ArticleLiterature Review

Clostridium difficile disease: Diagnosis, pathogenesis, and treatment update

March 2017
Surgery 162(2)

March 2017
162(2)

DOI:10.1016/j.surg.2017.01.018

Authors:

Clostridium difficile infections are the leading cause of health care-associated infectious diarrhea, posing a significant risk for both medical and surgical patients. Because of the significant morbidity and mortality associated with C difficile infections, knowledge of the epidemiology of C difficile in combination with a high index of suspicion and susceptible patient populations (including surgical, postcolectomy, and inflammatory bowel disease patients) is warranted. C difficile infections present with a wide spectrum of disease, ranging from mild diarrhea to fulminant colitis or small bowel enteritis and recurrent C difficile infections. Early implementation of medical and operative treatment strategies for C difficile infections is imperative for optimal patient outcomes. National and international guidelines recommend early operative consultation and total abdominal colectomy with end ileostomy and preservation of rectum. Diverting loop ileostomy and colonic lavage followed by intravenous metronidazole and intracolonic vancomycin administered via the efferent limb of the ileostomy should be considered as an alternative to total colectomy in selected patients. New and emerging strategies for C difficile infection treatment include monoclonal antibodies, vaccines, probiotics, biotherapeutics, and new antibiotics. A successful C difficile prevention and eradication program requires a multidisciplinary approach that includes early disease recognition, implementation of guidelines for monitoring adherence to environmental control, judicious hand hygiene, evidence-based treatment and management strategies, and a focused antibiotic stewardship program. Surgeons are an important part of the clinical team in the management of C difficile infection prevention and treatment.

Minimally invasive approach in appendectomy and cholecystectomy reduces risk for early but not late-onset Clostridioides difficile infection

Article

Jan 2022

Incidence of Early and Late-Onset Clostridioides difficile Infection following Appendectomy Compared to Other Common Abdominal Surgical Procedures

Article

Full-text available

Jun 2022

Introduction: Clostridioides difficile associated diarrhea (CDAD) is a major public health issue. The appendix may function as a reservoir for the intestinal microbiome, which may repopulate the intestine following enteric infections including CDAD. Patients/Methods. This retrospective cohort study includes a total of 12,039 patients undergoing appendectomy, hemicolectomy, and cholecystectomy at a single center between 1992 and 2011 who were diagnosed with early and late-onset CDAD and were followed for a minimum of two years. Results: Cumulative CDAD rates were 2.3% after appendectomy, 6.4% after left and 6.8% after right hemicolectomy, and 4% after cholecystectomy with a median onset of 76 (range 1-6011) days after the procedure. Median time to CDAD onset was 76 days after appendectomy, 23 days after left, 54 days after right hemicolectomy, and 122 days after cholecystectomy (p < 0.05). Late-onset CDAD (>1 year) was significantly more common following appendectomy (37%) and cholecystectomy (39%) than after left (17%) and right (21%) hemicolectomy. Significant differences in age, gender, complication rate, and length of hospitalization between the four groups need to be considered when interpreting the results. Conclusion: The incidence of CDAD after various abdominal surgeries ranged between 2% and 7% in this study. Whereas, hemicolectomy patients had predominantly early onset CDAD, and appendectomy and cholecystectomy may increase the risk for late-onset CDAD. Appendectomy per se does not seem to increase the risk for late-onset CDAD.

Testing and Diagnosis of Clostridioides difficile Infection in Special Scenarios: A Systematic Review

Article

Apr 2024

New treatment approaches for Clostridioides difficile infections: alternatives to antibiotics and fecal microbiota transplantation

Article

Full-text available

Apr 2024

Clostridioides difficile causes a range of debilitating intestinal symptoms that may be fatal. It is particularly problematic as a hospital-acquired infection, causing significant costs to the health care system. Antibiotics, such as vancomycin and fidaxomicin, are still the drugs of choice for C. difficile infections, but their effectiveness is limited, and microbial interventions are emerging as a new treatment option. This paper focuses on alternative treatment approaches, which are currently in various stages of development and can be divided into four therapeutic strategies. Direct killing of C. difficile (i) includes beside established antibiotics, less studied bacteriophages, and their derivatives, such as endolysins and tailocins. Restoration of microbiota composition and function (ii) is achieved with fecal microbiota transplantation, which has recently been approved, with standardized defined microbial mixtures, and with probiotics, which have been administered with moderate success. Prevention of deleterious effects of antibiotics on microbiota is achieved with agents for the neutralization of antibiotics that act in the gut and are nearing regulatory approval. Neutralization of C. difficile toxins (iii) which are crucial virulence factors is achieved with antibodies/antibody fragments or alternative binding proteins. Of these, the monoclonal antibody bezlotoxumab is already in clinical use. Immunomodulation (iv) can help eliminate or prevent C. difficile infection by interfering with cytokine signaling. Small-molecule agents without bacteriolytic activity are usually selected by drug repurposing and can act via a variety of mechanisms. The multiple treatment options described in this article provide optimism for the future treatment of C. difficile infection.

Design of 8-mer peptides that block Clostridioides difficile toxin A in intestinal cells

Article

Full-text available

Aug 2023

Infections by Clostridioides difficile , a bacterium that targets the large intestine (colon), impact a large number of people worldwide. Bacterial colonization is mediated by two exotoxins: toxins A and B. Short peptides that can be delivered to the gut and inhibit the biocatalytic activity of these toxins represent a promising therapeutic strategy to prevent and treat C. diff . infection. We describe an approach that combines a Pep tide B inding D esign (PepBD) algorithm, molecular-level simulations, a rapid screening assay to evaluate peptide:toxin binding, a primary human cell-based assay, and surface plasmon resonance (SPR) measurements to develop peptide inhibitors that block Toxin A in colon epithelial cells. One peptide, SA1, is found to block TcdA toxicity in primary-derived human colon (large intestinal) epithelial cells. SA1 binds TcdA with a K D of 56.1 ± 29.8 nM as measured by surface plasmon resonance (SPR).

Clostridioides difficile infection in infants: a case report and literature review

Article

Full-text available

Jun 2023

Background Clostridioides difficile (C. difficile) is the major pathogen causing antibiotic-associated diarrhea. There are a variety of symptoms associated with C. difficile infection (CDI) in adults, including self-limiting diarrhea, pseudomembranous colitis, toxic megacolon, septic shock, and even death from the infection. However, the infant’s intestine appears to be completely resistant to the effects of C. difficile toxins A and B with rare development of clinical symptoms. Case presentation In this study, we reported a 1-month-old girl with CDI who was born with neonatal hypoglycemia and necrotizing enterocolitis. Her symptom of diarrhea occurred after extensive use of broad-spectrum antibiotics during hospitalization and was accompanied by elevated white blood cell, platelet, and C-reactive protein levels, and repeated routine stool examinations were abnormal. She was recovered by norvancomycin (an analogue of vancomycin) and probiotic treatment. The results of 16 S rRNA gene sequencing also demonstrated the recovery of intestinal microbiota with the enrichment of Firmicutes and Lactobacillus. Conclusions Based on the literature review and this case report, clinicians should also pay attention to diarrhea caused by C. difficile in infants and young children. More strong evidence is needed to explain the true prevalence of CDI in this population and to better understand the C. difficile-associated diarrhea in infants.

Influence of Binary Toxin Gene Detection and Decreased Susceptibility to Antibiotics among Clostridioides difficile Strains on Disease Severity: a Single-Center Study

Article

Full-text available

Jul 2022
ANTIMICROB AGENTS CH

Clostridioides difficile infection (CDI) is the fifth leading cause of death from nonmalignant gastrointestinal disease in the United States. The contribution of resistance to C. difficile-active antibiotics to the outcomes of CDI is unclear. We evaluated the antimicrobial susceptibility of C. difficile isolates in a U.S. hospital and determined associations of clinical variables and binary toxin positivity with antibiotic resistance. C. difficile spores were cultured from fecal specimens of adult patients with CDI for genotyping and antimicrobial susceptibility assay (for clindamycin [CLI], fidaxomicin [FDX], metronidazole [MTZ], moxifloxacin [MXF], tigecycline [TGC], and vancomycin [VAN]). Electronic medical records were reviewed for clinical data extraction. Ninety-seven of 130 (75%) fecal samples grew toxigenic C. difficile in culture. Most of the isolates were tcdA+ tcdB+ cdtB- (80.4%), and 18.6% and 1% were tcdA+ tcdB+ cdtB+ and tcdA- tcdB+ cdtB+, respectively. Susceptibility to VAN, MTZ, FDX, TGC, MXF, and CLI was 96%, 94%, 100%, 100%, 8%, and 79%, respectively. Six isolates, all cdtB positive and belonging to the 027 ribotype, were resistant to VAN and/or MTZ. Higher MICs were found in isolates with a mutation in the VAN-related resistance gene vanR, but not vanS. In addition, cdtB+ isolates exhibited higher MICs of VAN, MTZ, TGC, CLI, and MXF compared to cdtB- strains. Patients with greater intestinal inflammation or severe disease were more likely to be infected with cdtB+ strains. Decreased susceptibility to antibiotics is not directly associated with either severe or recurrent CDI. However, antimicrobial susceptibility of C. difficile is decreased in strains positive for the binary toxin gene.

Article

Full-text available

Apr 2022

Background The health-related quality of life (HrQoL) can be substantially affected in patients with recurrent Clostridioides difficile infection (rCDI) but the impact of effective treatment of the infection remains unclear. This study aimed to evaluate the HrQoL in patients with rCDI and estimate the gain in HrQoL associated with effective treatment of rCDI. Methods Patients’ HrQoL was estimated based on EuroQol 5-Dimensions 3-Levels (EQ-5D-3L) questionnaires obtained from a Danish randomised controlled trial (RCT). In the RCT, 64 patients with rCDI were randomised to receive either vancomycin (n = 16), fidaxomicin (n = 24) or faecal microbiota transplantation (FMT) preceded by vancomycin (n = 24). The primary outcome in the RCT was rCDI resolution. Patients were closely monitored during the RCT, and rescue FMT was offered to those who failed their primary treatment. Patients’ HrQoL was measured at baseline and at 8- and 26-weeks follow-up. Linear regression analyses conditional on the differences between baseline and follow-up measurements were used to assess statistical significance (p < 0.05). Results Within 26 weeks of follow-up, 13 (81%) patients treated with vancomycin, 12 (50%) patients treated with fidaxomicin, and 3 (13%) patients treated with FMT had a subsequent recurrence and received a rescue FMT. The average HrQoL for untreated patients with rCDI was 0.675. After receiving effective treatment, this value increased by 0.139 to 0.813 (p < 0.001) at week 8 and by 0.098 to 0.773 (p = 0.003) at week 26 of follow-up compared with baseline. Conclusion The HrQoL was adversely affected in patients with an active episode of rCDI but increased substantially after receiving an effective treatment algorithm in which rescue FMT was provided in case of a primary treatment failure. Trial registration The RCT was preregistered at EudraCT (j.no. 2015-003004-24, https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-003004-24/results) and at ClinicalTrials.gov (study identifier NCT02743234, https://clinicaltrials.gov/ct2/show/NCT02743234).

Impact of Primary and Secondary Bile Acids on Clostridioides difficile Infection

Article

Full-text available

Mar 2022
Pol J Microbiol

Primary bile acids (BAs), synthesized from cholesterol in the liver, after their secretion with bile into the intestinal lumen, are transformed by gut microbiota to secondary BAs. As natural detergents, BAs play a key role in the digestion and absorption of lipids and liposoluble vitamins. However, they have also been recognized as important signaling molecules involved in numerous metabolic processes. The close bidirectional interactions between BAs and gut microbiota occur since BAs influence microbiota composition, whereas microbiota determines BA metabolism. In particular, it is well established that BAs modulate Clostridioides difficile life cycle in vivo . C. difficile is a cause of common nosocomial infections that have become a growing concern. The aim of this review is to summarize the current knowledge regarding the impact of BAs on the pathogenesis, prevention, and treatment of C. difficile infection.

Antigen-Specific vs. Neutralizing Antibodies Against Conditioned Media of Patients With Clostridioides difficile Infection: A Prospective Exploratory Study

Article

Full-text available

Feb 2022

The immunological response against Clostridioides difficile (C. difficile) is crucial for an improved understanding of disease mechanisms and the development of novel therapeutic strategies. From April 2014 to February 2015, adult patients with C. difficile infection (CDI) were recruited, and the clinical course and treatment response were carefully monitored. On day 1, 3, and 6 after diagnosis, patient plasma samples were screened for anti-GDH (glutamate dehydrogenase), anti-TcdA, anti-TcdB, and anti-CWP84 (cell-wall protein 84) antibodies by ELISA. Additionally, neutralization assays of toxins from conditioned media of clinical isolates (RT010, RT014, and RT027) were performed. Most patients with CDI ( n = 46) had antibodies against GDH (85%) and CWP84 (61%), but only few had antibodies against TcdA (11%) and TcdB (28%). We found patients with neutralizing antibodies against C. difficile toxins (conditioned media) produced by RT027 (26%). A subgroup of these samples could neutralize both toxins from RT027 and RT014 [11%, (5/46)]; however, no single sample neutralized only RT014. Overall, neutralizing antibody titers were low (≤1:16). In a one week follow-up of acute infection, we never observed an early booster effect with seroconversion or antibody increases, irrespective of disease severity. No correlation was found between the presence of antigen-specific (ELISA) or neutralizing antibodies and the clinical course of disease. Anti-TcdB but not anti-TcdA antibodies correlated with the occurrence of neutralizing antibodies. In conclusion, natural antibody titers against C. difficile toxins were absent or low and were not associated with disease severity. The correlation between the anti-TcdB with toxin neutralization confirms the importance of TcdB for virulence of CDI. Alternative sensitization strategies, e.g., through vaccine development, are required to overcome the regular low-titer antibody production following natural intestinal C. difficile exposure.

Outcomes of total versus partial colectomy in fulminant Clostridium difficile colitis: a propensity matched analysis

Article

Full-text available

Feb 2022
World J Emerg Surg

Background The Total Abdominal Colectomy (TAC) is the recommended procedure for Fulminant Clostridium Difficile Colitis (FCDC), however, occasionally, FCDC is also treated with partial colectomies. The purpose of the study was to identify the outcomes of partial colectomy in FCDC cases. Method The National Surgical Quality Improvement Program database was accessed and eligible patients from 2012 through 2016 were reviewed. Patients 18 years and older who were diagnosed with FCDC and who underwent colectomies were included in the study. Patients’ demography, clinical characteristics, comorbidities, mortality, morbidities, length of hospital stay and discharge disposition were compared between the group who underwent partial colectomy and the group who underwent TAC. Univariate analysis followed by propensity matching was performed. A P value of < 0.05 is considered as statistically significant. Results Out of 491 patients who qualified for the study, 93 (18.9%) patients underwent partial colectomy. The pair matched analysis showed no significant difference in patients’ characteristics and comorbidities in the two groups. There was no significant difference found in mortality between the two groups (30.1% vs. 30.1%, P > 0.99). There were no differences found in the median [95% CI] hospital length of stay (LOS) (23 days [19–31] vs. 21 [17–25], P = 0.30), post-operative complications (all P > 0.05), and discharged disposition to home ( 33.8% vs. 43.1%) or transfer to rehab (21.55 vs. 12.3%, P = 0.357) between the TAC and partial colectomy groups. Conclusion The overall 30 days mortality remains very high in FCDC. Partial colectomy did not increase risk of mortality or morbidities and LOS. Level of evidence Level IV. Study type Observational cohort.

