Recurrent Clostridium difficile infections:The importance of the intestinal microbiota

Clostridium difficile infections(CDI)are a leading cause of antibiotic-associated and nosocomial diarrhea.Despite effective antibiotic treatments,recurrent infections are common.With the recent emergence of hypervirulent isolates of C.difficile,CDI is a growing epidemic with higher rates of recurrence,increasing severity and mortality.Fecal microbiota transplantation(FMT)is an alternative treatment for recurrent CDI.A better understanding of intestinal microbiota and its role in CDI has opened the door to this promising therapeutic approach.FMT is thought to resolve dysbiosis by restoring gut microbiota diversity thereby breaking the cycle of recurrent CDI.Since the first reported use of FMT for recurrent CDI in 1958,systematic reviews of case series and case report have shown its effectiveness with high resolution rates compared to standard antibiotic treatment.This article focuses on current guidelines for CDI treatment,the role of intestinal microbiota in CDI recurrence and current evidence about FMT efficacy,adverse effects and acceptability.

Impact of Clostridium difficile infection on inflammatory bowel disease outcome: A review

Although a considerable number of studies support a substantial increase in incidence, severity, and healthcare costs for Clostridium difficile infection (CDI) in inflammatory bowel disease (IBD), only few evaluate its impact on IBD outcome. Medline and several other electronic databases from January 1993 to October 2013 were searched in order to identify potentially relevant literature. Most of the studies showed that IBD patients with CDI present a greater proportion of worse outcomes than those without CDI. These patients have longer length of hospital stay, higher rates of colectomies, and increased mortality. Patients with ulcerative colitis are more susceptible to CDI and have more severe outcomes than those with Crohn’s disease. However, studies reported variable results in both short- and long-term outcomes. Contrasting results were also found between studies using nationwide data and those reporting from single-center, or between some North-American and European studies. An important limitation of all studies analyzed was their retrospective design. Due to contrasting data often provided by retrospective studies, further prospective multi-center studies are necessary to evaluate CDI impact on IBD outcome. Until then, a rapid diagnosis and adequate therapy of infection are of paramount importance to improve IBD patients’ outcome. The aim of this article is to provide up to date information regarding CDI impact on outcome in IBD patients.

Faecal microbiota transplantation in patients with Clostridium difficile and significant comorbidities as well as in patients with new indications:A case series

Fecal microbiota transplantation(FMT) is effective in recurrent Clostridium difficile infection(r CDI). Knowledge of the safety and efficacy of FMT treatment in immune deficient patients is scarce. FMT has been suggested as a potential method for an increasing number of new indications besides r CDI. Among our FMT-treated r CDI patients, we reviewed those with major comorbidities: two human immunodeficiency virus patients, six haemodialysis patients, two kidney transplant patients, two liver transplant patients and a patient with chronic lymphatic leukaemia. We also reviewed those treated with FMT for indications other than r CDI: Salmonella carriage(two patients), trimethylaminuria(two patients), small intestinal bacterial overgrowth(SIBO;one patient), and lymphocytic colitis(one patient), as well as a common variable immunodeficiency patient with chronic norovirus infection and ESBL-producing Escherichia coli(E. coli) carriage. Of the thirteen r CDI patients treated with FMT, eleven cleared the CDI. The observed adverse events were not directly attributable to FMT. Concerning the special indications, both Salmonellas and ESBL-producing E. coli were eradicated. One trimethylaminuria patient and one SIBO-patient reported a reduction of symptoms. Three patients did not experience a benefit from FMT: chronic norovirus, lymphocytic colitis and the other fish malodour syndrome. There were no reported side effects in this group. FMT appeared to be safe and effective for immunocompromised patients with r CDI. FMT showed promise for the eradication of antibiotic-resistant bacteria, but further research is warranted.

A case of Clostridium difficile infection complicated by acute respiratory distress syndrome treated with fecal microbiota transplantation

Acute respiratory distress syndrome is a life-threatening disorder caused mainly by pneumonia.Clostridium difficile infection(CDI)is a common nosocomial diarrheal disease.Disruption of normal intestinal flora by antibiotics is the main risk factor for CDI.The use of broadspectrum antibiotics for serious medical conditions can make it difficult to treat CDI complicated by acute respiratory distress syndrome.Fecal microbiota transplantation is a highly effective treatment in patients with refractory CDI.Here we report on a patient with refractory CDI and acute respiratory distress syndrome caused by pneumonia who was treated with fecal microbiota transplantation.

