Pseudomembranous colitis as a complication in Covid-19.

OBJECTIVE: Aim: To improve the results of treatment of patients with pseudomembranous colitis against the background of coronavirus infection. PATIENTS AND METHODS: Materials and Methods: The study presents the results of a retrospective analysis of 96 patients with pseudomembranous colitis, who were treated in the infectious Covid department at the base of the Uzhhorod City Clinical Hospital since 2020 to 2022. The average age of patients was 55.2 years, there were 38 (39.5%) men and 58 (60.5%) women. Diagnosis of complications - pseudomembranous colitis (PMC) - was based on clinical data, ultrasound and CT of the abdominal organs, fibrocolonoscopy, laparoscopy. RESULTS: Results: The frequency of PMC from the total number of patients who were in hospital treatment (8205 patients) due to COVID-19 was 1.17%, and this indicator was 0.62% in 2020, and 2.28% in 2021. Indications for operative treatment were: colon perforation - 9.4% of patients; peritonitis (diffuse, widespread) without obvious perforation of the colon wall - 85.5% of patients; mesenteric thrombosis - 4.1% of patients. In the case of perforation of the colon, resection of the colon was performed with the formation of a proximal colostomy and ileostomy. In case of mesenteric thrombosis, resection of the affected part of the small intestine was performed. In case of peritonitis without clear intraoperative detection of perforation of the colon wall, intraoperative lavage was performed. CONCLUSION: Conclusions: 1) The frequency of detection of PMC in patients with COVID-19 in 2020 was 0.62%, and in 2021 - 2.28%. 2) The sensitivity of CT in the diagnosis of surgical complications of PMC was 72%, and the specificity was 58%. 3) Conservative treatment was effective in patients with PMC in 88.8% of cases, 21.2% had complications that required emergency surgical interventions. 4) The total mortality in patients with PMC was 11.36%, although this indicator was significantly higher in the event of surgical complications and operative treatment (22.4%).

Pseudomembranous colitis and Parabacteroides distasonis bacteraemia: a rare clinical presentation.

We present the case of a male with end-stage diabetic nephropathy on haemodialysis who initially presented with acute-on-chronic digital ulceration. While awaiting vascular intervention, he became septic with abdominal pain and diarrhoea. Flexible sigmoidoscopy confirmed pseudomembranous colitis secondary to Clostridium difficile. Blood cultures grew Parabacteroides distasonis, a Gram-negative gut anaerobe. Enterobacter cloacae, another Gram-negative anaerobic gut bacilli, was grown in colonic cultures and swabs of the digital ulcers. We hypothesise that the pseudomembranous colitis increased gut translocation and thus led to the systemic spread of both gut anaerobes. This is the first reported case of Parabacteroides distasonis bacteraemia in the context of Clostridium difficile infection. Our patient recovered with antibiotics and went on to have vascular intervention for his digital ulceration.

Investigating the impact of antibiotic-induced dysbiosis on protection from Clostridium difficile colitis by mouse colonic innate lymphoid cells.

Innate lymphoid cells (ILCs) play a critical role in maintaining intestinal health in homeostatic and diseased conditions. During Clostridium difficile infection (CDI), IL-33 activates ILC2 to protect from colonic damage and mortality. The function of IL-33 and ILC is tightly regulated by the intestinal microbiota. We set out to determine the impact of antibiotic-induced disruption of the microbiome on ILC function. Our goal was to understand antibiotic-induced changes in ILC function on susceptibility to C. difficile colitis in a mouse model. We utilized high-throughput single-cell RNAseq to investigate the phenotypic features of colonic ILC at baseline, after antibiotic administration with or without IL-33 treatment. We identified a heterogeneous landscape of colonic ILCs with gene signatures of inflammatory, anti-inflammatory, migratory, progenitor, plastic, and antigen-presenting ILCs. Antibiotic treatment decreased ILC2 while coordinately increasing ILC1 and ILC3 phenotypes. Notably, Ifng+, Ccl5+, and Il23r+ ILC increased after antibiotics. IL-33 treatment counteracted the antibiotic effect by downregulating ILC1 and ILC3 and activating ILC2. In addition, IL-33 treatment markedly induced the expression of type 2 genes, including Areg and Il5. Finally, we identified amphiregulin, produced by ILC2, as protective during C. difficile infection. Together, our data expand our understanding of how antibiotics induce susceptibility to C. difficile colitis through their impact on ILC subsets and function.IMPORTANCEClostridium difficile infection (CDI) accounts for around 500,000 symptomatic cases and over 20,000 deaths annually in the United States alone. A major risk factor of CDI is antibiotic-induced dysbiosis of the gut. Microbiota-regulated IL-33 and innate lymphoid cells (ILCs) are important in determining the outcomes of C. difficile infection. Understanding how antibiotic and IL-33 treatment alter the phenotype of colon ILCs is important to identify potential therapeutics. Here, we performed single-cell RNAseq of mouse colon ILCs collected at baseline, after antibiotic treatment, and after IL-33 treatment. We identified heterogeneous subpopulations of all three ILC subtypes in the mouse colon. Our analysis revealed several potential pathways of antibiotic-mediated increased susceptibility to intestinal infection. Our discovery that Areg is abundantly expressed by ILCs, and the protection of mice from CDI by amphiregulin treatment, suggests that the amphiregulin-epidermal growth factor receptor pathway is a potential therapeutic target for treating intestinal colitis.