Development of an oral vaccine against Clostridioides difficile

Article

Oct 2021

Cansu Karyal

Clostridioides difficile (C. difficile) is the leading cause of hospital acquired diarrhoeal infection. The major risk factors associated with C. difficile infection (CDI) is age (65 and over), use of broad-spectrum antibiotics and prolonged hospital stays. Symptoms range from mild diarrhoea to life threatening fulminant colitis. Clinical manifestation is mainly due to two toxins; TcdA and TcdB. The failure to treat recurrent infection can culminate in death and thus preventative measures are of urgent need. Current vaccine trials in humans are exclusively focused on parenteral delivery of toxin-based formulations. These vaccines elicit toxin-neutralising serum antibody responses, however they fail to provide protection against CDI which occurs in the gut. A more effective way to vaccinate against this gut pathogen would be with a mucosal vaccine via the oral route. This would potentially generate a local mucosal immune response, i.e., secretory IgA (sIgA) that directly targets the site of infection. Mucosal vaccines require adjuvants to elicit potent immune responses. Bacterial lipoproteins harbour intrinsic adjuvant properties due to their lipid moiety interactions with Toll-like receptor 2 (TLR2) found on antigen presenting cells (APCs) which leads to APC activation and antigen uptake. Thus, synthetic bacterial lipids that act as TLR2 agonists have been extensively studied through their attachment to synthesised peptides to serve as potential adjuvants. However, using synthetic peptides allow for recognition of only smaller immunogenic fragments/epitopes which limits their target for whole proteins. We set out to formulate an oral mucosal vaccine using recombinant C. difficile antigens expressed with a unique N-terminal cysteine used to conjugate a synthetic lipid with a maleimide head group, to mimic bacterial lipoproteins. These semi-synthetic lipoproteins were presented on liposomes as a delivery vehicle and to also mimic the native presentation of lipoproteins on the bacterial cell surface. In this study we tested two antigens; colonisation factor CD630_08730 and a fragment of the receptor binding domain of TcdB and compared these administered either as antigen alone or with being presented on liposomes with conjugation to a lipid adjuvant. The formulations were lyophilised and packed into enteric coated capsule. Hamsters immunised with both CD630_08730 formulations showed strong intestinal sIgA and serum IgG responses compared to the naïve group and other control groups, which reduced C. difficile adherence to Caco-2 cells in vitro. The adherence blocking was further reduced for those hamsters receiving CD630_08730 adjuvanted with the synthetic lipid, presented on liposomes compared to the antigen alone. As hamsters receiving CD630_08730 alone showed good immunological responses, its protective efficacy was tested. Hamsters immunised with CD630_08730 antigen alone were challenged with hypervirulent strain R20291ermB and showed an 80% increase in mean time to end point compared to naïve animals. The survival was correlated with bacterial clearance and reduced toxin-mediated damage as determined from histopathology assessment of the caecum. This study highlights the potential of using semi-synthetic lipoproteins presented on liposomes as an oral vaccine platform and also highlights the potential of CD630_08730 as a vaccine candidate against CDI.

Subtractive genomic approach toward introduction of novel immunogenic targets against Clostridioides difficile: Thinking out of the box

Article

Dec 2021
MICROB PATHOGENESIS

Clostridioides difficile is one of the major causes of nosocomial infections worldwide. Antibiotic-associated diarrhea, pseudomembranous colitis, and toxic megacolon are the most common forms of C. difficile infection (CDI). Considering the high antibiotic resistance of C. difficile isolates and the low efficacy of immunization with toxin-related vaccines, we suggested that surface-exposed and secreted proteins could be considered as potential immunogenic targets against CDI. Various immuninformatics databases were used to predict antigenicity, allergenicity, B-cell epitopes, MHC-II binding sites, conserved domains, prevalence and conservation of proteins among the most common sequence types, molecular docking, and immunosimulation of immunogenic targets. Finally, 16 proteins belonging to three functional groups were identified, including proteins involved in the cell wall and peptidoglycan layer (9 proteins), flagellar assembly (5 proteins), spore germination (1 protein), and a protein with unknown function. Molecular docking results showed that among all the mentioned proteins, WP_009892971.1 (Acd) and WP_009890599.1 (a C40 family peptidase) had the strongest interactions with human Toll-like receptor 2 (TLR-2) and TLR-4. This study proposes a combination of C. difficile toxoid (Tcd) and surface-exposed proteins such as Acd as promising vaccine formulation for protection against circulating clinical strains of C. difficile.

Updates and Opinions in Diagnosis and Treatment of Clostridiodes difficile in Pediatrics

Article

Full-text available

Dec 2021

Purpose of review Clostridiodes difficile infection (CDI) has unique challenges for diagnosis and treatment in pediatrics. Though new antibiotics and biologics are being approved or developed for adults, most of the pediatric therapies still rely on multiple or extended antibiotic courses. This review aims to highlight emerging evidence and our clinical experience with CDI in children and can help inform readers’ approach to pediatric CDI. Recent findings Use of fidaxomicin for CDI in pediatrics has been shown to be to be non-inferior to vancomycin and is associated with higher global cure rates and decreased risk of recurrence. Fecal microbiota transplant is a successful emerging therapy with cure rates of up to 90%, though safety alerts should be noted. Diagnostic laboratory testing for C. difficile remains a challenge as it still cannot definitively distinguish between colonization and true infection, and this is particularly relevant to pediatric patients as they have the highest rates of colonization. Summary The diagnosis and treatment of C. difficile infection in pediatrics remain challenging and recommendations lag behind advances made in the adult field. Recent data suggests that use of fidaxomicin both as treatment of first episode or recurrences may be beneficial in pediatrics just as in adults. At an experienced center, FMT is associated with high cure rates. Bezlotuxumab a monoclonal antibody to toxin B that is already recommended for use in adults is being studied in children and should be available for clinical use soon. Oral vancomycin prophylaxis is also an emerging strategy for high-risk patients. Finally, a possible vaccine may be on the horizon for pediatrics.

Outcomes of Total versus Partial Colectomy in Fulminant Clostridium Difficile Colitis. A Propensity Matched Analysis.

Preprint

Full-text available

Nov 2021

Background The Total Abdominal Colectomy (TAC) is the recommended procedure for Fulminant Clostridium Difficile Colitis (FCDC), however, occasionally, FCDC is also treated with partial colectomies. The purpose of the study was to identify the outcomes of partial colectomy in FCDC cases. Method The National Surgical Quality Improvement Program (NSQIP) database was accessed and eligible patients from 2012 through 2016 were reviewed. Patients 18 years and older who were diagnosed with FCDC and who underwent colectomies were included in the study. Patients’ demography, clinical characteristics, comorbidities, mortality, morbidities, length of hospital stay and discharge disposition were compared between the group who underwent partial colectomy and the group who underwent TAC. Univariate analysis followed by propensity matching were performed. A p value of <0.05 is considered as statistically significant. Results Out of 491 patients who qualified for the study, 93 (18.94%) patients underwent partial colectomy. The pair matched analysis showed no significant difference in patients’ characteristics and comorbidities in the two groups. There was no significant difference found in mortality between the two groups (30.1% vs. 30.15, P>0.99). There were no differences found in the median [95% CI] hospital length of stay [LOS] (23 days [19-31] vs. 21 [17-25], P=0.30), post-operative complications (P>0.05), and discharged disposition to home (43.1% vs. 33.8%) or transfer to rehab (21.55 vs. 12.3%, P=0.357) between the TAC and partial colectomy groups. Conclusion The overall 30 days mortality remains very high in FCDC. Partial colectomy did not increase risk of mortality or morbidities and LOS.

Updating changes in human gut microbial communities associated with Clostridioides difficile infection

Article

Full-text available

Jan 2021

Clostridioides difficile is the causative agent of antibiotic-associated diarrhea, a worldwide public health problem. Different factors can promote the progression of C. difficile infection (CDI), mainly altered intestinal microbiota composition. Microbial species belonging to different domains (i.e., bacteria, archaea, eukaryotes, and even viruses) are synergistically and antagonistically associated with CDI. This review was aimed at updating changes regarding CDI-related human microbiota composition using recent data and an integral approach that included the different microorganism domains. The three domains of life contribute to intestinal microbiota homeostasis at different levels in which relationships among microorganisms could explain the wide range of clinical manifestations. A holistic understanding of intestinal ecosystem functioning will facilitate identifying new predictive factors for infection and developing better treatment and new diagnostic tools, thereby reducing this disease’s morbidity and mortality.

Gut microbiota composition in health-care facility-and community-onset diarrheic patients with Clostridioides difficile infection

Article

Full-text available

May 2021

The role of gut microbiota in the establishment and development of Clostridioides difficile infection (CDI) has been widely discussed. Studies showed the impact of CDI on bacterial communities and the importance of some genera and species in recovering from and preventing infection. However, most studies have overlooked important components of the intestinal ecosystem, such as eukaryotes and archaea. We investigated the bacterial, archaea, and eukaryotic intestinal microbiota of patients with health-care-facility- or community-onset (HCFO and CO, respectively) diarrhea who were positive or negative for CDI. The CDI-positive groups (CO/+, HCFO/+) showed an increase in microorganisms belonging to Bacteroidetes, Firmicutes, Proteobacteria, Ascomycota, and Opalinata compared with the CDI-negative groups (CO/−, HCFO/−). Patients with intrahospital-acquired diarrhea (HCFO/+, HCFO/−) showed a marked decrease in bacteria beneficial to the intestine, and there was evidence of increased Archaea and Candida and Malassezia species compared with the CO groups (CO/+, CO/−). Characteristic microbiota biomarkers were established for each group. Finally, correlations between bacteria and eukaryotes indicated interactions among the different kingdoms making up the intestinal ecosystem. We showed the impact of CDI on microbiota and how it varies with where the infection is acquired, being intrahospital-acquired diarrhea one of the most influential factors in the modulation of bacterial, archaea, and eukaryotic populations. We also highlight interactions between the different kingdoms of the intestinal ecosystem, which need to be evaluated to improve our understanding of CDI pathophysiology.

Alternative Strategies in the Treatment of Clostridioides difficile Infection

Article

May 2021

Ryan Goon Hon Au

Clostridioides difficile (C. diff.) is a leading cause of nosocomial infections worldwide and is a major challenge to public health. Widespread use of antibiotic agents have caused increasing incidence rates of C. diff. infections and the emergence of antibiotic-resistant strains of the potentially-deadly bacteria. The current treatment guidelines include the use of various antibiotics, which further contributes to the problem of antibiotic resistance. There is an urgent need for novel treatment methods in order to halt the emergence of even more antibiotic-resistant bacteria. This review discusses the pathogenesis of C. diff. infections, current treatment strategies, and possible alternative treatment strategies based on breakthrough scientific research.

Early diagnosis and antibiotic treatment for fulminant Clostridium difficile infection

Article

Full-text available

Dec 2020

In fulminant Clostridium difficile infection (CDI), early diagnosis is important, and early diagnosis could save fulminant CDI patients that do not qualify for surgery due to severe complicating conditions by conservative antibiotic therapy.

The combined effect of systemic antibiotics and proton pump inhibitors on Clostridioides difficile infection and recurrence

Article

Full-text available

Jan 2024
J ANTIMICROB CHEMOTH

Background Antibiotics and proton pump inhibitors (PPI) are recognized risk factors for acquisition and recurrence of Clostridioides difficile infection (CDI), yet combined effects remain unclear. Objectives To assess the short- and long-term effects of antibiotics and PPIs on CDI risk and recurrence. Methods Population-based study including all 43 152 patients diagnosed with CDI in Sweden (2006–2019), and 355 172 matched population controls without CDI. The impact of antibiotics and PPIs on CDI risk and recurrence was explored for recent (0–30 days) and preceding (31–180 days) use prior to their first CDI diagnosis, using multivariable conditional logistic regression presented as odds ratios (ORs) and 95% confidence interval, adjusted for demographics, comorbidities and other drugs. Results Compared to controls, the combined effect of recent PPIs and antibiotics [ORAB+PPI = 17.51 (17.48–17.53)] on CDI risk was stronger than the individual effects [ORAB = 15.37 (14.83–15.93); ORPPI = 2.65 (2.54–2.76)]. Results were less pronounced for exposure during the preceding months. Dose–response analyses showed increasing exposure correlated with CDI risk [recent use: ORAB = 6.32 (6.15–6.49); ORPPI = 1.65 (1.62–1.68) per prescription increase]. Compared to individuals without recurrence (rCDI), recent [ORAB = 1.30 (1.23–1.38)] and preceding [ORAB = 1.23 (1.16–1.31); ORPPI = 1.12 (1.03–1.21)] use also affected the risk of recurrence yet without significant interaction between both. Recent macrolides/lincosamides/streptogramins; other antibacterials including nitroimidazole derivates; non-penicillin beta lactams and quinolones showed the strongest association with CDI risk and recurrence, particularly for recent use. PPI use, both recent and preceding, further increased the CDI risk associated with almost all antibiotic classes. Conclusion Recent and less recent use of PPIs and systemic antibiotics was associated with an increased risk of CDI, particularly in combination.

Improving Clostridioides difficile Infectious Disease Treatment Response via Adherence to Clinical Practice Guidelines

Article

Full-text available

Jan 2024

Clostridioides difficile (C. difficile) is a predominant nosocomial infection, and guidelines for improving diagnosis and treatment were published in 2017. We conducted a single-center, retrospective 10-year cohort study of patients with primary C. difficile infectious disease (CDID) at the largest referral Lithuanian university hospital, aiming to evaluate the clinical and laboratory characteristics of CDID and their association with the outcomes, as well as implication of concordance with current Clinical Practice Guidelines. The study enrolled a total of 370 patients. Cases with non-concordant CDID treatment resulted in more CDID-related Intensive Care Unit (ICU) admissions (7.5 vs. 1.8%) and higher CDID-related mortality (13.0 vs. 1.8%) as well as 30-day all-cause mortality (61.0 vs. 36.1%) and a lower 30-day survival compared with CDID cases with concordant treatment (p < 0.05). Among cases defined by two criteria for severe CDID, only patients with non-concordant metronidazole treatment had refractory CDID (68.8 vs. 0.0%) compared with concordant vancomycin treatment. In the presence of non-concordant metronidazole treatment for severe CDID, only cases defined by two severity criteria had more CDID-related ICU admissions (18.8 vs. 0.0%) and higher CDID-related mortality (25.0 vs. 2.0%, p < 0.05) compared with cases defined by one criterion. Severe comorbidities and the continuation of concomitant antibiotics administered at CDID onset reduced (p < 0.05) the 30-day survival and increased (p = 0.053) 30-day all-cause mortality, with 57.6 vs. 10.7% and 52.0 vs. 25.0%, respectively. Conclusions: CDID treatment non-concordant with the guidelines was associated with various adverse outcomes. In CDID with leukocytes ≥ 15 × 109/L and serum creatinine level > 133 µmol/L (>1.5 mg/dL), enteral vancomycin should be used to avoid refractory response, as metronidazole use was associated with CDID-related ICU admission and CDID-related mortality. Severe comorbidities worsened the outcomes as they were associated with reduced 30-day survival. The continuation of concomitant antibiotic therapy increased 30-day all-cause mortality; thus, it needs to be reasonably justified, deescalated or stopped.