Prophylactic antibiotics for variceal hemorrhage: Clostridium difficile infection still can be a risk

Bron et al presented a retrospective study regarding the prophylactic use of antibiotics for variceal hemorrhage. Antibiotics appeared to improve the survival rate of patients without increasing clostridium difficile infection (CDI). We argue against the conclusion of the authors and consider that this result may be simply due to concurrent use of metronidazole, a therapeutic agent against CDI.

Did the severe acute respiratory syndrome-coronavirus 2 pandemic cause an endemic Clostridium difficile infection?

BACKGROUND Clostridium difficile infection(CDI)has increased in prevalence during the last years.The coronavirus disease 2019(COVID-19)pandemic has negatively influenced patient outcomes.The majority of the severe acute respiratory syndrome-coronavirus 2(SARS-CoV-2)-infected patients received antibiotics during hospitalization.AIM To analyze the factors that influenced CDI development after SARS-CoV-2 infection.METHODS Between March 2020 to December 2020,we performed a prospective observational study including 447 patients diagnosed with CDI who were admitted to our tertiary referral university hospital.The diagnosis of CDI was based on the presence of diarrhea(≥3 watery stools within 24 h)associated with Clostridium difficile toxins A or B.We excluded patients with other etiology of acute diarrhea.RESULTS Among the total 447(12.5%)patients with CDI,most were male(54.3%)and mean age was 59.7±10.8 years.Seventy-six(17.0%)had history of COVID-19,most being elderly(COVID-19:62.6±14.6 years vs non-COVID-19:56.8±17.6 years,P=0.007),with history of alcohol consumption(43.4%vs 29.4%,P=0.017),previous hospitalizations(81.6%vs 54.9%,P<0.001)and antibiotic treatments(60.5%vs 35.5%,P<0.001),requiring higher doses of vancomycin and prone to recurrent disease(25.0%vs 13.1%,P=0.011).Age over 60 years[odds ratio(OR):2.591,95%confidence interval(CI):1.452-4.624,P=0.001],urban residence(OR:2.330,95%CI:1.286-4.221,P=0.005),previous antibiotic treatments(OR:1.909,95%CI:1.083-3.365,P=0.025),previous hospitalizations(OR:2.509,95%CI:1.263-4.986,P=0.009)and alcohol consumption(OR:2.550,95%CI:1.459-4.459,P=0.001)were risk factors of CDI in COVID-19.CONCLUSION CDI risk is unrelated to history of SARS-CoV-2 infection.However,previous COVID-19 may necessitate higher doses of vancomycin for CDI.

Clostridium difficile Toxin B: Insights into Its Target Genes

Clostridium difficile is a grossly Gram-positive anaerobic bacterium that has been a key factor in inducing imbalances in the gut microbiota in recent years, leading to intestinal-associated inflammation. The main pathogenic toxins of Clostridium difficile are toxin A (TcdA) and toxin B (TcdB). TcdB is the main pathogenic factor of Clostridium difficile infection. This review revealed the pathogenic mechanism of Clostridium difficile toxin B, expounded the impact of Clostridium difficile on the intestinal system, and predicted the genes on which TcdB may act, thereby providing a new therapeutic target for Clostridium difficile infection, offering theoretical basis and new strategies for clinical prevention and control.

Efficacy and safety of fidaxomicin versus vancomycin for Clostridium difficile infection: systematic review and meta-analysis