An Updated View on the Cellular Uptake and Mode-of-Action of Clostridioides difficile Toxins.

Research on the human gut pathogen Clostridioides (C.) difficile and its toxins continues to attract much attention as a consequence of the threat to human health posed by hypervirulent strains. Toxin A (TcdA) and Toxin B (TcdB) are the two major virulence determinants of C. difficile. Both are single-chain proteins with a similar multidomain architecture. Certain hypervirulent C. difficile strains also produce a third toxin, namely binary toxin CDT (C. difficile transferase). C. difficile toxins are the causative agents of C. difficile-associated diseases (CDADs), such as antibiotics-associated diarrhea and pseudomembranous colitis. For that reason, considerable efforts have been expended to unravel their molecular mode-of-action and the cellular mechanisms responsible for their uptake. Many of these studies have been conducted in European laboratories. Here, we provide an update on our previous review (Papatheodorou et al. Adv Exp Med Biol, 2018) on important advances in C. difficile toxins research.

The microbial metabolite urolithin A reduces Clostridioides difficile toxin expression and toxin-induced epithelial damage.

Clostridioides difficile is a Gram-positive, anaerobic, spore-forming bacterium responsible for antibiotic-associated pseudomembranous colitis. Clostridioides difficile infection (CDI) symptoms can range from diarrhea to life-threatening colon damage. Toxins produced by C. difficile (TcdA and TcdB) cause intestinal epithelial injury and lead to severe gut barrier dysfunction, stem cell damage, and impaired regeneration of the gut epithelium. Current treatment options for intestinal repair are limited. In this study, we demonstrate that treatment with the microbial metabolite urolithin A (UroA) attenuates CDI-induced adverse effects on the colon epithelium in a preclinical model of CDI-induced colitis. Moreover, our analysis suggests that UroA treatment protects against C. difficile-induced inflammation, disruption of gut barrier integrity, and intestinal tight junction proteins in the colon of CDI mice. Importantly, UroA treatment significantly reduced the expression and release of toxins from C. difficile without inducing bacterial cell death. These results indicate the direct regulatory effects of UroA on bacterial gene regulation. Overall, our findings reveal a novel aspect of UroA activity, as it appears to act at both the bacterial and host levels to protect against CDI-induced colitis pathogenesis. This research sheds light on a promising avenue for the development of novel treatments for C. difficile infection.IMPORTANCETherapy for Clostridioides difficile infections includes the use of antibiotics, immunosuppressors, and fecal microbiota transplantation. However, these treatments have several drawbacks, including the loss of colonization resistance, the promotion of autoimmune disorders, and the potential for unknown pathogens in donor samples. To date, the potential benefits of microbial metabolites in CDI-induced colitis have not been fully investigated. Here, we report for the first time that the microbial metabolite urolithin A has the potential to block toxin production from C. difficile and enhance gut barrier function to mitigate CDI-induced colitis.

Detection of Clostridium difficile among diarrheic children using cultural and polymerase chain reaction technique.