Red Blood Cell Transfusions Are Not Associated With Incident Complications or Poor Outcomes in Patients With Intracerebral Hemorrhage

Article

Full-text available

May 2023

Background Anemia is associated with poor intracerebral hemorrhage (ICH) outcomes, yet the relationship of red blood cell (RBC) transfusions to ICH complications and functional outcomes remains unclear. We investigated the impact of RBC transfusion on hospital thromboembolic and infectious complications and outcomes in patients with ICH. Methods and Results Consecutive patients with spontaneous ICH enrolled in a single‐center, prospective cohort study from 2009 to 2018 were assessed. Primary analyses assessed relationships of RBC transfusions on incident thromboembolic and infectious complications occurring after the transfusion. Secondary analyses assessed relationships of RBC transfusions with mortality and poor discharge modified Rankin Scale score 4 to 6. Multivariable logistic regression models adjusted for baseline demographics and medical disease severity (Acute Physiology and Chronic Health Evaluation II), and ICH severity (ICH score).Of 587 patients with ICH analyzed, 88 (15%) received at least one RBC transfusion. Patients receiving RBC transfusions had worse medical and ICH severity. Though patients receiving RBC transfusions had more complications at any point during the hospitalization (64.8% versus 35.9%), we found no association between RBC transfusion and incident complications in our regression models (adjusted odds ratio [aOR], 0.71 [95% CI, 0.42–1.20]). After adjusting for disease severity and other relevant covariates, we found no significant association between RBC transfusion and mortality (aOR, 0.87 [95% CI, 0.45–1.66]) or poor discharge modified Rankin Scale score (aOR, 2.45 [95% CI, 0.80–7.61]). Conclusions In our cohort with ICH, RBC transfusions were expectedly given to patients with higher medical and ICH severity. Taking disease severity and timing of transfusions into account, RBC transfusion was not associated with incident hospital complications or poor clinical ICH outcomes.

Fecal Microbiota Transplantation for Fulminant Clostridioides Difficile Infection: A Combined Medical and Surgical Case Series

Article

Full-text available

Feb 2023

Introduction: Urgent abdominal colectomy is indicated for patients with fulminant Clostridioides difficile infection (CDI) when other medical therapies fail, yet mortality remains high. Fecal microbiota transplant is a less invasive alternative approach for patients with fulminant CDI. We report the 30-day complications of patients with fulminant CDI who underwent either abdominal colectomy, fecal microbiota transplantation (FMT), or FMT followed by abdominal colectomy (FMT-CO). Methods: We performed a single-center, retrospective case review of combined medical and surgical patients with CDI at a large academic medical center between 2008 and 2016. Cohorts were identified as patients with fulminant CDI who underwent total abdominal colectomy alone (CO), FMT alone (FMT), or FMT-CO. We analyzed patient demographics, history, comorbidities, clinical and laboratory variables, CDI severity scores, and mortality outcomes at 30 days. Results: We identified 5,150 patients with CDI at our center during the review period; 16 patients met the criteria for fulminant CDI and were included in this study, with four patients in the CO cohort, eight patients in the FMT cohort, and four patients in the FMT-CO cohort. Demographics and CDI severity scores were similar for all three groups, although the selected comorbidity profiles differed significantly among the three cohorts. The 30-day mortality rates for patients in the CO, FMT, and FMT-CO groups were 25%, 12.5%, and 25%, respectively. Conclusions: FMT is an alternative or adjunctive therapy to colectomy for patients with fulminant CDI that is not associated with increased mortality. Implementation of FMT protocols in clinical practice would be dependent on the availability of qualified transplant material and successful early identification of patients likely to benefit from FMT.

Design of 8-mer Peptides that Block Clostridioides difficile Toxin A in Intestinal Cells

Preprint

Full-text available

Jan 2023

Clostridioides difficile ( C. diff .) is a bacterium that causes severe diarrhea and inflammation of the colon. The pathogenicity of C. diff . infection is derived from two major toxins, toxins A (TcdA) and B (TcdB). Peptide inhibitors that can be delivered to the gut to inactivate these toxins are an attractive therapeutic strategy. In this work, we present a new approach that combines a pep tide b inding d esign algorithm (PepBD), molecular-level simulations, rapid screening of candidate peptides for toxin binding, a primary human cell-based assay, and surface plasmon resonance (SPR) measurements to develop peptide inhibitors that block the glucosyltransferase activity of TcdA by targeting its glucosyltransferase domain (GTD). Using PepBD and explicit-solvent molecular dynamics simulations, we identified seven candidate peptides, SA1-SA7. These peptides were selected for specific TcdA GTD binding through a custom solid-phase peptide screening system, which eliminated the weaker inhibitors SA5-SA7. The efficacies of SA1-SA4 were then tested using a trans-epithelial electrical resistance (TEER) assay on monolayers of the human gut epithelial culture model. One peptide, SA1, was found to block TcdA toxicity in primary-derived human jejunum (small intestinal) and colon (large intestinal) epithelial cells. SA1 bound TcdA with a K D of 56.1 ± 29.8 nM as measured by surface plasmon resonance (SPR). Significance Statement Infections by Clostridioides difficile , a bacterium that targets the large intestine (colon), impact a significant number of people worldwide. Bacterial colonization is mediated by two exotoxins: toxins A and B. Short peptides that can inhibit the biocatalytic activity of these toxins represent a promising strategy to prevent and treat C. diff . infection. We describe an approach that combines a Peptide B inding D esign (PepBD) algorithm, molecular-level simulations, a rapid screening assay to evaluate peptide:toxin binding, a primary human cell-based assay, and surface plasmon resonance (SPR) measurements to develop peptide inhibitors that block Toxin A in small intestinal and colon epithelial cells. Importantly, our designed peptide, SA1, bound toxin A with nanomolar affinity and blocked toxicity in colon cells.

Clostridium difficile virulence factors as the cause of antibiotic-associated diarrhea (AAD): a literature review

Article

Full-text available

Oct 2022

Clostridium difficile is an anaerobic gram-positive bacillus, capable of forming spores and toxins, transmitted to humans by the faecal-oral route C. difficile infection (CDI) is recognized as a typical cause of healthcare-associated infections (HAIs) and contributes to a significant proportion of morbidity and mortality of hospitalized patients. C. difficile culture and toxin examinations are still minimal in many hospitals in various Asian countries. As a result, reports of C. difficile in Asia are still rare, while reports of cases of CDI in Indonesia are still rare. Several risk factors including advanced age, antibiotic exposure, and hospitalization are strongly associated with CDI. C. difficile has the ability to colonize the large intestine, then release exotoxin proteins (TcdA, TcdB) causing colitis in people with risk factors. A diagnosis of suspected C. difficile infection in a patient with diarrhea without a clear alternative explanation, with relevant risk factors (including long antibiotic consumption, hospitalization events, and elderly age), was then performed microbiological examination to carry out proper management and control of infection. This study aims to review C. difficile virulence factors as the cause of antibiotic-associated diarrhea.

Pathogenicity and virulence of Clostridioides difficile

Article

Full-text available

Jan 2023

Clostridioides difficile is the most common cause of nosocomial antibiotic-associated diarrhea, and is responsible for a spectrum of diseases characterized by high levels of recurrence, morbidity, and mortality. Treatment is complex, since antibiotics constitute both the main treatment and the major risk factor for infection. Worryingly, resistance to multiple antibiotics is becoming increasingly widespread, leading to the classification of this pathogen as an urgent threat to global health. As a consummate opportunist, C. difficile is well equipped for promoting disease, owing to its arsenal of virulence factors: transmission of this anaerobe is highly efficient due to the formation of robust endospores, and an array of adhesins promote gut colonization. C. difficile produces multiple toxins acting upon gut epithelia, resulting in manifestations typical of diarrheal disease, and severe inflammation in a subset of patients. This review focuses on such virulence factors, as well as the importance of antimicrobial resistance and genome plasticity in enabling pathogenesis and persistence of this important pathogen.

Surface layer protein A from hypervirulent Clostridioides difficile ribotypes induce significant changes in the gene expression of tight junctions and inflammatory response in human intestinal epithelial cells

Article

Full-text available

Oct 2022
BMC MICROBIOL

Background Surface layer protein A (SlpA), the primary outermost structure of Clostridioides difficile , plays an essential role in C. difficile pathogenesis, although its interaction with host intestinal cells are yet to be understood. The aim of this study was to investigate the effects of SlpA extracted from C. difficile on tight junction (TJ) proteins expression and induction of pro-inflammatory cytokines in human colon carcinoma cell line HT-29. SlpA was extracted from three toxigenic C. difficile clinical strains including RT126, RT001, RT084 as well as C. difficile ATCC 700057 as non-toxigenic strain. Cell viability was performed by MTT assay, and the mRNA expression of TJ proteins and inflammation-associated genes was determined using quantitative RT-PCR. Additionally, the secretion of IL-8, IL-1β and TNF-α cytokines was measured by ELISA. Results C. difficile SlpA from selected RTs variably downregulated the expression level of TJs-assassinated genes and increased the expression level of TLR-4 and pro-inflammatory cytokines in HT-29 treated cells. SlpA from RT126 significantly (p adj <0.05) decreased the gene expression level of claudins family and JAM-A and increased the secretion of IL-8, TNF-α and IL1-β as compared to untreated cells. Moreover, only SlpA from RT001 could significantly induce the expression of IL-6 (p adj <0.05). Conclusion The results of the present study highlighted the importance of SlpA in the pathogenesis of CDI and C. difficile -induced inflammatory response in the gut. Further studies are required to unravel the significance of the observed results in promoting the intestinal inflammation and immune response induced by C. difficile SlpA from different RTs.

Characterization of the glmS Ribozymes from Listeria Monocytogenes and Clostridium Difficile

Article

Full-text available

Nov 2022
CHEM-EUR J

The glmS ribozyme regulates the expression of the essential GlmS enzyme being involved in cell wall biosynthesis. While >450 variants of the glmS ribozyme were identified by in silico approaches and homology searches, only a few have yet been experimentally investigated. Herein, we validate and characterize the glmS ribozymes of the human pathogens Clostridium difficile and Listeria monocytogenes. Both ribozymes, as their previous characterized homologs rely on glucosamine‐6‐phosphate as co‐factor and the presence of divalent cations for exerting the cleavage reaction. The observed EC50 values in turn were found to be in the submicromolar range, at least an order of magnitude lower than observed for glmS ribozymes from other bacteria. The glmS ribozyme of L. monocytogenes was further shown to bear unique properties. It discriminates between co‐factors very stringently and other than the glmS ribozyme of C. difficile retains activity at low temperatures. This finding illustrates that albeit being highly conserved, glmS ribozymes have unique characteristics.

Cureus Article

Article

Full-text available

Apr 2022

Arslan Iqbal

Outcomes of Continuous Enteral Vancomycin Infusion in Intensive Care Unit Patients: A Novel Treatment Modality for Severe Clostridium Difficile Colitis

Article

Full-text available

Mar 2022

Background and objective Severe Clostridium difficile (C. difficile) infection (CDI)-related colitis is associated with high morbidity and mortality. Current guidelines recommend oral vancomycin plus intravenous metronidazole as the first-line treatment and early total colectomy in case of medication failure. In critically ill patients at high surgical risk and with multiple comorbidities, loop ileostomy creation and enteral vancomycin infusion have been employed albeit with limited success. We hypothesized that continuous enteral vancomycin (CEV) infusion via a postpyloric feeding tube would provide a less invasive, efficacious, and safer route to treat high surgical risk patients. Methods All adult (>18 years) non-pregnant patients admitted to the ICU for severe CDI from October 2012 to October 2016 and received CEV after the failure of conventional therapy were included. Vancomycin was prepared as a 1-2-mg/ml enteral solution and run continuously through a feeding pump at 42 ml/hour via a post-pyloric feeding tube. The primary efficacy endpoint was clinical improvement defined as (a) decrease in stool output, (b) decreased vasopressor requirement, or (c) improved leukocytosis, and the secondary endpoint was treatment failure defined as the need for total colectomy or death due to severe CDI. Results Our cohort comprised 11 patients in total. The median age of the participants was 64 years, and there were more females (67%) than males (36%). Clinical improvement was seen in seven patients (63%); treatment failure documented as the need for total colectomy was observed in two patients (18%), and death attributable to CDI occurred in three patients (27%). Conclusion CEV resulted in clinical improvement in most patients with severe CDI who were at high surgical risk. Sustained intestinal vancomycin delivery may increase luminal concentration and bactericidal effect. The use of a feeding tube and pump provides an effective and less invasive route of vancomycin delivery in critically ill patients.

Clostridioides difficile infection and One Health: An Equine Perspective

Article

Full-text available

Jan 2022

Clostridioides (Clostridium) difficile presents a significant health risk to humans and animals. The complexity of the bacterial-host interaction affecting pathogenesis and disease development creates an ongoing challenge for epidemiological studies, control strategies and prevention planning. The recent emergence of human disease caused by strains of C. difficile found in animals adds to mounting evidence that C. difficile infection (CDI) may be a zoonosis. In equine populations, C. difficile is a known cause of diarrhoea and gastrointestinal inflammation, with considerable mortality and morbidity. This has a significant impact on both the well-being of the animal and, in the case of performance and production animals, it may have an adverse economic impact on relevant industries. While C. difficile is regularly isolated from horses, many questions remain regarding the impact of asymptomatic carriage as well as optimization of diagnosis, testing and treatment. This review provides an overview of our understanding of equine CDI while also identifying knowledge gaps and the need for a holistic One Health approach to a complicated issue. This article is protected by copyright. All rights reserved.

A rare case of severe gastroenteritis caused by Aeromonas hydrophila after colectomy in a patient with anti-Hu syndrome: a case report

Article

Full-text available

Oct 2021
BMC INFECT DIS

Background Aeromonas hydrophila is a gram-negative facultative anaerobic coccobacillus, which is an environmental opportunistic pathogen. A. hydrophila are involved in several infectious diseases such as gastroenteritis, septicemia and wound infections. However, gastroenteritis caused by Aeromonas spp. are rare and the clinical relevance of Aeromonas species in stool specimens is still under debate. Case presentation Our case concerns a 32-year-old woman who presented at hospital with a worsening watery diarrhea and fever requiring intensive care. A cholera-like illness was diagnosed. The patient had a past history of an anti-Hu syndrome with a myenteric ganglionitis. A molecular multiplex RT-PCR (QIAstat-Dx Gastrointestinal Panel, QIAGEN) covering a broad spectrum of diverse gastrointestinal pathogens performed directly from the stool was negative but the stool culture revealed growth of A. hydrophila. Further investigations of the A. hydrophila strain in cell cultures revealed the presence of a cytotoxic enterotoxin. Conclusions Although A. hydrophila rarely causes gastroenteritis, Aeromonas spp. should be considered as a causative agent of severe gastroenteritis with a cholera-like presentation. This case highlights the need to perform culture methods from stool samples when PCR-based methods are negative and gastrointestinal infection is suspected.

Protective Effect of Baicalin against Clostridioides difficile Infection in Mice

Article

Full-text available

Jul 2021

This study investigated the prophylactic and therapeutic efficacies of baicalin (BC), a plant-derived flavone glycoside, in reducing the severity of Clostridioides difficile infection (CDI) in a mouse model. In the prophylactic trial, C57BL/6 mice were provided with BC (0, 11, and 22 mg/L in drinking water) from 12 days before C. difficile challenge through the end of the experiment, whereas BC administration started day 1 post challenge in the therapeutic trial. Both challenge and control groups were infected with 106 CFU/mL of hypervirulent C. difficile BAA 1803 spores or sterile PBS, and the clinical and diarrheal scores were recorded for 10 days post challenge. On day 2 post challenge, fecal and tissue samples were collected from mice prophylactically administered with BC for microbiome and histopathologic analysis. Both prophylactic and therapeutic supplementation of BC significantly reduced the severity of colonic lesions and improved CDI clinical progression and outcome compared with control (p < 0.05). Microbiome analysis revealed a significant increase in Gammaproteobacteria and reduction in the abundance of protective microbiota (Firmicutes) in antibiotic-treated and C. difficile-infected mice compared with controls (p < 0.05). However, baicalin supplementation favorably altered the microbiome composition, as revealed by an increased abundance in beneficial bacteria, especially Lachnospiraceae and Akkermansia. Our results warrant follow-up investigations on the use of BC as an adjunct to antibiotic therapy to control gut dysbiosis and reduce C. difficile infection in humans.