To compare the efficacy and safety of fidaxomicin and vancomycin for the treatment of patients with Clostridium difficile infection （CD1）, randomized controlled trials （RCTs） of fidaxomicin versus vancomycin for the treatment of CDI published in Pubmed, Embase, Web of Science and the Cochrane library were searched. Two reviewers independently extracted the data. The primary outcome was the rates of clinical cure. The secondary endpoints were the rates of CDI recurrence in the 4 weeks period after the end of therapy and rates of global cure, adverse events. Meta-analysis was performed using the Mantle-Haenszel fixed effect method （FEM）. Odds ratios （ORs） with 95% confidence intervals （95% CIs） were reported. The results indicated that two large randomized controlled trials were included in the meta-analysis. Clinical cure with fidaxomicin was similar to with vancomycin both in the modified intention to treat （OR = 1.17, 95% CI 0.82-1.66, P = 0.40） and in the per-protocol population （OR = 1.24, 95% CI 0.80-1.92, P = 0.34）. There were no significant differences in the rates of clinical cure between fidaxomicin and vancomycin in the subgroups analyzed by age, patients＇ status, and previous CDI, infection with B 1 strain, severity baseline, and exposure to concomitant antibiotics. Recurrence of CDI was significantly less common among fidaxomicin-treated patients compared with vancomycin-treated patients both in the modified intention-to-treat population （OR = 0.47, 95% CI 0.34-0.65, P〈0.00001） and in the per-protocol population （OR = 0.45, 95% CI 0.31-0.62, P〈0.0001）. Treatment with fidaxomicin compared with vancomycin was associated with significantly higher rates of global cure both in the modifed intention-to-treat population （OR = 1.75, 95% CI 1.35-2.27, P〈0.0001） and in the per-protocol population （OR = 1.86, 95% CI 1.40-2.47, P〈0.0001）. Our recta-analysis suggests that fidaxomicin is not superior to vancomycin in rates of clinical cure, while fidaxomicin significantly decreases the rates of CDI recurrence and significantly improves the rates of global cure compared with vancomycin. Thus, fidaxomicin is a promising candidate for treatment of the CDI, especially in decreasing the rates of CDI recurrence and improving the rates of global cure.

Clinical and microbiological characterization of Clostridium difficile infection in a tertiary care hospital in Shanghai, China

Background Over the last decade,Clostridium difficile infection （CDI） has emerged as a significant nosocomial infection,yet little has been reported from China.This study aimed to characterize the clinical and microbiological features of CDI from a hospital in Shanghai.Methods Patients with CDI seen between December 2010 and March 2013 were included in this study,of which clinical data were retrospectively collected.The microbiological features of corresponding isolates were analyzed including genotype by multi-locus sequence typing （MLST）,antimicrobial susceptibility,toxin production,sporulation capacity,biofilm formation,and motility.Results Ninety-four cases of CDI were included during this study period,12 of whom were severe cases.By reviewing the clinical data,all patients were treated empirically with proton pump inhibitor or antibiotics or both,and they were distributed widely across various wards,most frequently to the digestive ward （28/94,29.79％）.Comparing the severe with mild cases,no significant differences were found in the basic epidemiological data or the microbiological features.Among the 94 isolates,31 were toxin A-negative toxin B-positive all genotyped as ST37.They generated fewer toxins and spores,as well as similar amounts of biofilm and motility percentages,but exhibited highest drug resistance to cephalosporins,quinolones,macrolide-lincosamide and streptogramin （MLSB）,and tetracycline.Conclusions No specific clinical genotype or microbiological features were found in severe cases; antimicrobial resistance could be the primary reason for epidemic strains leading to the dissemination and persistence of CDI.

Update on gut microbiota in gastrointestinal diseases

The human gut is a complex microbial ecosystem comprising approximately 100 trillion microbes collectively known as the“gut microbiota”.At a rough estimate,the human gut microbiome contains almost 3.3 million genes,which are about 150 times more than the total human genes present in the human genome.The vast amount of genetic information produces various enzymes and physiologically active substances.Thus,the gut microbiota contributes to the maintenance of host health;however,when healthy microbial composition is perturbed,a condition termed“dysbiosis”,the altered gut microbiota can trigger the development of various gastrointestinal diseases.The gut microbiota has consequently become an extremely important research area in gastroenterology.It is also expected that the results of research into the gut microbiota will be applied to the prevention and treatment of human gastrointestinal diseases.A randomized controlled trial conducted by a Dutch research group in 2013 showed the positive effect of fecal microbiota transplantation(FMT)on recurrent Clostridioides difficile infection(CDI).These findings have led to the development of treatments targeting the gut microbiota,such as probiotics and FMT for inflammatory bowel diseases(IBD)and other diseases.This review focuses on the association of the gut microbiota with human gastrointestinal diseases,including CDI,IBD,and irritable bowel syndrome.We also summarize the therapeutic options for targeting the altered gut microbiota,such as probiotics and FMT.