INTRODUCTION: Clostridium difficile is the most common cause of antibiotic-associated diarrhea and colitis. Several methods are available for the detection of C. difficile in stool samples. This study aimed to use glutamate dehydrogenase (GDH), toxin detection, culture and polymerase chain reaction (PCR) techniques for the diagnosis of this pathogen. METHODOLOGY: A total of 300 stool samples were collected from children with hospital acquired diarrhea (HA-D), community acquired diarrhea (CA-D), and hospitalized non-diarrheic children as control with ages ranging from 6 months to 6 years (mean 3.7 ± 1.7). Each stool sample was divided into two parts; one part was tested for the enzyme GDH, toxin A and B and then cultured on selective media; and the other part for direct DNA extraction. RESULTS: From a total of 300 stool samples, 9 (3.0%) were positive for C. difficile by the PCR technique, 7 (7%) samples of which were from HA-D cases and 2 (2.0%) from CA-D cases; the control group samples were negative. The enzyme GDH was detected in 12 (12%) samples and toxins A and B in 8 (8%) samples from HA-D cases compared to 5 (5%) and 2 (2%), respectively from CA-D cases. Both GDH and the toxins were negative in control samples. Only 19 (19.0%) samples from HA-D cases gave suspected growth and all of these were negative by PCR. CONCLUSIONS: Based on the results of this study, we conclude that the PCR technique is the only reliable method for the diagnosis of this pathogen.

Azithromycin Treatment for Acne Vulgaris: A Case Report on the Risk of Clostridioides difficile Infection.

BACKGROUND Clostridium difficile (C. difficile) is a gram-positive, anaerobic, spore-forming bacillus. It can lead to pseudomembranous colitis characterized by electrolyte disturbances, toxic megacolon, and septic shock. The risk of C. difficile infection is higher with use of certain classes of antibiotics, or when an antibiotic used for a long time. Azithromycin is a macrolide antibiotic known to be safe, with few adverse effects such as diarrhea, stomach pain, and constipation. Azithromycin is currently used for the treatment of acne, with different dosing regimens for patients who cannot receive traditional treatment based on practice guidelines. CASE REPORT A 41-year-old woman was treated with a course of azithromycin 500 mg by mouth 3 times weekly for 6 weeks for acne vulgaris. This was her second antibiotic course of acne treatment within 10 months. A few days after completion of the second azithromycin course, she presented to the clinic with worsening abdominal pain and frequent soft bloody stool. A complete blood count test, C. difficile toxin test, stool culture, and colonoscopy were ordered. She was diagnosed with C. difficile infection confirmed by C. difficile toxin and symptoms. CONCLUSIONS Despite the safety profile of azithromycin, our patient was predisposed to a non-severe case of C. difficile-associated diarrhea, most likely due to the repeated course of the azithromycin regimen that was used to treat her acne vulgaris. This report highlights the importance of managing patients with acne vulgaris according to current practice guidelines, and to report a link between the use of azithromycin as an acne treatment and the occurrence of C. difficile colitis.

Diagnosis and treatment of "chronic Lyme": primum non nocere.

BACKGROUND: Approximately 10% of patients experience prolonged symptoms after Lyme disease. PTLDS (post treatment Lyme disease syndrome) is a controversial topic. It has been described as a source of overdiagnosis and off-label treatment. This review aims to describe the diagnostic errors and adverse events associated with the diagnosis and treatment of PTLDS. METHODS: systematic review of the literature in the Medline and Cochrane Library databases, according to PRISMA criteria, including randomized clinical trials (RCT), observational studies, and case reports addressing diagnostic errors and adverse events published between January 2010 and November 2020 in English or French. Selection used a quadruple reading process on the basis of the titles and abstracts of the different articles, followed by a full reading. RESULTS: 17 studies were included: 1 RCT, 6 observational studies and 10 case reports. In the 6 observational studies, overdiagnosis rates were very high, ranging from 80 to 100%. The new diagnoses were often psychiatric, rheumatological and neurological. Disorders with somatic symptoms were often cited. Diagnostic delays were identified for cancers and frontoparietal dementia. In the RCT and observational studies, prolonged anti-infective treatments were also responsible for adverse events, with emergency room visits and/or hospitalization. The most common adverse events were diarrhea, sometimes with Clostridium difficile colitis, electrolyte abnormalities, sepsis, bacterial and fungal infections, and anaphylactic reactions. CONCLUSION: This review highlights the risks of prolonged anti-infective treatments that have not been proven to be beneficial in PTLDS. It emphasizes the ethical imperative of the "primum non nocere" principle, which underscores the importance of not causing harm to patients. Physicians should exercise caution in diagnosing PTLDS and consider the potential risks associated with off-label treatments.