A Palmitoylethanolamide Producing Lactobacillus paracasei Improves Clostridium difficile Toxin A-Induced Colitis

Article

Full-text available

Apr 2021

Genetically engineered probiotics, able to in situ deliver therapeutically active compounds while restoring gut eubiosis, could represent an attractive therapeutic alternative in Clostridium difficile infection (CDI). Palmitoylethanolamide is an endogenous lipid able to exert immunomodulatory activities and restore epithelial barrier integrity in human models of colitis, by binding the peroxisome proliferator–activated receptor-α (PPARα). The aim of this study was to explore the efficacy of a newly designed PEA-producing probiotic (pNAPE-LP) in a mice model of C. difficile toxin A (TcdA)-induced colitis. The human N-acyl-phosphatidylethanolamine-specific phospholipase D (NAPE-PLD), a key enzyme involved in the synthesis of PEA, was cloned and expressed in a Lactobacillus paracasei that was intragastrically administered to mice 7 days prior the induction of the colitis. Bacteria carrying the empty vector served as negative controls (pLP).In the presence of palmitate, pNAPE-LP was able to significantly increase PEA production by 27,900%, in a time- and concentration-dependent fashion. Mice treated with pNAPE-LP showed a significant improvement of colitis in terms of histological damage score, macrophage count, and myeloperoxidase levels (−53, −82, and −70.4%, respectively). This was paralleled by a significant decrease both in the expression of toll-like receptor-4 (−71%), phospho-p38 mitogen-activated protein kinase (−72%), hypoxia-inducible factor-1-alpha (−53%), p50 (−74%), and p65 (−60%) and in the plasmatic levels of interleukin-6 (−86%), nitric oxide (−59%), and vascular endothelial growth factor (−71%). Finally, tight junction protein expression was significantly improved by pNAPE-LP treatment as witnessed by the rescue of zonula occludens-1 (+304%), Ras homolog family member A-GTP (+649%), and occludin expression (+160%). These protective effects were mediated by the specific release of PEA by the engineered probiotic as they were abolished in PPARα knockout mice and in wild-type mice treated with pLP. Herein, we demonstrated that pNAPE-LP has therapeutic potential in CDI by inhibiting colonic inflammation and restoring tight junction protein expression in mice, paving the way to next generation probiotics as a promising strategy in CDI prevention.

Health economic evaluations comparing faecal microbiota transplantation with antibiotics for treatment of recurrent Clostridioides difficile infection: a systematic review

Article

Full-text available

Jan 2021

Background Faecal microbiota transplantation (FMT) is increasingly being used in the treatment of recurrent Clostridioides difficile infection (rCDI). Health economic evaluations may support decision-making regarding the implementation of FMT in clinical practice. Previous reviews have highlighted several methodological concerns in published health economic evaluations examining FMT. However, the impact of these concerns on the conclusions of the studies remains unclear. Aims To present an overview and assess the methodological quality of health economic evaluations that compare FMT with antibiotics for treatment of rCDI. Furthermore, we aimed to evaluate the degree to which any methodological concerns would affect conclusions about the cost-effectiveness of FMT. Methods We conducted a systematic literature review based on a search in seven medical databases up to 16 July 2020. We included research articles reporting on full health economic evaluations comparing FMT with antibiotic treatment for rCDI. General study characteristics and input estimates for costs, effectiveness and utilities were extracted from the articles. The quality of the studies was assessed by two authors using the Drummonds ten-point checklist. Results We identified seven cost-utility analyses. All studies applied decision-analytic modelling and compared various FMT delivery methods with vancomycin, fidaxomicin, metronidazole or a combination of vancomycin and bezlotoxumab. The time horizons used in the analyses varied from 78 days to lifelong, and the perspectives differed between a societal, a healthcare system or a third-party payer perspective. The applied willingness-to-pay threshold ranged from 20,000 to 68,000 Great Britain pound sterling (GBP) per quality-adjusted life-year (QALY). FMT was considered the most cost-effective alternative in all studies. In five of the health economic evaluations, FMT was both more effective and cost saving than antibiotic treatment alternatives. The quality of the articles varied, and we identified several methodological concerns. Conclusions Economic evaluations consistently reported that FMT is a cost-effective and potentially cost-saving treatment for rCDI. Based on a comparison with recent evidence within the area, the multiple methodological concerns seem not to change this conclusion. Therefore, implementing FMT for rCDI in clinical practice should be strongly considered.

Clostridium difficile: An Important Opportunistic Pathogen in Healthcare-Associated Infections

Article

Full-text available

Jan 2018

Healthcare-associated infections are infections that patients can get while receiving medical treatment in a healthcare facility. One opportunistic pathogen, Clostridium difficile, has been getting more attention in recent years because of its association with antibiotic use and a high death rate among the elderly. This 7-page factsheet will provide an overview of Clostridium difficile infection (CDI) with a focus on healthcare-associated infections. Written by Soohyoun Ahn and Amarat H. Simonne and published by the UF/IFAS Department of Food Science and Human Nutrition, January 2018. http://edis.ifas.ufl.edu/fs253

Genome Characterization of a Novel Binary Toxin-Positive Strain of Clostridium difficile and Comparison with the Epidemic 027 and 078 Strains

Preprint

Full-text available

May 2017

A novel binary toxin-positive non-027, non-078 Clostridium difficile strain designated LC693 whose sequence type was ST201 was isolated from the fecal sample of a patient with severe diarrhea in China. To understand the pathogenesis basis of C. difficile ST201, this recently recovered isolate LC693 was then chosen for whole genome sequencing. The project finally generated an estimated genome size of approximately 4.07 Mbp. The genome sequence was then analyzed together with the other two ST201 strains VL-0104 and VL-0391 and compared to the epidemic 027/ST1 and 078/ST11 strains. Phylogenetic analysis demonstrated that the ST201 strains belonged to clade 3. Genome size of the three ST201 strains ranged from 4.07 Mb~4.16 Mb, with an average GC content between 28.5%~28.9%. The ST201 genomes contained more than 40 antibiotic resistance genes and 15 of them were predicted to be associated with vancomycin-resistance, suggesting that they may have a strong antibiotic resistance. The ST201 strains contained a typical clade 3 specific PaLoc with a Tn6218 element inserted, and those genes harbored on their PaLoc that participated in the toxin expression and regulation were highly homologues to the epidemic 027 and 078 strains, with the exception of tcdC. A truncated TcdC was found in the ST201 strains, which is suggestive to have a contribution to the toxin production of the ST201 strains. In addition, the ST201 strains contained intact binary toxin coding and regulation genes, which is also proposed to contribute to the virulence. Genome comparison of the ST201 strains with the epidemic 027 and 078 strain identified 641 genes specific for the C. difficile ST201, and a number of them were predicted as fitness and virulence associated genes. The identification of those genes also contributes to the pathogenesis of the ST201 strain. To our knowledge, this is the first study that the genome sequence of C. difficile ST201 was discussed in detail, and the present study would have a contribution to understanding the pathogenesis basis of C. difficile ST201.

Necrotising Vasculitis in Covid-19: watch out for bowel perforation

Preprint

Full-text available

Sep 2020

Introduction: SARS-Cov-2 infection can be asymptomatic, greatly impair respiratory function and, sometimes, affect other organs. Gastro-enteric involvement seems to be not so rare and many patients suffered for abdominal pain, anorexia, nausea and vomiting, diarrhoea or jaundice. Case presentation: Here we report a case of a Covid-19 patient who developed a right colon perforation due to a pseudomembranous colitis without Clostridium Difficile toxins finding associated to a necrotising vasculitis. In this patient a PCR test performed on gastric fluid showed SARS-CoV-2 enteric replication. Discussion: Necrotizing vasculitis is an anatomopathological typical findings in Covid-19. It has been documented in several organs and tissues. In our case, evident foci of necrotizing vasculitis with intravascular obliteration by fibrin thrombi with macrophagic cells infiltration are anatomopathological findings of a CD toxins free pseudomembranous colitis leading to bowel perforation. Conclusions: Bowel perforation due to necrotizing vasculitis leading to pseudomembranous colitis could be a SARS-Cov-2 related clinical finding.

C. difficile biomarkers, pathogenicity and detection

Article

Apr 2024
CLIN CHIM ACTA

Testing and diagnosis of Clostridioides difficile infection in special scenarios: A systematic review

Preprint

Full-text available

Feb 2024

Aim To evaluate Clostridioides difficile testing and diagnosis in specific patient populations. Background Clostridioides difficile infection (CDI) is a biochemical and clinical diagnosis. Certain patient populations are at higher risk and testing must be interpreted correctly to avoid overdiagnosis and overtreatment. Consequently, we need to understand the limitations of the tests used to avoid increase morbidity and mortality due to false negative test results. Diagnostic assays should be ordered in a step wise approach in specific patient populations to confirm CDI. Methods Manuscripts were extracted from three different databases based on keywords. Data were extracted based on the PRISMA 2020 guidelines. Each manuscript was analyzed using appropriate critical appraisal tools. Results A total of 70 reports were evaluated. 18 review articles, 4 retrospective cohorts, 3 guidelines, 1 experimental, and 1 cross sectional study were eligible for inclusion. A total of 27 reports were included. Discussion CDI should be considered in all patients with traditional risk factors. Increased clinical suspicion of CDI is required in special populations such as hypogammaglobulinemia, transplant recipients, surgery, and inflammatory bowel disease. Testing should be limited to patients with the clinical manifestations of CDI to ensure a high pre-test probability for test interpretation. Diagnostic assays should follow a sequential, stepwise approach to accurately categorize the toxin expression status of the bacteria.

Colitis fulminante por Clostridium Difficile en paciente con antecedentes de trasplante de hígado: una complicación potencialmente mortal

Article

Full-text available

Apr 2023
Rev Fac Cien Med Univ Nac Cordoba

La colitis fulminante por Clostridium difficile se caracteriza por el desarrollo de una inflamación aguda severa del colon, asociada a toxicidad sistémica, y es la forma más grave de colitis aguda con una mortalidad de hasta el 80%. Presentamos el caso de un varón de 45 años que acude al servicio de urgencias por dolor abdominal agudo, diarrea y fiebre. La tomografía computarizada mostró engrosamiento parietal difuso circunferencial del colon, incluido el recto, asociado con estriación de los tejidos circundantes y formaciones ganglionares. En las horas siguientes el paciente evolucionó con empeoramiento del estado general, aumento de los requerimientos de inotrópicos y acidosis láctica. Se decide laparotomía de urgencia y se realiza colectomía total. La colitis fulminante por Clostridium difficile es una enfermedad potencialmente mortal. La labilidad de la patología obliga en muchas ocasiones a tomar una rápida conducta, por lo que representa una urgencia médico-quirúrgica siendo el tiempo crucial.

Retrospective Cohort Analysis of Outpatient Antibiotic Use for Clostridioides difficile-Indicated Agents in British Columbia, from 2000 to 2018

Article

Full-text available

Feb 2023
CAN J INFECT DIS MED

Background: Clostridioides difficile (CDI) is the most common cause of nosocomial diarrheal infections. Historically, metronidazole was the first-line treatment, but guidelines now indicate oral vancomycin and fidaxomicin as primary antibiotics for initial episodes. A provincial stewardship program has operated in British Columbia (BC), since 2005. Since the program's inception, surveillance of antibiotic use has been ongoing. However, this is the first study to review community-acquired CDI-indicated antibiotic use. Moreover, this study offers the first interpretation of fidaxomicin use in BC since its addition to the provincial formulary. Methods: A retrospective cohort analysis included all outpatient dispensations for CDI-related antibiotics from January 1, 2000, to December 31, 2018. Antibiotic dispensations were extracted for metronidazole, vancomycin, and fidaxomicin. Consumption rates were calculated as prescriptions per 1000 population. Rates were examined overall and then stratified by medication, age, and sex. Secondary outcomes of interest included an examination of adherence to provincial special authority criteria; and proportions of outpatient antibiotic use attributable to administrative health records for CDI. Results: The average annual rate of prescribing was 18.5 per 1000 population for all CDI-indicated antibiotics. The rate of prescribing increased (15%) over the 19-year study period, from 17.2 to 19.8 dispensations per 1000 population. Metronidazole accounted for the most antibiotics dispensed in every study year; however, by 2018 it demonstrated the most modest increase in use (15%). In comparison, fidaxomicin increased by 226% by 2018. Vancomycin had the highest percentage increase (621%), with the greatest change occurring from 2014 to 2015, correlating to the dissemination of new clinical practice guidelines. Conclusion: This is the first study to evaluate outpatient prescribing for CDI-indicated antibiotics, and one of the few studies to examine fidaxomicin since its introduction to Canadian formularies. Although causation cannot be inferred from study results, oral vancomycin, and fidaxomicin use has increased in line with, or in advance-of guidelines.

Emerging alternatives against Clostridioides difficile infection

Article

Sep 2022
ANAEROBE

Clostridioides difficile infection (CDI) is a significant worry within healthcare institutions and the community. It is one of the leading agents causing severe diarrhea worldwide. Effective management is critical since the morbidity and mortality attributed to CDI have increased exponentially over the past 20 years. Currently, antibiotics are the standard treatment for primary C. difficile infection, but at the same time, they are associated with disease relapse and increased drug resistance. CDI's high recurrence rates, spore generation, and antimicrobial resistance are currently significant challenges that urge the development of new options to combat this infection. This review describes up-and-coming alternatives and how they can mitigate the challenges associated with CDI. Here we have discussed the advantages and challenges of current and experimental alternatives against CDI.

The Prevalence of Clostridium difficile Colitis and Effect on All-Cause Mortality in Elderly Patients after Hip Fracture Surgery: A Korean Nationwide Cohort Study

Article

Full-text available

Sep 2022

Background: This study aimed to investigate the prevalence of Clostridium difficile colitis (CDC) in elderly patients with hip fractures using a nationwide cohort database and to analyze the effect of CDC on the all-cause mortality rate after hip fracture. Methods: This retrospective nationwide study identified subjects from the Korean National Health Insurance Service-Senior cohort. The subjects of this study were patients who were over 65 years old and underwent surgical treatment for hip fractures from January 1, 2002, to December 31, 2015. The total number of patients included in this study was 10,158. The diagnostic code used in this study was A047 of the International Classification of Diseases, 10th revision for identifying CDC. Procedure codes for C. difficile culture or toxin assay were BY021 and BY022. CDC patients were defined as follows: patients treated with oral vancomycin or metronidazole over 10 days and patients with procedure codes BY021 and BY022 or diagnostic code A047 after hip fracture. Incidence date (index date, time zero) of hip fracture for analyzing risk of all-cause mortality was defined as the date of discharge. A generalized estimating equation model with Poisson distribution and logarithmic link function was used for estimating adjusted risk ratios and 95% confidence intervals to assess the association between CDC and cumulative mortality risk. Results: The prevalence of CDC during the hospitalization period in the elderly patients with hip fractures was 1.43%. Compared to the non-CDC group, the CDC group had a 2.57-fold risk of 30-day mortality after discharge, and a 1.50-fold risk of 1-year mortality after discharge (p < 0.05). Conclusions: The prevalence of CDC after hip fracture surgery in elderly patients was 1.43%. CDC after hip fracture in the elderly patients significantly increased the all-cause mortality rate after discharge.

