (STEMI) has not been definitively established. The purpose of this study was to examine the relationship between peak high-sensitivity cardiac troponin T (hs-cTnT) and all-cause mortality at 30 days and 1 year, and left ventricular ejection fraction (LVEF) in STEMI. METHODS: A single-centre retrospective observational study was conducted of all patients with STEMI between January 2015 and December 2017. Demographics and clinical data were obtained through electronic patient records. Standard Bayesian statistics were employed for analysis. RESULTS: During the study period, 568 patients presented with STEMI. The mean age was 63.6±12 years and 76.4% were men. Of these, 535 (94.2%) underwent primary percutaneous coronary intervention, 12 (2.1%) underwent urgent coronary artery bypass and 21 (3.7%) were treated medically. Mean peak hs-cTnT levels were significantly higher in those who died within 30 days compared with those who survived (12 238 ng/L vs 4657 ng/L, respectively; p=0.004). Peak hs-cTnT levels were also significantly higher in those who died within 1 year compared with those who survived (10 319 ng/L vs 4622 ng/L, respectively; p=0.003). The left anterior descending artery was associated with the highest hs-cTnT and was the most common culprit in those who died at 1 year. An inverse relationship was demonstrated between peak hs-cTnT and LVEF (Pearson's R=0.379; p<0.00001). CONCLUSIONS: In STEMI, those who died at 30 days and 1 year had significantly higher peak troponin levels than those who survived. Peak troponin is also inversely proportional to LVEF with higher troponins associated with lower LVEF.

Mechanical Chest Compressions and Intra-Aortic Balloon Pump Combination for Refractory Ventricular Fibrillation During Primary PCI.

This case highlights the successful resuscitation of a 43-year-old man with ST-segment elevation myocardial infarction and refractory ventricular fibrillation by using a combination of mechanical chest compressions and intra-aortic balloon pump insertion. This bailout strategy facilitated primary multivessel percutaneous coronary intervention in a center without on-site extracorporeal membrane oxygenation. (Level of Difficulty: Advanced.).

Use your head: overcoming epicardial complications during a single-catheter chronic total occlusion-a case-based review.

The success of attempts at opening chronic total occlusions (CTO) has dramatically increased in recent times due to the development of new techniques such as the use of the retrograde approach through epicardial collaterals. However, this approach admittedly brings with it an increased risk, and this must be balanced against the potential benefits. We present the case of a 61-year-old gentleman with Canadian Cardiovascular Society (CCS) Class III angina with a background history of hypertension and dyslipidaemia, who was an ex-smoker, and whose diagnostic coronary angiogram revealed CTOs of both the right and left circumflex coronary arteries. Following a heart team discussion, a percutaneous approach to treatment by staged approach was favoured, with the first stage being opening of the CTO of the right coronary artery. A retrograde approach with the use of a Corsair microcatheter facilitated reverse CART (controlled antegrade and retrograde tracking). Unfortunately, upon removal of the Corsair, a rupture of the epicardial collateral was noted with profuse bleeding into the pericardial space. This was treated successfully with a BeGraft-covered stent to obtain proximal control, and a Cooke Tornado neuro-interventional coil to obtain distal control, delivered antegrade through the now recanalized RCA. This case-based review then highlights several unique learning points, in particular to understand, in general terms, the approach to CTO; to understand the potential complications associated with a retrograde epicardial collateral approach; to understand the stepwise approach to dealing with perforation; and, finally, to understand how an occlusion coil works.

Can SARS-CoV-2 be transmitted via faeces?

PURPOSE OF REVIEW: COVID-19 patients can present gastrointestinal symptoms, being diarrhoea one of the most frequent, suggesting intestinal health can be impacted by COVID-19. Here, we will discuss whether there is a correlation between the presence of SARS-CoV-2 RNA in faeces and diarrhoea, the relevance of gastrointestinal symptoms in disease diagnosis and transmission, and how COVID-19 can impact the gut microbial balance. RECENT FINDINGS: SARS-CoV-2 RNA has been reported in faeces or rectal swabs of COVID-19 patients with and without diarrhoea, suggesting faecal shedding can occur independently of gastrointestinal symptoms. However, the presence of the virus in the intestine can persist beyond its presence in the respiratory tract, with some reports suggesting that SARS-CoV-2 in the faeces can be infectious.COVID-19 can impact the gut microbiota causing an enhancement of biosynthesis pathways that favour the expansion of bacterial pathogens in the inflamed gut, and causing a decline in commensals involved in the human immune response. SUMMARY: Gastrointestinal symptoms may be the first indication of COVID-19. SARS-CoV-2 in faeces can potentiate routes of disease transmission, particularly as the high viral loads reported in patients with severe illness suggest virus replication in the intestine may be possible.