Absence of toll-like receptor 7 ameliorates survival and reduces intestinal injury in mice after Clostridium difficile infection.

Clostridioides difficile (CD) is a major cause of antibiotic-associated diarrhea and pseudomembranous enteritis. C. difficile infection (CDI) is increasingly present in the community and represents a significant burden on the healthcare system. Identification of novel immune-based therapeutic targets from a better understanding of their molecular pathogenesis is urgently required. Toll-like receptor 7 (TLR7) is an important pattern recognition receptor and function as an immune sensor that can trigger host defenses against pathogens, but the relationship between TLR7 and CDI remains unknown. Here, we reported that the expression levels of TLR7 increased significantly in patients and mice with CDI. Absence of TLR7 in mice with CDI demonstrated enhanced bacterial clearance of intestinal contents and reduced intestinal inflammation, edema, injury and prolonged the survival. TLR7 loss decreased the concentrations of tumor necrosis factor (TNF)-α, interferon (IFN)-γ and IFN-α1 in the intestine and improved tissue damage and inflammation. Flow cytometry and immunofluorescence results indicated that TLR7 enhanced leukocyte recruitment in the infected intestine. In-vitro results have shown that TLR7 impairs the phagocytosis and killing ability of macrophages to CD, prompts reactive oxygen species (ROS) production and accelerates apoptosis. To our knowledge, our study first identified TLR7 as a critical factor that contributes to the immunopathology of CDI, suggesting that targeting TLR7 might serve as a potential treatment for CDI.

Clostridioides difficile and colorectal cancer: a dangerous liaison.

Many colorectal diseases depend on complex interactions between several pathophysiological factors, including the intestinal microbiota. In recent years, the widespread use of antibiotics has been recognized as a main cause of intestinal dysbiosis and a favouring factor for Clostridioides difficile infection. The latter, in addition, causes infectious diarrhoea, pseudomembranous colitis, and toxic megacolon by means of its toxins (A and, especially, B), is characterized by frequent relapses; thus, its persistence in a host may be long-lasting. Based on recent experimental evidence, here we analyse the possibility that, similarly to other bacteria, Clostridioides difficile may be considered a potential carcinogen for colorectal cancer.

Chronic Diarrhea Caused by a Klebsiella oxytoca Toxin Producer Strain Following Antibiotic-Associated Hemorrhagic Colitis: Successful Treatment by Fecal Microbiota Transplant.

Klebsiella oxytoca is a gram-negative bacterium found in fecal microbiota and known to cause several infections in humans, including antibiotic-associated hemorrhagic colitis. We present here a case of colitis caused by K. oxytoca toxin-producing strains that evolved in chronic diarrhea successfully treated by fecal microbiota transplant.

Butyrate Protects against Clostridium difficile Infection by Regulating Bile Acid Metabolism.

Clostridium difficile infection (CDI) is caused by a prevalent nosocomial enteric pathogen, leading to high morbidity and mortality. CDI recurrence after antibiotic treatment is high; therefore, it is necessary to develop novel therapeutics against this enteric pathogen. Butyrate is used to treat many diseases because it provides energy, has anti-inflammatory properties, and maintains intestinal barrier function. An anti-CDI effect for butyrate has been reported; however, the specific mechanism remains elusive. This study aimed to explore the potential role and mechanism of butyrate in the treatment of CDI. Using a CDI mouse model, we found that butyrate significantly inhibited CDI development by regulating bile acid metabolism. Dysregulation of fecal bile acid was significantly higher, and levels of short-chain fatty acids were significantly lower in patients with CDI than those in controls. In CDI mice, butyrate exhibited a protective role by enhancing barrier protection, exerting anti-inflammatory effects, and regulating bile acid metabolism. Butyrate treatment also regulated the production of bile salt hydrolase (BSH) flora and activated farnesoid X receptor (FXR), and its therapeutic effects were reduced in CDI mice treated with BSH or FXR inhibitors. Thus, butyrate treatment may serve as a novel therapeutic approach for patients with CDI. IMPORTANCE Here, we show that levels of fecal short-chain fatty acids (SCFAs), particularly butyrate, are reduced, and normal colon structure is damaged in patients with CDI compared with those in healthy individuals. Bile acid (BA) metabolic disorder in patients with CDI is characterized by increased primary BA levels and decreased secondary BAs. In mice, butyrate alters BA metabolism in CDI and may play a vital role in CDI treatment by promoting secondary BA metabolism. Lastly, butyrate-mediated therapeutic effects in CDI require FXR. Our findings demonstrate that butyrate treatment significantly decreases the severity of CDI-induced colitis in mice and affects BA metabolism and FXR activation, which provides a potential alternative treatment for CDI.