Antigenspezifische und neutralisierende Antikörper bei Patienten mit Clostridioides difficile-Infektion

Thesis

Jan 2022

Sophie Roth

Oncology and Hematology in the ICU

Chapter

May 2022

In the coming years, accelerated progress against oncologic and hematologic diseases will be associated with a greater number of patients requiring life support therapies. In this chapter, we seek to highlight recent changes in the use and outcomes of intensive care in onco-hematologic patients. In recent decades, we have shown a substantial increase in our understanding of organ dysfunctions in the population of patients with solid and hematological malignancies, in the more appropriate use of life support therapies and in the selection of new and better therapeutic approaches that have been increasing survival of these patients. While reading this chapter, the reader is expected to reflect on the daily management of critically ill onco-hematological patients, from the management of toxicity to palliative care, and to understand the role and importance of the pharmacist within the field of oncology among critically ill patients.

Diseases of the Small and Large Bowel

Chapter

Jan 2022

Defining the black box: a narrative review of factors associated with adverse outcomes from severe Clostridioides difficile infection

Article

Full-text available

Oct 2021

In the United States, Clostridioides difficile infection (CDI) is the leading cause of healthcare-associated infection, affecting nearly half a million people and resulting in more than 20,000 in-hospital deaths every year. It is therefore imperative to better characterize the intricate interplay between C. difficile microbial factors, host immunologic signatures, and clinical features that are associated with adverse outcomes of severe CDI. In this narrative review, we discuss the implications of C. difficile genetics and virulence factors in the molecular epidemiology of CDI, and the utility of early biomarkers in predicting the clinical trajectory of patients at risk of developing severe CDI. Furthermore, we identify associations between host immune factors and CDI outcomes in both animal models and human studies. Next, we highlight clinical factors including renal dysfunction, aging, blood biomarkers, level of care, and chronic illnesses that can affect severe CDI diagnosis and outcome. Finally, we present our perspectives on two specific treatments pertinent to patient outcomes: metronidazole administration and surgery. Together, this review explores the various venues of CDI research and highlights the importance of integrating microbial, host, and clinical data to help clinicians make optimal treatment decisions based on accurate prediction of disease progression.

Diseases of the Small and Large Bowel

Chapter

Jan 2021

Ulcerative colitis-related severe enteritis: an infrequent but serious complication after colectomy

Article

Nov 2020

Background and aim: After colectomy for ulcerative colitis (UC), very severe and sometimes lethal enteritis can develop. However, the clinical features remain uncertain because of the low incidence, diversity of symptoms, and undefined diagnostic criteria. The aim of this study was to define postoperative ulcerative colitis-related severe enteritis (UCRSE) and to investigate its clinical features. Methods: A retrospective multicenter study was performed as a survey of major medical facilities utilizing surgical supplies for inflammatory bowel disease in Japan from 2001 to 2014. UCRSE was defined as a case with massive intestinal bleeding, intestinal perforation, high-output stoma, and/or a requirement for medications, such as steroids and biologics. Patients with gastroduodenal lesions or pouchitis alone were excluded. The incidence, symptoms, involvement of bacteria, cytomegalovirus reactivation, treatment, and prognosis were examined for patients with UCRSE after colectomy. Results: Forty-two (0.8%) out of 5284 cases met the criteria for UCRSE. Major symptoms were massive intestinal bleeding (76.2%), which required a median of 3850 (560-18900) mL blood transfusion; high-output stoma (38.1%) with excretion of fluid of 5000 (2000-7800) mL/day; and intestinal perforation (7.1%). Hypovolemic shock (35.7%) and/or disseminated intravascular coagulation (31.0%) developed as serious complications. Tests for cytomegalovirus reactivation were positive in 26.2% of cases. The presence of pathogenic bacteria was confirmed in only 5 cases. Corticosteroids or infliximabs were effective in half of the patients. Thirteen cases (31.0%) were treated surgically and 22 cases (56.4%) required maintenance therapy. The mortality rate was 11.9%. Conclusion: UCRSE is a rare but serious complication after colectomy and is sometimes life-threatening.

Bezlotoxumab for Prevention of Clostridium difficile Infection Recurrence

Article

Full-text available

Nov 2016

Background Clostridium difficile is the most common cause of infectious diarrhea in hospitalized patients. Recurrences are common after antibiotic therapy. Actoxumab and bezlotoxumab are human monoclonal antibodies against C. difficile toxins A and B, respectively. Methods We conducted two double-blind, randomized, placebo-controlled, phase 3 trials, MODIFY I and MODIFY II, involving 2655 adults receiving oral standard-of-care antibiotics for primary or recurrent C. difficile infection. Participants received an infusion of bezlotoxumab (10 mg per kilogram of body weight), actoxumab plus bezlotoxumab (10 mg per kilogram each), or placebo; actoxumab alone (10 mg per kilogram) was given in MODIFY I but discontinued after a planned interim analysis. The primary end point was recurrent infection (new episode after initial clinical cure) within 12 weeks after infusion in the modified intention-to-treat population. Results In both trials, the rate of recurrent C. difficile infection was significantly lower with bezlotoxumab alone than with placebo (MODIFY I: 17% [67 of 386] vs. 28% [109 of 395]; adjusted difference, −10.1 percentage points; 95% confidence interval [CI], −15.9 to −4.3; P<0.001; MODIFY II: 16% [62 of 395] vs. 26% [97 of 378]; adjusted difference, −9.9 percentage points; 95% CI, −15.5 to −4.3; P<0.001) and was significantly lower with actoxumab plus bezlotoxumab than with placebo (MODIFY I: 16% [61 of 383] vs. 28% [109 of 395]; adjusted difference, −11.6 percentage points; 95% CI, −17.4 to −5.9; P<0.001; MODIFY II: 15% [58 of 390] vs. 26% [97 of 378]; adjusted difference, −10.7 percentage points; 95% CI, −16.4 to −5.1; P<0.001). In prespecified subgroup analyses (combined data set), rates of recurrent infection were lower in both groups that received bezlotoxumab than in the placebo group in subpopulations at high risk for recurrent infection or for an adverse outcome. The rates of initial clinical cure were 80% with bezlotoxumab alone, 73% with actoxumab plus bezlotoxumab, and 80% with placebo; the rates of sustained cure (initial clinical cure without recurrent infection in 12 weeks) were 64%, 58%, and 54%, respectively. The rates of adverse events were similar among these groups; the most common events were diarrhea and nausea. Conclusions Among participants receiving antibiotic treatment for primary or recurrent C. difficile infection, bezlotoxumab was associated with a substantially lower rate of recurrent infection than placebo and had a safety profile similar to that of placebo. The addition of actoxumab did not improve efficacy. (Funded by Merck; MODIFY I and MODIFY II ClinicalTrials.gov numbers, NCT01241552 and NCT01513239.)

Antimicrobial stewardship programs that target only high-cost, broad-spectrum antimicrobials miss opportunities to reduce Clostridium difficile infections

Article

Full-text available

Dec 2016
AM J INFECT CONTROL

Antimicrobial stewardship programs are promoted as a strategy to reduce Clostridium difficile infections. We implemented an antimicrobial stewardship program comprised of formulary restriction plus prospective audit with feedback for high-cost and broad-spectrum antimicrobials. Subsequently, we reviewed all heath care facility–onset, health care facility–associated C difficile infections. We found that most of these infections were associated with the antecedent receipt of nonaudited, and often unnecessary, antimicrobials.

Effect of Fecal Microbiota Transplantation on Recurrence in Multiply Recurrent Clostridium difficile Infection: A Randomized Trial

Article

Full-text available

Aug 2016
ANN INTERN MED

Background: To date, evidence for the efficacy of fecal microbiota transplantation (FMT) in recurrent Clostridium difficile infection (CDI) has been limited to case series and open-label clinical trials. Objective: To determine the efficacy and safety of FMT for treatment of recurrent CDI. Design: Randomized, controlled, double-blind clinical trial. (ClinicalTrials.gov: NCT01703494). Setting: Two academic medical centers. Patients: 46 patients who had 3 or more recurrences of CDI and received a full course of vancomycin for their most recent acute episode. Intervention: Fecal microbiota transplantation with donor stool (heterologous) or patient's own stool (autologous) administered by colonoscopy. Measurements: The primary end point was resolution of diarrhea without the need for further anti-CDI therapy during the 8-week follow-up. Safety data were compared between treatment groups via review of adverse events (AEs), serious AEs (SAEs), and new medical conditions for 6 months after FMT. Fecal microbiota analyses were performed on patients' stool before and after FMT and also on donors' stool. Results: In the intention-to-treat analysis, 20 of 22 patients (90.9%) in the donor FMT group achieved clinical cure compared with 15 of 24 (62.5%) in the autologous FMT group (P = 0.042). Resolution after autologous FMT differed by site (9 of 10 vs. 6 of 14 [P = 0.033]). All 9 patients who developed recurrent CDI after autologous FMT were free of further CDI after subsequent donor FMT. There were no SAEs related to FMT. Donor FMT restored gut bacterial community diversity and composition to resemble that of healthy donors. Limitation: The study included only patients who had 3 or more recurrences and excluded those who were immunocompromised and aged 75 years or older. Conclusion: Donor stool administered via colonoscopy seemed safe and was more efficacious than autologous FMT in preventing further CDI episodes. Primary funding source: National Institute of Diabetes and Digestive and Kidney Diseases.

An update on antibody-based immunotherapies for Clostridium difficile infection

Article

Full-text available

Aug 2016

Clostridium difficile continues to be one of the most prevalent hospital-acquired bacterial infections in the developed world, despite the recent introduction of a novel and effective antibiotic agent (fidaxomicin). Alternative approaches under investigation to combat the anaerobic Gram-positive bacteria include fecal transplantation therapy, vaccines, and antibody-based immunotherapies. In this review, we catalog the recent advances in antibody-based approaches under development and in the clinic for the treatment of C. difficile infection. By and large, inhibitory antibodies that recognize the primary C. difficile virulence factors, toxin A and toxin B, are the most popular passive immunotherapies under investigation. We provide a detailed summary of the toxin epitopes recognized by various antitoxin antibodies and discuss general trends on toxin inhibition efficacy. In addition, antibodies to other C. difficile targets, such as surface-layer proteins, binary toxin, motility factors, and adherence and colonization factors, are introduced in this review.

Australasian Society of Infectious Diseases updated guidelines for the management of Clostridium difficile infection in adults and children in Australia and New Zealand

Article

Full-text available

Apr 2016

The incidence of Clostridium difficile infection (CDI) continues to rise, whilst treatment remains problematic due to recurrent, refractory and potentially severe nature of disease. The treatment of C. difficile is a challenge for community and hospital-based clinicians. With the advent of an expanding therapeutic arsenal against C. difficile since the last published Australasian guidelines, an update on CDI treatment recommendations for Australasian clinicians was required. On behalf of the Australasian Society of Infectious Diseases, we present the updated guidelines for the management of CDI in adults and children.

Burden of Nursing Home-Onset Clostridium difficile Infection in the United States: Estimates of Incidence and Patient Outcomes

Article

Full-text available

Jan 2016

Background. Approximately 4 million Americans receive nursing home (NH) care annually. Nursing home residents commonly have risk factors for Clostridium difficile infection (CDI), including advanced age and antibiotic exposures. We estimated national incidence of NH-onset (NHO) CDI and patient outcomes. Methods. We identified NHO-CDI cases from population-based surveillance of 10 geographic areas in the United States. Cases were defined by C difficile-positive stool collected in an NH (or from NH residents in outpatient settings or ≤3 days after hospital admission) without a positive stool in the prior 8 weeks. Medical records were reviewed on a sample of cases. Incidence was estimated using regression models accounting for age and laboratory testing method; sampling weights were applied to estimate hospitalizations, recurrences, and deaths. Results. A total of 3503 NHO-CDI cases were identified. Among 262 sampled cases, median age was 82 years, 76% received antibiotics in the 12 weeks prior to the C difficile-positive specimen, and 57% were discharged from a hospital in the month before specimen collection. After adjusting for age and testing method, the 2012 national estimate for NHO-CDI incidence was 112 800 cases (95% confidence interval [CI], 93 400–131 800); 31 400 (28%) were hospitalized within 7 days after a positive specimen (95% CI, 25 500–37 300), 20 900 (19%) recurred within 14–60 days (95% CI, 14 600–27 100), and 8700 (8%) died within 30 days (95% CI, 6600–10 700). Conclusions. Nursing home onset CDI is associated with substantial morbidity and mortality. Strategies focused on infection prevention in NHs and appropriate antibiotic use in both NHs and acute care settings may decrease the burden of NHO CDI.

Hospital‐Onset Clostridium difficile Infection Among Solid Organ Transplant Recipients

Article

Full-text available

Nov 2015
AM J TRANSPLANT

Clostridium difficile infection (CDI) is a considerable health issue in the United States and represents the most common healthcare-associated infection. Solid organ transplant recipients are at increased risk of CDI, which can affect both graft and patient survival. However, little is known about the impact of CDI on health services utilization posttransplantation. We examined hospital-onset CDI from 2012 to 2014 among transplant recipients in the University HealthSystem Consortium, which includes academic medical center–affiliated hospitals in the United States. Infection was five times more common among transplant recipients than among general medicine inpatients (209 vs 40 per 10 000 discharges), and factors associated with CDI among transplant recipients included transplant type, risk of mortality, comorbidities, and inpatient complications. Institutional risk-standardized CDI varied more than 3-fold across high-volume hospitals (infection ratio 0.54–1.82, median 1.04, interquartile range 0.78–1.28). CDI was associated with increased 30-day readmission, transplant organ complications, cytomegalovirus infection, inpatient costs, and lengths of stay. Total observed inpatient days and direct costs for those with CDI were substantially higher than risk-standardized expected values (40 094 vs 22 843 days, costs $198 728 368 vs $154 020 528). Further efforts to detect, prevent, and manage CDI among solid organ transplant recipients are warranted.

WSES guidelines for management of Clostridium difficile infection in surgical patients

Article

Full-text available

Aug 2015
World J Emerg Surg

In the last two decades there have been dramatic changes in the epidemiology of Clostridium difficile infection (CDI), with increases in incidence and severity of disease in many countries worldwide. The incidence of CDI has also increased in surgical patients. Optimization of management of C difficile, has therefore become increasingly urgent. An international multidisciplinary panel of experts prepared evidenced-based World Society of Emergency Surgery (WSES) guidelines for management of CDI in surgical patients.