The Wattson temporary pacing guidewire for transcatheter heart valve implantation.

Transcatheter aortic valve implantation and implantation of other transcatheter heart valves, generally requires insertion of a temporary venous pacemaker. Implantation of a temporary venous pacemaker adds complexity, time and risk to the procedure. Guidewire modification to allow pacing is increasingly popular, however it requires technical expertise and provides unipolar pacing resulting in high thresholds and potential capture loss. The Wattson temporary pacing guidewire is a novel device which offers guidewire support for valve delivery and concomitant bipolar pacing. It may offer a safe and effective solution to guidewire pacing for transcatheter aortic valve implantation and other transcatheter heart valve implantations. Herein, we review the literature surrounding left ventricular guidewire pacing along with the features and clinical data of the Wattson wire.

Replacing a heart valve, such as in transcatheter aortic valve implantation, requires the use of a pacemaker. This is often inserted through the veins into the opposite side of the heart to the valve being replaced. However, this method adds risk, time and complexity. New technologies have been developed to simplify this process, by using one wire in only one side of the heart to stimulate the heart muscle and support the valve replacement. The Wattson wire is a new device which acts this way and promises to make the transcatheter aortic valve implantation procedure safer and more efficient.

The potential of microbiome replacement therapies for Clostridium difficile infection.

PURPOSE OF REVIEW: There is a paradox when treating Clostridium difficile infection (CDI); treatment antibiotics reduce C. difficile colonization but cause further microbiota disruption and can lead to recurrent disease. The success of faecal microbiota transplants (FMT) in treating CDI has become a new research area in microbiome restorative therapies but are they a viable long-term treatment option? RECENT FINDINGS: C. difficile displays metabolic flexibility to use different nutritional sources during CDI. Using microbiome therapies for the efficient restoration of bile homeostasis and to reduce the bioavailability of preferential nutrients will target the germination ability of C. difficile spores and the growth rate of vegetative cells. Several biotechnology companies have developed microbiome therapeutics for treating CDI, which are undergoing clinical trials. SUMMARY: There is confidence in using restorative microbiome therapies for treating CDI after the demonstrated efficacy of FMT, where several biotechnology companies are aiming to supply what would be a 'first in class' treatment option. Efficient removal of C. difficile from the different intestinal biogeographies should be considered in future microbiome therapies. With the gut microbiota implicated in different diseases, more work is needed to assess the long-term consequences of microbiome therapies.

The use of first-generation cephalosporin antibiotics, cefalexin and cefradine, is not associated with induction of simulated Clostridioides difficile infection.

OBJECTIVES: The use of broad-spectrum cephalosporins is associated with induction of Clostridioides difficile infection (CDI). Recent knowledge on the importance of the healthy microbiota in preventing pathogen colonization/outgrowth highlights the caution needed when prescribing broad-spectrum antibiotics. The use of historical narrow-spectrum antibiotics, such as first-generation cephalosporins, is gaining increased attention once more as they have a reduced impact on the microbiota whilst treating infections. Here, the effects of two first-generation cephalosporins, compared with a third-generation cephalosporin, on the human microbiota were investigated and their propensity to induce simulated CDI. METHODS: Three in vitro chemostat models, which simulate the physiochemical conditions of the human colon, were seeded with a human faecal slurry and instilled with either narrow-spectrum cephalosporins, cefalexin and cefradine, or a broad-spectrum cephalosporin, ceftriaxone, at concentrations reflective of colonic levels. RESULTS: Instillation of cefalexin was associated with reduced recoveries of Bifidobacterium and Enterobacteriaceae; however, Clostridium spp. recoveries remained unaffected. Cefradine exposure was associated with decreased recoveries of Bifidobacterium spp., Bacteroides spp. and Enterobacteriaceae. These changes were not associated with induction of CDI, as we observed a lack of C. difficile spore germination/proliferation, thus no toxin was detected. This is in contrast to a model exposed to ceftriaxone, where CDI was observed. CONCLUSIONS: These model data suggest that the minimal impact of first-generation cephalosporins, namely cefalexin and cefradine, on the intestinal microbiota results in a low propensity to induce CDI.