Clostridium difficile Infections in an Emergency Surgical Unit from North-East Romania.

Background and Objectives: Colitis with Clostridium difficile is an important health problem that occurs with an intensity that varies between mild and severe. Surgical interventions are required only in fulminant forms. There is little evidence regarding the best surgical intervention in these cases. Materials and Methods: Patients with C. difficile infection were identified from the two surgery clinics from the 'Saint Spiridon' Emergency Hospital Iași, Romania. Data regarding the presentation, indication for surgery, antibiotic therapy, type of toxins, and post-operative outcomes were collected over a 3-year period. Results: From a total of 12,432 patients admitted for emergency or elective surgery, 140 (1.12%) were diagnosed with C. difficile infection. The mortality rate was 14% (20 cases). Non-survivors had higher rates of lower-limb amputations, bowel resections, hepatectomy, and splenectomy. Additional surgery was necessary in 2.8% of cases because of the complications of C. difficile colitis. In three cases, terminal colostomy was performed and as well as one case with subtotal colectomy with ileostomy. All patients who required the second surgery died within the 30-day mortality period. Conclusions: In our prospective study, the incidence was increased both in cases of patients with interventions on the colon and in those requiring limb amputations. Surgical interventions are rarely required in patients with C. difficile colitis.

Case of Pseudomembranous Colitis Caused by a Clostridioides difficile Infection Concomitant with Cytomegalovirus colitis Mimicking Ischemic Colitis.

A Clostridioides difficile infection (CDI) is one of the major nosocomial diarrheal diseases. Pseudomembranous colitis (PMC) is a characteristic endoscopic finding of CDI, manifested by white or yellowish plaque covering the colonic mucosa. Ischemic colitis is inflammation of the colon manifested by mucosal denudation and friability. Ischemic colitis is rarely associated with CDI. The treatment response might be delayed when CDI is complicated with other diseases that cause diarrhea. Thus far, reports of CDI concomitant with Cytomegalovirus (CMV) colitis are rare. This paper reports a case of PMC and ischemic colitis associated with CDI and CMV infection. After two weeks of oral vancomycin and intravenous metronidazole, the patient's diarrhea was not improved. Follow-up sigmoidoscopy was performed, and a CMV infection was identified at areas of broad ulceration where ischemic colitis occurred. Finally, the patient was cured with ganciclovir. Follow-up sigmoidoscopy showed an improvement in ischemic colitis.

Clostridium difficile colitis following geriatric hip fracture surgery: incidence, trends, and risk factors from 45,910 patients.