Development and validation of digital ELISAs for ultrasensitive detection and quantification of C. difficile toxins in stool

Article

Full-text available

Sep 2015
J CLIN MICROBIOL

Currently available diagnostics for Clostridium difficile infection(CDI) have major limitations. Despite mounting evidence that toxin detection is paramount for diagnosis, conventional toxin immunoassays are insufficiently sensitive and cytotoxicity assays too complex; assays that detect toxigenic organism [toxigenic culture(TC) and nucleic acid amplification testing(NAAT)] are confounded by asymptomatic colonization by toxigenic C. difficile. We developed ultrasensitive "digital ELISA" assays for toxins A and B using single molecule array technology and validated the assays using a) culture filtrates from a panel of clinical C. difficile isolates and b) 149 adult stool specimens already tested routinely by NAAT. The digital ELISAs detected toxins A and B in stool with limits of detection of 0.45 and 1.5 pg/mL respectively, quantified toxins across a 4-log range, and detected toxins from all clinical strains studied. Using specimens negative by cytotoxicity assay/TC/NAAT, clinical cutoffs were set at 29.4 pg/mL(A) and 23.3 pg/mL(B); resulting clinical specificities were 96% and 98%, respectively. The toxin B digital ELISA was 100% sensitive vs cytotoxicity assay. 25% and 22% of samples positive by NAAT and TC, respectively, were negative by the toxin B digital ELISA, consistent with the presence of organism but minimal or no toxin. Mean toxin levels by digital ELISA were 1.5-1.7-fold higher in five patients with CDI-attributable severe outcomes, vs. 68 patients without, but this difference was not statistically significant. Ultrasensitive digital ELISAs for detection and quantification of toxins A and B in stool can provide a rapid, simple tool for diagnosis of CDI with both high analytical sensitivity and high clinical specificity. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

A meta-analysis of metronidazole and vancomycin for the treatment of Clostridium difﬁcile infection, stratiﬁed by disease severity

Article

Full-text available

May 2015
BRAZ J INFECT DIS

The aim of this meta-analysis was to compare the efficacy of metronidazole and vancomycin for the treatment of Clostridium difficile infection, especially to investigate which agent was superior for treating either mild or severe C. difficile infection. A meta-analysis of randomized controlled trials and cohort studies identified in Pubmed, Embase, and the Cochrane Library was conducted. Four randomized controlled trials and two cohort studies involving 1218 patients were included in this meta-analysis. Metronidazole was inferior to vancomycin for treating C. difficile infection in terms of both initial clinical cure rates (risk ratio, RR=0.91, 95% confidence interval, CI=0.84-0.98, p=0.02) and sustained cure rates (RR=0.88, 95% CI=0.82-0.96, p=0.003). For mild C. difficile infection, the efficacy of metronidazole and vancomycin resulted in similar clinical cure rates (RR=0.94, 95% CI=0.84-1.04, p=0.21) and sustained cure rates (RR=0.93, 95% CI=0.83-1.05, p=0.26). For severe C. difficile infection the efficacy of vancomycin was superior to metronidazole in terms of clinical cure rates (RR=0.81, 95% CI=0.69-0.95, p=0.009), whereas sustained cure rates were similar (RR=0.86, 95% CI=0.72-1.02, p=0.08). Regarding microbiological cure metronidazole therapy was as effective as vancomycin therapy (RR=0.88, 95% CI=0.64-1.21, p=0.43). Recurrence rates with metronidazole and vancomycin for both mild C. difficile infection (RR=0.95, 95% CI=0.56-1.60, p=0.85) and severe C. difficile infection (RR=1.27, 95% CI=0.85-1.91, p=0.25) were not different. Likewise, no difference in all-cause mortality was found as well (RR=0.87, 95% CI=0.56-1.35, p=0.53). In conclusion, vancomycin provides improved initial clinical and sustained cure rates in patients with C. difficile infection compared with metronidazole, especially in patients with severe C. difficile infection. In view of these data, vancomycin may be considered first line therapy for severe C. difficile infection.

Pathway to Prevention of Nosocomial Clostridium difficile Infection

Article

Full-text available

May 2015
CLIN INFECT DIS

To address the significant morbidity and mortality rates associated with nosocomial Clostridium difficile-associated diarrhea (CDAD), a series of recommendations and a pathway to prevention were developed. An expert panel of infectious disease (ID) specialists participated in a modified Delphi process with specific objectives: (1) conduct a review for CDAD and prevention; (2) develop statements based upon panel members' opinions; (3) hold a panel meeting during the 2012 IDWeek; and (4) review the final recommendations and prevention pathway prior to submission for publication. The panel voted on (1) antibiotic stewardship (7 of 8 panelists); (2) reduction of other potentially modifiable risk factors (variable); (3) utilization of specific probiotics to prevent C. difficile overgrowth (8/8); (4) staff education regarding CDAD preventive measures (8/8); (5) appropriate hand hygiene for everyone (7/8); (6) environmental cleaning (8/8); (7) medical equipment disinfection (7/8); (8) early detection of CDAD in symptomatic patients (7/8); (9) usage of protective clothing/gloves (8/8); (10) proper measures during outbreak (8/8); and (11) surveillance to monitor efficacy data of preventive measures (8/8). The panel members agreed with 11 of 17 recommendations presented. The additional recommendations by the panel were proton pump inhibitor use as a risk factor and the use of adjunctive therapy with specific probiotic, as it was approved by Health Canada for the risk reduction of CDAD in hospitalized patients. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Differences of the Fecal Microflora With Clostridium difficile Therapies

Article

Full-text available

May 2015
CLIN INFECT DIS

During treatment of Clostridium difficile infection (CDI), patterns of pathogen reduction in relationship to changes in components of the normal microbiota are hypothesized to be predictive of response to treatment and subsequent sustained cure. At a single center, subjects enrolled into phase 2 and 3 C. difficile treatment clinical trials (2003-2008) provided fecal samples to assess killing of C. difficile and changes to components of the microbiome. Quantitative bacterial cultures, measurement of C. difficile toxin titers, quantitative polymerase chain reaction of fecal samples for Bacteroidetes, Clostridium clusters XIVa and IV, and C. difficile were performed. Quantitative bacterial cultures showed a mean log10 C. difficile count (colony-forming units [CFU]) of 6.7 ± 2.0 at study entry; vancomycin treatment consistently reduced C. difficile counts to the limit of detection (2.0 log10 CFU/g), whereas metronidazole was associated with mean C. difficile counts 1.5-2 log10 higher at 10 days of treatment. In patients receiving tolevamer, C. difficile persisted in high counts during treatment; response to treatment was correlated with neutralization of toxin along with persistence of normal microbiota components. However, this was achieved in approximately half of subjects. Both vancomycin and metronidazole further suppressed microbiome components during treatment of CDI. Lactobacilli were observed to be a microbiome component that persisted during treatment of CDI. Differences of pathogen clearance and microbiome perturbation during treatment of CDI appear to explain treatment outcomes. The hypothesis that probiotic microbes could help prevent onset of CDI is supported by the observation of persistence of lactobacilli during and after treatment of CDI. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Novel Fidaxomicin Treatment Regimens for Patients With Multiple Clostridium difficile Infection Recurrences That Are Refractory to Standard Therapies

Article

Full-text available

Sep 2014

Reports of fidaxomicin treatment for patients with multiple recurrent Clostridium difficile infections ([mrCDI] ie, more than 2 CDI episodes) indicate symptomatic response to this agent, but 50% have subsequent mrCDI episodes. In an effort to improve outcomes in patients with mrCDI we used novel regimens of fidaxomicin based on strategies used with vancomycin. Of 8 patients who received a 10-day chaser of fidaxomicin given twice daily after a course of vancomycin, 3 (38%) experienced a subsequent recurrence. Two (18%) of 11 patients who completed a 14- to 33-day course of fidaxomicin in a tapering dose experienced a recurrence, both of whom received additional antibiotics before that recurrence. The median symptom-free interval (SFI) after fidaxomicin taper was greater than the median SFI after the most effective prior regimen for those patients (257 days [interquartile range, 280] vs 25 days [interquartile range, 30], respectively; P = .003). A fidaxomicin chaser or taper regimen may be effective in patients with mrCDI, but the number of patients treated is small, and randomized comparative data are not available.

Burden of Clostridium difficile Infection in the United States

Article

Full-text available

Feb 2015
NEW ENGL J MED

The magnitude and scope of Clostridium difficile infection in the United States continue to evolve. In 2011, we performed active population- and laboratory-based surveillance across 10 geographic areas in the United States to identify cases of C. difficile infection (stool specimens positive for C. difficile on either toxin or molecular assay in residents ≥ 1 year of age). Cases were classified as community-associated or health care-associated. In a sample of cases of C. difficile infection, specimens were cultured and isolates underwent molecular typing. We used regression models to calculate estimates of national incidence and total number of infections, first recurrences, and deaths within 30 days after the diagnosis of C. difficile infection. A total of 15,461 cases of C. difficile infection were identified in the 10 geographic areas; 65.8% were health care-associated, but only 24.2% had onset during hospitalization. After adjustment for predictors of disease incidence, the estimated number of incident C. difficile infections in the United States was 453,000 (95% confidence interval [CI], 397,100 to 508,500). The incidence was estimated to be higher among females (rate ratio, 1.26; 95% CI, 1.25 to 1.27), whites (rate ratio, 1.72; 95% CI, 1.56 to 2.0), and persons 65 years of age or older (rate ratio, 8.65; 95% CI, 8.16 to 9.31). The estimated number of first recurrences of C. difficile infection was 83,000 (95% CI, 57,000 to 108,900), and the estimated number of deaths was 29,300 (95% CI, 16,500 to 42,100). The North American pulsed-field gel electrophoresis type 1 (NAP1) strain was more prevalent among health care-associated infections than among community-associated infections (30.7% vs. 18.8%, P<0.001). C. difficile was responsible for almost half a million infections and was associated with approximately 29,000 deaths in 2011. (Funded by the Centers for Disease Control and Prevention.).

Risk Factors for Recurrent Clostridium difficile Infection: A Systematic Review and Meta-Analysis

Article

Full-text available

Jan 2015
INFECT CONT HOSP EP

Objective: An estimated 20-30% of patients with primary Clostridium difficile infection (CDI) develop recurrent CDI (rCDI) within 2 weeks of completion of therapy. While the actual mechanism of recurrence remains unknown, a variety of risk factors have been suggested and studied. The aim of this systematic review and meta-analysis was to evaluate current evidence on the risk factors for rCDI. Design: We searched MEDLINE and 5 other databases for subject headings and text related to rCDI. All studies investigating risk factors of rCDI in a multivariate model were eligible. Information on study design, patient population, and assessed risk factors were collected. Data were combined using a random-effects model and pooled relative risk ratios (RRs) were calculated. Results: A total of 33 studies (n=18,530) met the inclusion criteria. The most frequent independent risk factors associated with rCDI were age≥65 years (risk ratio [RR], 1.63; 95% confidence interval [CI], 1.24-2.14; P=.0005), additional antibiotics during follow-up (RR, 1.76; 95% CI, 1.52-2.05; P<.00001), use of proton-pump inhibitors (PPIs) (RR, 1.58; 95% CI, 1.13-2.21; P=.008), and renal insufficiency (RR, 1.59; 95% CI, 1.14-2.23; P=.007). The risk was also greater in patients previously on fluoroquinolones (RR, 1.42; 95% CI, 1.28-1.57; P<.00001). Conclusions: Multiple risk factors are associated with the development of rCDI. Identification of modifiable risk factors and judicious use of antibiotics and PPI can play an important role in the prevention of rCDI.

Diagnosis and Treatment of Clostridium difficile in Adults A Systematic Review

Article

Full-text available

Jan 2015

Since 2000, the incidence and severity of Clostridium difficile infection (CDI) have increased. To review current evidence regarding best practices for the diagnosis and treatment of CDI in adults (age ≥ 18 years). Ovid MEDLINE and Cochrane databases were searched using keywords relevant to the diagnosis and treatment of CDI in adults. Articles published between January 1978 and October 31, 2014, were selected for inclusion based on targeted keyword searches, manual review of bibliographies, and whether the article was a guideline, systematic review, or meta-analysis published within the past 10 years. Of 4682 articles initially identified, 196 were selected for full review. Of these, the most pertinent 116 articles were included. Clinical trials, large observational studies, and more recently published articles were prioritized in the selection process. Laboratory testing cannot distinguish between asymptomatic colonization and symptomatic infection with C difficile. Diagnostic approaches are complex due to the availability of multiple testing strategies. Multistep algorithms using polymerase chain reaction (PCR) for the toxin gene(s) or single-step PCR on liquid stool samples have the best test performance characteristics (for multistep: sensitivity was 0.68-1.00 and specificity was 0.92-1.00; and for single step: sensitivity was 0.86-0.92 and specificity was 0.94-0.97). Vancomycin and metronidazole are first-line therapies for most patients, although treatment failures have been associated with metronidazole in severe or complicated cases of CDI. Recent data demonstrate clinical success rates of 66.3% for metronidazole vs 78.5% for vancomycin for severe CDI. Newer therapies show promising results, including fidaxomicin (similar clinical cure rates to vancomycin, with lower recurrence rates for fidaxomicin, 15.4% vs vancomycin, 25.3%; P = .005) and fecal microbiota transplantation (response rates of 83%-94% for recurrent CDI). Diagnostic testing for CDI should be performed only in symptomatic patients. Treatment strategies should be based on disease severity, history of prior CDI, and the individual patient's risk of recurrence. Vancomycin is the treatment of choice for severe or complicated CDI, with or without adjunctive therapies. Metronidazole is appropriate for mild disease. Fidaxomicin is a therapeutic option for patients with recurrent CDI or a high risk of recurrence. Fecal microbiota transplantation is associated with symptom resolution of recurrent CDI but its role in primary and severe CDI is not established.

Clostridium difficile infection and inflammatory bowel disease: Understanding the evolving relationship

Article

Full-text available

Oct 2010
WORLD J GASTROENTERO

Udayakumar Navaneethan

Clostridium difficile (C. difficile) infection (CDI) is the leading identifiable cause of antibiotic-associated diarrhea. While there is an alarming trend of increasing incidence and severity of CDI in the United States and Europe, superimposed CDI in patients with inflammatory bowel disease (IBD) has drawn considerable attention in the gastrointestinal community. The majority of IBD patients appear to contract CDI as outpatients. C. difficile affects disease course of IBD in several ways, including triggering disease flares, sustaining activity, and in some cases, acting as an “innocent” bystander. Despite its wide spectrum of presentations, CDI has been reported to be associated with a longer duration of hospitalization and a higher mortality in IBD patients. IBD patients with restorative proctocolectomy or with diverting ileostomy are not immune to CDI of the small bowel or ileal pouch. Whether immunomodulator or corticosteroid therapy for IBD should be continued in patients with superimposed CDI is controversial. It appears that more adverse outcomes was observed among patients treated by a combination of immunomodulators and antibiotics than those treated by antibiotics alone. The use of biologic agents does not appear to increase the risk of acquisition of CDI. For CDI in the setting of underlying IBD, vancomycin appears to be more efficacious than metronidazole. Randomized controlled trials are required to clearly define the appropriate management for CDI in patients with IBD.

Mechanisms of Protection against Clostridium difficile Infection by the Monoclonal Antitoxin Antibodies Actoxumab and Bezlotoxumab

Article

Full-text available

Jan 2015
INFECT IMMUN

Clostridium difficile infection (CDI) represents the most prevalent cause of antibiotic-associated gastrointestinal infections in health care facilities in the developed world. Disease symptoms are caused by the two homologous exotoxins, TcdA and TcdB. Standard therapy for CDI involves administration of antibiotics that are associated with a high rate of disease recurrence, highlighting the need for novel treatment paradigms that target the toxins rather than the organism itself. A combination of human monoclonal antibodies - actoxumab and bezlotoxumab, directed against TcdA and TcdB respectively - has been shown to decrease the rate of recurrence in patients treated with standard of care antibiotics. However, the exact mechanism of antibody-mediated protection is poorly understood. In this study, we show that the antitoxin antibodies are protective in multiple murine models of CDI, including systemic and local (gut) toxin challenge models, as well as primary and recurrent models of infection in mice. Systemically-administered actoxumab/bezlotoxumab prevents both the damage to the gut wall and the inflammatory response that are associated with C. difficile in these models, including in mice challenged with a strain of the hypervirulent ribotype 027. Furthermore, mutant antibodies (N297Q) that do not bind to Fcγ receptors provide a similar level of protection compared to wild type antibodies, demonstrating that the mechanism of protection is through direct neutralization of the toxins and does not involve host effector functions. These data provide a mechanistic basis for the prevention of recurrent disease observed in CDI patients in clinical trials. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Gas Gangrene and Other Clostridium-Associated Diseases

Chapter

Jan 2010

Bezlotoxumab: First Global Approval

Article

Nov 2016

Anthony Markham

Bezlotoxumab (Zinplava™) is a human monoclonal antibody against Clostridium difficile toxin B developed by Merck & Co. In October 2016 it was approved in the USA for reducing the recurrence of C. difficile infection. This article summarizes the milestones in the development of bezlotoxumab leading to this first approval for use in patients receiving antibacterial drug treatment for C. difficile infection who are at high risk for recurrence of C. difficile infection.