Trehalose-Induced Remodelling of the Human Microbiota Affects Clostridioides difficile Infection Outcome in an In Vitro Colonic Model: A Pilot Study.

Within the human intestinal tract, dietary, microbial- and host-derived compounds are used as signals by many pathogenic organisms, including Clostridioides difficile. Trehalose has been reported to enhance virulence of certain C. difficile ribotypes; however, such variants are widespread and not correlated with clinical outcomes for patients suffering from C. difficile infection (CDI). Here, we make preliminary observations on how trehalose supplementation affects the microbiota in an in vitro model and show that trehalose-induced changes can reduce the outgrowth of C. difficile, preventing simulated CDI. Three clinically reflective human gut models simulated the effects of sugar (trehalose or glucose) or saline ingestion on the microbiota. Models were instilled with sugar or saline and further exposed to C. difficile spores. The recovery of the microbiota following antibiotic treatment and CDI induction was monitored in each model. The human microbiota remodelled to utilise the bioavailable trehalose. Clindamycin induction caused simulated CDI in models supplemented with either glucose or saline; however, trehalose supplementation did not result in CDI, although limited spore germination did occur. The absence of CDI in trehalose model was associated with enhanced abundances of Finegoldia, Faecalibacterium and Oscillospira, and reduced abundances of Klebsiella and Clostridium spp., compared with the other models. Functional analysis of the microbiota in the trehalose model revealed differences in the metabolic pathways, such as amino acid metabolism, which could be attributed to prevention of CDI. Our data show that trehalose supplementation remodelled the microbiota, which prevented simulated CDI, potentially due to enhanced recovery of nutritionally competitive microbiota against C. difficile.

Interhospital and interindividual variability in secondary prevention: a comparison of outpatients with a history of chronic coronary syndrome versus outpatients with a history of acute coronary syndrome (the iASPIRE Study).

BACKGROUND: Studying variability in the care provided to secondary prevention coronary heart disease (CHD) outpatients can identify interventions to improve their outcomes. METHODS: We studied outpatients who had an index CHD event in the preceding 6-24 months. Eligible CHD events included acute coronary syndrome (ACS) and coronary revascularisation for stable chronic coronary syndrome (CCS). Site training was provided by a core team and data were collected using standardised methods. RESULTS: Between 2017 and 2019, we enrolled 721 outpatients at nine Irish study sites; 81% were men and mean age was 63.9 (SD ±8.9) years. The study examination occurred a median of 1.16 years after the index CHD event, which was ACS in 399 participants (55%) and stable-CCS in 322. On examination, 42.5% had blood pressure (BP) >140/90 mm Hg, 63.7% had low-density lipoprotein cholesterol (LDL-C) >1.8 mmol/L and 44.1% of known diabetics had an HbA1c >7%. There was marked variability in risk factor control, both by study site and, in particular, by index presentation type. For example, 82% of outpatients with prior-ACS had attended cardiac rehabilitation versus 59% outpatients with prior-CCS (p<0.001) and there were also large differences in control of traditional risk factors like LDL-C (p=0.002) and systolic BP (p<0.001) among outpatients with prior-ACS versus prior-CCS as the index presentation. CONCLUSIONS: Despite international secondary prevention guidelines broadly recommending the same risk factor targets for all adults with CHD, we found marked differences in outpatient risk factor control and management on the basis of hospital location and index CHD presentation type (acute vs chronic). These findings highlight the need to reduce hospital-level and patient-level variability in preventive care to improve outcomes; a lesson that should inform CHD prevention programmes in Ireland and around the world.

Biofilms harbour Clostridioides difficile, serving as a reservoir for recurrent infection.

C. difficile infection (CDI) is a worldwide healthcare problem with ~30% of cases failing primary therapy, placing a burden on healthcare systems and increasing patient morbidity. We have little understanding of why these therapies fail. Here, we use a clinically validated in vitro gut model to assess the contribution of biofilms towards recurrent disease and to investigate biofilm microbiota-C. difficile interactions. Initial experiments show that C. difficile cells became associated with the colonic biofilm microbiota and are not depleted by vancomycin or faecal microbiota transplant therapies. We observe that transferring biofilm encased C. difficile cells into a C. difficile naïve but CDI susceptible model induces CDI. Members of the biofilm community can impact C. difficile biofilm formation by acting either antagonistically or synergistically. We highlight the importance of biofilms as a reservoir for C. difficile, which can be a cause for recurrent infections.