PURPOSE: Clostridium difficile colitis is a serious complication in elderly patients undergoing surgery. The objectives of this study were: (1) to use a nationwide sample of patients to report the incidence and timing of C. difficile colitis in geriatric patients who underwent surgery for hip fractures, (2) to identify preoperative factors associated with developing C. difficile colitis and mortality. METHODS: This was a retrospective evaluation of the 2016-2019 ACS Targeted Hip Fracture database merged with the ACS-NSQIP database. Patients undergoing surgery for hip fracture were included. Outcomes studied were incidence, preoperative, and postoperative risk factors for occurrence of C. difficile infection and mortality. Chi-squared tests were used to compare demographics between the patients infected (study) and not infected (control). Logistic regression models were utilized to compute the odds ratios (OR) testing for the association of independent factors on developing C. difficile infection postoperatively and mortality. A statistical threshold was set at p < 0.008. RESULTS: The incidence of C. difficile infection within 30 days of hip fracture surgery was 0.81%. Fifty percent of infections were diagnosed within 9 days postoperatively. Preoperative and hospital-associated factors associated with development of C. difficile infection were ≥ 2 days until operation (OR 1.88 [95% CI 1.39-2.55], p < 0.001) and dependent functional status (OR 1.43 [95% CI 1.14-1.79], p = 0.002). After adjusting for multiple comorbidities, increased age, male sex, COPD, CHF, dependent functional status, and C. difficile infection were associated with increased mortality within 30 days of surgery (all p < 0.001). CONCLUSION: Clostridium difficile colitis is a serious infection after hip fracture surgery in geriatric patients with an incidence of about 1%. Patients at increased risk should be targeted with preventative measures to prevent the morbidity from this complication.

Estudio de casos-controles de la infección por Clostridioides difficile en un área sanitaria rural / Case-control study of Clostridioides difficile in a rural health care area

Objetivo: Determinar los factores de riesgo y factores pronósticos de la infección por Clostridioides difficile (ICD). Pacientes y métodos: Estudio prospectivo de casos-controles (61 casos y 64 controles) de 2 años o más con diarrea, atendidos en un área sanitaria manchega durante 14 meses. El diagnóstico se realizó mediante inmunocromatografía (glutamato deshidrogenasa y toxina A/B), realizando amplificación isotérmica en los casos discordantes. Se recogieron variables demográficas, comorbilidades, tipo de adquisición, administración previa de antibióticos, antiácidos e inmunosupresores y evolución. Los datos se analizaron mediante la prueba de χ2 y el efecto de los factores de riesgo y pronósticos se cuantificó mediante odds ratio con intervalos de confianza del 95%. Resultados: Como factores de riesgo independientes de ICD encontramos el ingreso hospitalario las 4 semanas previas a la infección, la hipoalbuminemia y la administración previa de antibióticos. Presentar estos 3 factores supuso un riesgo casi 3 veces mayor de infectarse. En el grupo de adquisición nosocomial se encontró mayor número de ingresos hospitalarios las 4-12 semanas previas a la ICD y, aunque hubo mayor tendencia a las recurrencias y al pronóstico desfavorable entre los casos intrahospitalarios, estas diferencias no fueron significativas. Identificamos como factores de pronóstico desfavorable la fiebre y el ingreso hospitalario las 4 semanas previas a la infección. Conclusiones:Los factores de riesgo independientes de ICD fueron: ingreso hospitalario las 4 semanas previas a la infección, hipoalbuminemia y administración previa de antibióticos. La fiebre y la hospitalización las 4 semanas anteriores se identificaron además como factores pronósticos de evolución desfavorable.(AU)

Objective: To determine the risk and prognostic factors for Clostridioides difficile infection (CDI). Patients and methods: Prospective, case-control study with 61 cases and 64 controls, aged ≥2 years with diarrhoea, carried out in Castilla-La Mancha Health Care Area for 14 months. The diagnosis was made by immunochromatography technics (glutamate dehydrogenase and toxin A/B), confirming discordant cases by isothermal amplification. Demographic variables, comorbidities, type of acquisition, previous administration of antibiotics, antacids and immunosuppressants, and evolution were collected. The data were analysed using the chi-square test and the effect of risk and prognostic factors was quantified using an odds ratio with 95% confidence intervals. Results: Hospital admission 4 weeks prior to infection, hypoalbuminemia, and previous administration of antibiotics were identified as independent risk factors for CDI. Presenting these 3 factors constitutes nearly 3-fold increase in the risk of becoming infected. A greater number of hospital admissions in the 4-12 weeks prior to CDI were found in the group of nosocomial acquisition. Although there was a greater tendency to recurrence and an unfavourable prognosis among nosocomial cases, these differences were not significant. We found that fever and hospital admission in the 4 weeks prior to infection were unfavourable prognostic factors of CDI. Conclusions: The independent risk factors for CDI were: Hospital admission in the 4 weeks prior to infection, hypoalbuminemia, and previous administration of antibiotics. Fever and hospitalisation in the previous 4 weeks were also identified as prognostic factors of unfavourable evolution.(AU)