Bezlotoxumab approved to prevent Clostridium difficile recurrence

Article

Dec 2016

Kate Traynor

Merck on October 21 announced the approval of bezlotoxumab injection to prevent the recurrence of Clostridium difficile infection in adults who are undergoing antimicrobial therapy for the condition and are at high risk for reinfection. Bezlotoxumab is a human monoclonal antibody that neutralizes C

New and emerging therapies for Clostridium difficile infection

Article

Oct 2016

Purpose of review: Clostridium difficile infection has attained high prominence given its prevalence and impacts on patients and healthcare institutions. Multiple new approaches to the prevention and treatment of C. difficile infection (CDI) are undergoing clinical trials. Recent findings: Bezlotoxumab is a monoclonal antibody against toxin B that has successfully completed phase III studies, demonstrating a significant reduction in recurrent CDI when given with standard of care antibiotics. Antibiotics under development include cadazolid and ridinilazole, whereas surotomycin has had disappointing phase III results. Multiple live biotherapeutics are being developed, including freeze thawed and encapsulated versions of faecal microbiota transplantation to improve the practicality of treating patients with recurrent CDI. Alternatives to faecal microbiota transplantation, that aim to improve safety, including a microbial suspension, RBX2660, and a complex spore formulation, SER-109, have progressed to phase II studies. A nontoxigenic C. difficile strain has also shown promise to prevent recurrent CDI. In addition, three C. difficile vaccines have progressed to phase II/III clinical trials. Summary: The diverse approaches to treating and preventing CDI offer substantial promise that new treatment options will soon emerge, particular ones that reduce the risk of recurrences.

Cost-Effectiveness Analysis of the Use of Probiotics for the Prevention of Clostridium difficile-Associated Diarrhea in a Provincial Healthcare System

Article

Jul 2016
INFECT CONT HOSP EP

OBJECTIVE To conduct a full economic evaluation assessing the costs and consequences related to probiotic use for the primary prevention of Clostridium difficile– associated diarrhea (CDAD). DESIGN Cost-effectiveness analysis using decision analytic modeling. METHODS A cost-effectiveness analysis was used to evaluate the risk of CDAD and the costs of receiving oral probiotics versus not over a time horizon of 30 days. The target population modeled was all adult inpatients receiving any therapeutic course of antibiotics from a publicly funded healthcare system perspective. Effectiveness estimates were based on a recent systematic review of probiotics for the primary prevention of CDAD. Additional estimates came from local data and the literature. Sensitivity analyses were conducted to assess how plausible changes in variables impacted the results. RESULTS Treatment with oral probiotics led to direct costs of CDN $24 per course of treatment per patient. On average, patients treated with oral probiotics had a lower overall cost compared with usual care (CDN $327 vs $845). The risk of CDAD was reduced from 5.5% in those not receiving oral probiotics to 2% in those receiving oral probiotics. These results were robust to plausible variation in all estimates. CONCLUSIONS Oral probiotics as a preventive strategy for CDAD resulted in a lower risk of CDAD as well as cost-savings. The cost-savings may be greater in other healthcare systems that experience a higher incidence and cost associated with CDAD. Infect Control Hosp Epidemiol 2016;37:1079–1086

Vaccines for Hospital-Associated Infections: Promise and Challenge

Article

May 2016

As antibiotic resistance increases and the rate of antibiotic development slows, it is becoming more urgent to develop novel approaches to prevent and mitigate serious bacterial and fungal infections. Hospital-associated infections (HAIs), including those caused by C. difficile, S. aureus, P. aeruginosa, A. baumanii, carbapenem-resistant Enterobacteriaceae and Candida spp., are a major cause of morbidity, mortality, and healthcare costs. HAIs are also a key driver of antibiotic use. Vaccines directed towards these pathogens could help prevent a large number of HAIs and associated antibiotic use if administered to targeted populations. Despite numerous scientific and operational challenges, there are vaccine candidates in late-stage clinical development for C. difficile, S. aureus and P. aeruginosa. Basic, preclinical and early clinical research to develop vaccines for other types of HAIs is also underway. In addition, other prophylactic immune interventions, such as monoclonal antibodies, for several of these pathogens are in advanced development. Here we describe the promise, challenges and current pipeline of vaccines to prevent HAIs.

Predictors of Early Failure After Fecal Microbiota Transplantation for the Therapy of Clostridium Difficile Infection: A Multicenter Study

Article

May 2016

Objectives: Fecal microbiota transplant (FMT) is a highly efficacious treatment for recurrent or refractory Clostridium difficile infection (CDI); however, 10-20% of patients fail to achieve cure after a single FMT. The aim of this study was to identify risk factors associated with FMT failure and to develop and validate a prediction model for FMT failure. Methods: Patient characteristics, CDI history, FMT characteristics, and outcomes data for patients treated between 2011 and 2015 at three academic tertiary referral centers were prospectively collected. Early FMT failure was defined as non-response or recurrence of diarrhea associated with positive stool C. difficile toxin or PCR within 1 month of FMT. Late FMT failure was defined as recurrence of diarrhea associated with positive stool C. difficile toxin or PCR between 1 and 3 months of the FMT. Patient data from two centers were used to determine independent predictors of FMT failure and to build a prediction model. A risk index was constructed based on coefficients of final predictors. The patient cohort from the third center was used to validate the prediction model. Results: Of 328 patients in the developmental cohort, 73.5% (N=241) were females with a mean age of 61.4±19.3 years; 19.2% (N=63) had inflammatory bowel disease (IBD), and 23.5% (N=77) were immunocompromised. The indication for FMT was recurrent CDI in 87.2% (N=286) and severe or severe-complicated in 12.8% (N=42). FMT was performed as an inpatient in 16.7% (N=54). The stool source was patient-directed donors in 40% (N=130) of cases. The early FMT failure rate was 18.6%, and the late failure rate was 2.7%. In the multivariable analysis, predictors of early FMT failure included severe or severe-complicated CDI (odds ratio (OR) 5.95, 95% confidence interval (CI): 2.26-15.62), inpatient status during FMT (OR 3.78, 95% CI: 1.55-9.24), and previous CDI-related hospitalization (OR 1.43, 95% CI: 1.18-1.75); with each additional hospitalization, the odds of failure increased by 43%. Risk scores ranged from 0 to 13, with 0 indicating low risk, 1-2 indicating moderate risk, and ≥3 indicating high risk. In the developmental cohort, early FMT failure rates were 5.6% for low risk, 12.7% for moderate risk, and 41% for high-risk patients. Of 134 patients in the validation cohort, 57% (N=77) were females with a mean age of 66±18.1 years; 9.7% (N=13) had IBD, and 17.9% (N=24) were immunocompromised. The early FMT failure rate at 1 month was 19.4%, with an additional 3% failing by 3 months. In the validation cohort, FMT failure rates were 2.1% for low risk, 16.1% for moderate risk, and 35.7% for high risk patients. The area under the receiver operating characteristic curve (AUROC) for FMT failure was 0.81 in the developmental cohort and 0.84 in the validation cohort. Conclusions: Severe and severe-complicated indication, inpatient status during FMT, and the number of previous CDI-related hospitalizations are strongly associated with early failure of a single FMT for CDI. The novel prediction model has good discriminative power at identifying individuals who are at high risk of failure after FMT therapy and may assist the treating physician in subsequent management plans.Am J Gastroenterol advance online publication, 17 May 2016; doi:10.1038/ajg.2016.180.

A phase 1, placebo-controlled, randomized study of the safety, tolerability, and immunogenicity of a Clostridium difficile vaccine administered with or without aluminum hydroxide in healthy adults

Article

Mar 2016

Introduction: Clostridium difficile is a significant cause of morbidity and mortality in hospitals, nursing homes, and long-term care facilities. The bacteria can produce 3 toxins, of which the C. difficile toxin A and C. difficile toxin B are the principal virulence factors for C. difficile-associated disease. Methods: A phase 1, first-in-human, placebo-controlled, dose-escalation study was performed to assess the safety and immunogenicity of an investigational vaccine candidate consisting of genetically and chemically detoxified, purified toxins A and B. The toxoids, either alone or in combination with aluminum hydroxide (Al(OH)3), were administered to healthy adults 50-85 years of age at antigen dose levels of 50, 100, or 200 μg in a 3-dose regimen administered at 0, 1, and 6 months. Results: Overall, the C. difficile vaccine formulations and doses administered were generally well tolerated. Local reactions and systemic events were predominantly mild to moderate, were more common in the 50-64-year age cohort, and comprised mostly injection site pain, headache, and fatigue. In subjects who received the vaccine formulations, both the toxin A- and toxin B-specific neutralizing antibody geometric mean concentrations increased substantially at 1 month after Dose 2 and after Dose 3 compared to baseline. In the 50-64-year age cohort, geometric mean fold rises (GMFRs) in toxin A-specific neutralizing antibodies from baseline at Month 7 ranged from 59.19 to 149.23 in the vaccine groups compared to 2.47 in the control group. For toxin-B specific neutralizing antibodies, the GMFRs from baseline at Month 7 ranged from 116.67 to 2503.75 in the vaccine groups compared to 2.48 in the control group. In the 65-85-year age cohort, GMFRs in toxin A-specific neutralizing antibodies from baseline at Month 7 ranged from 42.73 to 254.77 in the vaccine groups compared to 2.03 in the control group. For toxin-B specific neutralizing antibodies, the GMFRs from baseline at Month 7 ranged from 136.12 to 4922.80 in the vaccine groups compared to 1.58 in the control group. Potent antitoxin neutralizing responses were still evident in immunized subjects in both age groups at Month 12. Although there was no clear dose-level response pattern, the data suggest that both the antitoxin A- and B-specific neutralizing responses were trending higher in the toxoid-only groups compared to the toxoid+Al(OH)3 groups. Furthermore, the magnitude of the immune response was similar in the 2 age cohorts. Conclusion: The vaccine formulations studied in this phase 1 study were immunogenic and well tolerated. The results presented support further development of the C. difficile vaccine candidate in a larger population of subjects to determine the optimal dose and immunization schedule. Clinical trial registry: NCT01706367.

Clostridium difficile infection: Epidemiology, diagnosis and understanding transmission

Article

Mar 2016
NAT REV GASTRO HEPAT

Clostridium difficile infection (CDI) continues to affect patients in hospitals and communities worldwide. The spectrum of clinical disease ranges from mild diarrhoea to toxic megacolon, colonic perforation and death. However, this bacterium might also be carried asymptomatically in the gut, potentially leading to 'silent' onward transmission. Modern technologies, such as whole-genome sequencing and multi-locus variable-number tandem-repeat analysis, are helping to track C. difficile transmission across health-care facilities, countries and continents, offering the potential to illuminate previously under-recognized sources of infection. These typing strategies have also demonstrated heterogeneity in terms of CDI incidence and strain types reflecting different stages of epidemic spread. However, comparison of CDI epidemiology, particularly between countries, is challenging due to wide-ranging approaches to sampling and testing. Diagnostic strategies for C. difficile are complicated both by the wide range of bacterial targets and tests available and the need to differentiate between toxin-producing and non-toxigenic strains. Multistep diagnostic algorithms have been recommended to improve sensitivity and specificity. In this Review, we describe the latest advances in the understanding of C. difficile epidemiology, transmission and diagnosis, and discuss the effect of these developments on the clinical management of CDI.

High Variability in Nosocomial Clostridium difficile Infection Rates Across Hospitals After Colorectal Resection

Article

Apr 2016

BACKGROUND: Hospital-acquired Clostridium difficile infection is associated with adverse patient outcomes and high medical costs. The incidence and severity of C. difficile has been rising in both medical and surgical patients. OBJECTIVE: Our aim was to assess risk factors and variation associated with the development of nosocomial C. difficile colitis among patients undergoing colorectal resection. DESIGN: This was a retrospective cohort study. SETTINGS: The study included segmental colectomy and proctectomy cases in New York State from 2005 to 2013. PATIENTS: The study cohort included 150,878 colorectal resections. Patients with a documented previous history of C. difficile infection or residence outside of New York State were excluded. MAIN OUTCOME MEASURES: A diagnosis of C. difficile colitis either during the index hospital stay or on readmission within 30 days was the main measure. RESULTS: C. difficile colitis occurred in 3323 patients (2.2%). Unadjusted C. difficile colitis rates ranged from 0% to 11.3% among surgeons and 0% to 6.8% among hospitals. After controlling for patient, surgeon, and hospital characteristics using mixed-effects multivariable analysis, significant unexplained variation in C. difficile rates remained present across hospitals but not surgeons. Patient factors explained only 24% of the total hospital-level variation, and known surgeon and hospital-level characteristics explained an additional 8% of the total hospital-level variation. Therefore, approximate to 70% of the hospital variation in C. difficile infection rates remained unexplained by captured patient, surgeon, and hospital factors. Furthermore, there was an approximate to 5-fold difference in adjusted C. difficile rates across hospitals. LIMITATIONS: A limited set of hospital and surgeon characteristics was available. CONCLUSIONS: Colorectal surgery patients appear to be at high risk for C. difficile infection, and alarming variation in nosocomial C. difficile infection rates currently exists among hospitals after colorectal resection. Given the high morbidity and cost associated with C. difficile colitis, adopting institutional quality improvement programs and maintaining strict prevention strategies are of the utmost importance.

Clostridium difficile infection (CDI) after restorative proctocolectomy and ileal pouch anal anastomosis for ulcerative colitis

Article

Mar 2016
COLORECTAL DIS

Aim: Clostridium difficile infection (CDI) of the ileal pouch following restorative proctocolectomy (RPC) is becoming increasingly recognized. We aimed to understand better (i) the associated risk factors, (ii) treatment practices and (iii) the pouch diversion and failure rate in patients who developed CDI of the pouch after RPC for ulcerative colitis (UC). Method: Patients who tested positive for C. difficile of the pouch between 2007 and 2010 were included in the analysis. Data collected included patient demographics, time from RPC to documented CDI, the treatment of CDI and rate of excision of the pouch. Results: Of 2785 patients recorded in the hospital CDI database, 15 had had an RPC with ileal pouch anal anastomosis. The median age was 44 years and the median interval from RPC to first documented episode of CDI was 3 years. Thirteen (81%) patients had had multiple episodes of pouchitis before and after CDI infection, and all were symptomatic at the time of testing for CDI. Within 30 days of the diagnosis of CDI, six (40%) patients were taking immunosuppressive medication, seven (47%) were taking a proton pump inhibitor and 12 (80%) had received antibiotics. Five patients required hospitalization for CDI and four had severe infections characterized by a serum creatinine more than 1.5 times baseline (n = 3) and a white cell count above 15 000 (n = 1). Six patients who underwent endoscopy had severe inflammation of the pouch including the presence of a pseudomembrane in one case. Ten patients were treated with metronidazole alone and five with vancomycin. Two patients had recurrent CDI of the pouch during a median follow-up period of 2.9 years and one had CDI refractory to medical management. This patient required diversion of the pouch with an ileostomy for refractory CDI but no patient required excision of the pouch. Conclusion: All 15 patients developing CDI of the pouch were successfully treated with antibiotics and only one required surgery in the form of an ileostomy.