Evaluation of gut dysbiosis using serum and fecal bile acid profiles

Dysbiosis in the intestinal microflora can affect the gut production of microbial metabolites,and toxic substances can disrupt the barrier function of the intestinal wall,leading to the development of various diseases.Decreased levels of Clostridium subcluster XIVa(XIVa)are associated with the intestinal dysbiosis found in inflammatory bowel disease(IBD)and Clostridium difficile infection(CDI).Since XIVa is a bacterial group responsible for the conversion of primary bile acids(BAs)to secondary BAs,the proportion of intestinal XIVa can be predicted by determining the ratio of deoxycholic acid(DCA)/[DCA+cholic acid(CA)]in feces orserum.For example,serum DCA/(DCA+CA)was significantly lower in IBD patients than in healthy controls,even in the remission period.These results suggest that a low proportion of intestinal XIVa in IBD patients might be a precondition for IBD onset but not a consequence of intestinal inflammation.Another report showed that a reduced serum DCA/(DCA+CA)ratio could predict susceptibility to CDI.Thus,the BA profile,particularly the ratio of secondary to primary BAs,can serve as a surrogate marker of the intestinal dysbiosis caused by decreased XIVa.

Outcomes in children with Clostridium difficile infection:results from a nationwide survey

Objective:Hospital-and population-based studies demonstrate an increasing incidence of Clostridium difficile infection(CDI)in adults and children;although pediatric CDI outcomes are incompletely understood.We analysed United States National Hospital Discharge Survey(NHDS)data to study CDI in hospitalized children.Methods:NHDS data for 2005–2009(demographics,diagnoses and discharge status)were obtained;cases and comorbidities were identified using ICD-9 codes.Weighted univariate and multivariate analyses were performed to ascertain incidence of CDI;associations between CDI and outcomes[length of stay(LOS),colectomy,all-cause in-hospital mortality and discharge to a care facility(DTCF)].Results:Of an estimated 13.8 million pediatric inpatients;46176 had CDI;median age was 3 years;overall incidence was 33.5/10000 hospitalizations.The annual frequency of CDI did not vary from 2005 to 2009(0.24–0.43%;P=0.64).On univariate analyses,children with CDI had a longer median LOS(6 vs 2 days),higher rates of colectomy[odds ratio(OR)2.0;95%confidence interval(CI)1.7–2.4],mortality(OR 2.5;95% CI 2.3–2.7),and DTCF(OR 1.6;95% CI 1.6–1.7)(all P<0.0001).After adjusting for age,sex and comorbidities,CDI was an independent and the strongest predictor of increased LOS(adjusted mean difference,6.4 days;95% CI 5.4–7.4),higher rates of colectomy(OR 2.1;95% CI 1.8–2.5),mortality(OR 2.3;95% CI 2.2–2.5),and DTCF(OR 1.7;95% CI 1.6–1.8)(all P<0.0001).On excluding infants from the analysis,children with CDI had higher rates of mortality,DTCF and longer LOS than children without CDI.Conclusions:Despite increased awareness and advancements in management,CDI remains a significant problem and is associated with increased LOS,colectomy,in-hospital mortality and DTCF in hospitalized children.

Fecal microbiota transplantation in childhood:past,present,and future

Background Fecal microbiota transplantation(FMT)has been well described in the treatment of pediatric diseases;however,the latest updates regarding its use in children are unclear and the concepts involved need to be revisited.Data sources We performed advanced searches in the MEDLINE,EMBASE,and Cochrane databases using the keywords“Fecal microbiota transplantation OR Fecal microbiota transfer”in the[Title/Abstract]to identify relevant articles published in English within the last five years.To identify additional studies,reference lists of review articles and included studies were manually searched.Retrieved manuscripts(case reports,reviews,and abstracts)were assessed by the authors.Results Among the articles,studies were based on the mechanism(n=28),sample preparation(n=9),delivery approaches(n=23),safety(n=26),and indications(n=67),including Clostridium difficile infection(CDI)and recurrent C.difficile infection(rCDI;n=21),non-alcoholic fatty liver disease(NAFLD;n=10),irritable bowel syndrome(IBS;n=5),inflammatory bowel disease(IBD;n=15),diabetes(n=5),functional constipation(FC;n=4),and autism spectrum disorder(ASD;n=7).Conclusions Concepts of FMT in pediatric diseases have been updated with respect to underlying mechanisms,methodology,indications,and safety.Evidence-based clinical trials for the use of FMT in pediatric diseases should be introduced to resolve the challenges of dosage,duration,initiation,and the end point of treatment.