Breakthroughs in the treatment and prevention of Clostridium difficile infection

Article

Feb 2016
NAT REV GASTRO HEPAT

This Review summarizes the latest advances in the treatment and prevention of Clostridium difficile infection (CDI), which is now the most common health-care-associated infection in the USA. As traditional, standard CDI antibiotic therapies (metronidazole and vancomycin) are limited by their broad spectrum and further perturbation of the intestinal microbiota, which result in unacceptably high recurrence rates, novel therapeutic strategies for CDI are needed. Emerging CDI therapies are focused on limiting further perturbation of the intestinal microbiota and/or restoring the microbiota to its pre-morbid state, reducing colonization of the intestinal tract by toxigenic strains of C. difficile and bolstering the host immune response against C. difficile toxins. Fidaxomicin is associated with reduced CDI recurrences, and other emerging narrow-spectrum CDI antibiotic therapies might eventually demonstrate a similar benefit. Prevention of intestinal colonization of toxigenic strains of C. difficile can be achieved through restoration of the intestinal microbiota with faecal microbiota transplantation, as well as by colonizing the gut with nontoxigenic C. difficile strains. Finally, emerging immunological therapies, including monoclonal antibodies and vaccines against C. difficile toxins, might protect against CDI and subsequent CDI recurrences. The available clinical data for these emerging therapies, and their relative advantages and disadvantages, are described.

The Risk of Clostridium difficile Associated Diarrhea in Nasogastric Tube Insertion: A Systematic Review and Meta-analysis

Article

Feb 2016

Background/objectives: Clostridium difficile-associated diarrhea (CDAD) is a major concern of public health worldwide. The risk of CDAD in patients with nasogastric tube (NGT) insertion is controversial. The aim of this study was to assess the risk of incidence of CDAD in patients with NGT insertion. Methods: A literature search was performed using MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews from inception through August 2015. Studies that reported relative risks, odds ratios, or hazard ratios comparing the risk of CDAD in patients with NGT insertion versus those who did not were included. Pooled risk ratios (RR) and 95% confidence interval (CI) were calculated using a random-effect, generic inverse variance method. Results: Eleven observational studies were included in our analysis to assess the association between NGT insertion and risk of CDAD. The pooled RR of CDAD in patients with NGT insertion was 1.87 (95% CI, 1.06-3.28, I(2)=73). When meta-analysis was limited only to cohort and case-control studies, the pooled RR of CDAD was 1.99 (95% CI, 1.05-3.77, I(2)=76). Conclusions: Our study demonstrated a statistically significant association between NGT insertion and risk of CDAD. This finding may impact clinical management and primary prevention of CDAD.

Older Is Not Wiser, Immunologically Speaking: Effect of Aging on Host Response to Clostridium difficile Infections

Article

Jan 2016

Clostridium difficile infection (CDI) is the most common cause of antibiotic-associated diarrhea and a significant burden on the health care system. Aging has been identified in the literature as a risk factor for CDI as well as adverse outcome from CDI. Although this effect of advanced age on CDI could be partially explained by clinical factors associated with aging, biologic factors are important. Innate immune system, responsible for immediate response to acute infections, plays a major role in CDI pathogenesis. Impairment in function of innate immunity with aging, demonstrated in other infection models, may lead to worse outcome with CDI. C. difficile toxin-specific antibody response protects the host against initial and recurrent infections as shown in observational studies and clinical trial. Effect of aging on antibody response to CDI has not been demonstrated, but the results from vaccine studies in other infections suggest a negative effect on humoral immunity from aging. Although intestinal microbiota from healthy people confers resistance to CDI by preventing C. difficile colonization, changes in composition of microbiota with aging may affect that resistance and increase risk for CDI. There are also age-associated changes in physiology, especially of the gastrointestinal tract, that may play a role in CDI risk and outcomes. In this review, we will first discuss the epidemiology of CDI in the elderly people, then the alteration in innate immunity, humoral response, and microbiota that increases susceptibility to CDI and severe disease and lastly, the physiological and functional changes that may modify outcomes of infection.

Gastro-enterostomy for cicatrizing ulcer of the pylorus

Article

Bull Johns Hopkins Hosp

J.M.T. Finney

Analysis of Morbidity and Mortality Outcomes in Postoperative Clostridium difficile Infection in the Veterans Health Administration

Article

Nov 2015

Importance This study analyzes and reports Clostridium difficile infection (CDI) rates, risk factors, and associations with postoperative outcomes in the Veterans Health Administration (VHA).Objective To report 30-day postoperative CDI rates and outcomes and identify associated risks by surgical procedures and preoperative patient demographics in a large integrated health care system.Design, Setting, and Participants In a retrospective observational study conducted from September 2014 to April 2015, the Veterans Affairs Surgical Quality Improvement Program database and the Decision Support System pharmacy database were linked to analyze the association of postoperative CDI with patients’ demographics, preoperative comorbidities, operative characteristics, and preoperative medications. The Veterans Affairs Surgical Quality Improvement Program assessments from October 1, 2009, to September 30, 2013, were investigated. The study was conducted at 134 VHA surgery programs, and the study population represents 12 surgical specialties: general, gynecological, neurosurgical, oral, orthopedics, otolaryngologic, plastic, podiatric, thoracic, transplant, urologic, and peripheral vascular.Main Outcomes and Measures Thirty-day postoperative CDI rates, risk factors of CDI, and association of CDI with postoperative morbidity and mortality.Results Among 468 386 surgical procedures, the postoperative CDI rate was 0.4% per year and varied by the VHA Surgery Program (0.0% to 1.4%) and surgical specialty (0.0% to 2.4%). Thirty-day CDI rates were higher in emergency procedures, procedures with greater complexity and higher relative value units, and those with a contaminated/infected wound classification. Patients with postoperative CDI were significantly older, more frequently hospitalized after surgery (59.9% vs 15.4%), had longer preoperative hospital stays (9.1 days vs 1.9 days), and had received 3 or more classes of antibiotics (1.5% vs 0.3% for a single antibiotic class) (all P < .001). Patients with CDI had higher rates of other postoperative morbidity (86.0% vs 7.1%), 30-day mortality (5.3% vs 1.0%), and longer postoperative hospital stays (17.9 days vs 3.6 days). Independent risk factors for CDI included commonly identified patient factors (albumin, functional class, and weight loss), procedural characteristics (complexity, relative value units, emergency, and wound classification), surgical program complexity, the number of preoperative antibiotic classes, and length of preoperative hospital stay.Conclusions and Relevance The number and class of antibiotics administered after surgery, preoperative length of stay, procedural characteristics, surgical program complexity, and patient comorbidities are associated with postoperative CDI in the VHA.

Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children

Article

Jan 2013
COCHRANE DB SYST REV

Antibiotics are widely prescribed; however they can cause disturbances in gastrointestinal flora which may lead to reduced resistance to pathogens such as Clostridium difficile (C. difficile). Probiotics are live organisms thought to balance the gastrointestinal flora. The 45%. These results proved robust to sensitivity analyses of plausible and worst-plausible assumptions regarding missing outcome data and were similar whether considering trials in adults versus children, lower versus higher doses, different probiotic species, or higher versus lower risk of bias. Our judgment is that the overall evidence warrants moderate confidence in this large relative risk reduction. We downgraded the overall quality of evidence for CDAD to 'moderate' due to imprecision. There were few events (154) and the calculated optimal information size (n = 8218) was more than the total sample size. With respect to the incidence of C. difficile infection, a secondary outcome, pooled complete case results from 13 trials (961 participants) did not show a statistically significant reduction. The incidence of C. difficile infection was 12.6% in the probiotics group compared to 12.7% in the placebo or no treatment control group (RR 0.89; 95% CI 0.64 to 1.24). Adverse events were assessed in 26 studies (3964 participants) and our pooled complete case analysis indicates probiotics reduce the risk of adverse events by 20% (RR 0.80; 95% CI 0.68 to 0.95). In both treatment and control groups the most common adverse events included abdominal cramping, nausea, fever, soft stools, flatulence, and taste disturbance. For the short-term use of probiotics in patients that are not immunocompromised or severely debilitated, we consider the strength of this evidence to be moderate. Based on this systematic review and meta-analysis of 23 randomized controlled trials including 4213 patients, moderate quality evidence suggests that probiotics are both safe and effective for preventing Clostridium difficile-associated diarrhea.

Clostridium difficile and the etiology of pseudomembranous colitis

Article

Jan 1978

H.E. Larson

Ursodeoxycholic Acid Inhibits Clostridium difficile Spore Germination and Vegetative Growth, and Prevents the Recurrence of Ileal Pouchitis Associated With the Infection

Article

Oct 2015
J CLIN GASTROENTEROL

Goals: To test whether ursodeoxycholic acid (UDCA) is inhibitory to Clostridium difficile and can be used in the treatment of C. difficile-associated ileal pouchitis. Background: The restoration of secondary bile metabolism may be the key mechanism for fecal microbiota transplantation (FMT) in treating recurrent C. difficile infections (RCDI). Therefore, it is possible that exogenous administration of inhibitory bile acids may be used directly as nonantibiotic therapeutics for this indication. The need for such a treatment alternative is especially significant in patients with refractory C. difficile-associated pouchitis, where the efficacy of FMT may be limited. Study: We measured the ability of UDCA to suppress the germination and the vegetative growth of 11 clinical isolate strains of C. difficile from patients treated with FMT for RCDI. In addition, we used oral UDCA to treat a patient with RCDI pouchitis that proved refractory to multiple antibiotic treatments and FMT. Results: UDCA was found to be inhibitory to the germination and the vegetative growth of all C. difficile strains tested. Fecal concentrations of UDCA from the patient with RCDI pouchitis exceeded levels necessary to inhibit the germination and the growth of C. difficile in vitro. The patient has remained infection free for over 10 months after the initiation of UDCA. Conclusions: UDCA can be considered as a therapeutic option in patients with C. difficile-associated pouchitis. Further studies need to be conducted to define the optimal dose and duration of such a treatment. In addition, bile acid derivatives inhibitory to C. difficile that are able to achieve high intracolonic concentrations may be developed as therapeutics for RCDI colitis.

Overdiagnosis of Clostridium difficile Infection in the Molecular Test Era

Article

Sep 2015

Importance: Clostridium difficile is a major cause of health care-associated infection, but disagreement between diagnostic tests is an ongoing barrier to clinical decision making and public health reporting. Molecular tests are increasingly used to diagnose C difficile infection (CDI), but many molecular test-positive patients lack toxins that historically defined disease, making it unclear if they need treatment. Objective: To determine the natural history and need for treatment of patients who are toxin immunoassay negative and polymerase chain reaction (PCR) positive (Tox-/PCR+) for CDI. Design, setting, and participants: Prospective observational cohort study at a single academic medical center among 1416 hospitalized adults tested for C difficile toxins 72 hours or longer after admission between December 1, 2010, and October 20, 2012. The analysis was conducted in stages with revisions from April 27, 2013, to January 13, 2015. Main outcomes and measures: Patients undergoing C difficile testing were grouped by US Food and Drug Administration-approved toxin and PCR tests as Tox+/PCR+, Tox-/PCR+, or Tox-/PCR-. Toxin results were reported clinically. Polymerase chain reaction results were not reported. The main study outcomes were duration of diarrhea during up to 14 days of treatment, rate of CDI-related complications (ie, colectomy, megacolon, or intensive care unit care) and CDI-related death within 30 days. Results: Twenty-one percent (293 of 1416) of hospitalized adults tested for C difficile were positive by PCR, but 44.7% (131 of 293) had toxins detected by the clinical toxin test. At baseline, Tox-/PCR+ patients had lower C difficile bacterial load and less antibiotic exposure, fecal inflammation, and diarrhea than Tox+/PCR+ patients (P < .001 for all). The median duration of diarrhea was shorter in Tox-/PCR+ patients (2 days; interquartile range, 1-4 days) than in Tox+/PCR+ patients (3 days; interquartile range, 1-6 days) (P = .003) and was similar to that in Tox-/PCR- patients (2 days; interquartile range, 1-3 days), despite minimal empirical treatment of Tox-/PCR+ patients. No CDI-related complications occurred in Tox-/PCR+ patients vs 10 complications in Tox+/PCR+ patients (0% vs 7.6%, P < .001). One Tox-/PCR+ patient had recurrent CDI as a contributing factor to death within 30 days vs 11 CDI-related deaths in Tox+/PCR+ patients (0.6% vs 8.4%, P = .001). Conclusions and relevance: Among hospitalized adults with suspected CDI, virtually all CDI-related complications and deaths occurred in patients with positive toxin immunoassay test results. Patients with a positive molecular test result and a negative toxin immunoassay test result had outcomes that were comparable to patients without C difficile by either method. Exclusive reliance on molecular tests for CDI diagnosis without tests for toxins or host response is likely to result in overdiagnosis, overtreatment, and increased health care costs.

Long-term Follow-up Study of Fecal Microbiota Transplantation for Severe and/or Complicated Clostridium difficile Infection: A Multicenter Experience

Article

Jun 2015
J CLIN GASTROENTEROL

Our aim was to investigate fecal microbiota transplantation (FMT) efficacy in patients with severe and/or complicated Clostridium difficile infection (CDI). FMT is successful for recurrent CDI, although its benefit in severe or complicated CDI has not specifically been evaluated. A multicenter long-term follow-up study was performed in patients who received FMT for severe and/or complicated CDI (diagnosed using standard criteria). Pre-FMT and post-FMT questionnaires were completed. Study outcomes included cure rates and time to resolution of symptoms. A total of 17 patients (82% inpatients, 18% outpatients) were included (76.4% women; mean age, 66.4 y; mean follow-up, 11.4 mo). Patients had severe and complicated (76.4%) or either severe or complicated (23.6%) CDI. Sixteen patients (94.1%) had diarrhea, which resolved in 12 (75%; mean time to resolution, 5.7 d) and improved in 4 (25%) after FMT. Eleven patients (64.7%) had abdominal pain, which resolved in 8 (72.7%; mean time to resolution, 9.6 d) and improved in 3 (27.3%) after FMT. Two of 17 patients experienced early CDI recurrence (≤90 d) after FMT (primary cure rate, 88.2%); and in 1 patient, a second FMT resulted in cure (secondary cure rate, 94.1%). Late CDI recurrence (≥90 d) was seen in 1 of 17 patients (5.9%) in association with antibiotics and was successfully treated with a repeat FMT. No adverse effects directly related to FMT occurred. FMT was successful and safe in this cohort of patients with severe or complicated CDI. Primary and secondary cure rates were 88.2% and 94.1%, respectively.

Clostridium difficile infection: A brief update on emerging therapies

Article

Jun 2015
AM J HEALTH-SYST PH

Established and investigational antibiotic, monoclonal antibody, vaccine, and microbe-based approaches to the prevention and treatment of Clostridium difficile infection (CDI) are reviewed. CDI is increasingly prevalent in the United States and other countries, particularly among hospitalized patients and the elderly, who are at high risk for potentially fatal CDI-related enterotoxic diarrhea. Established therapies for CDI such as vancomycin and metronidazole (an off-label use) are limited by poor efficacy and high recurrence rates. An investigational antibiotic with potent in vitro activity against all C. difficile strains (including the hypervirulent BI/NAP1/027 strain) has yielded encouraging results in early clinical trials. Another promising approach involves the use of monoclonal antibodies with selective activity against toxins responsible for CDI-associated diarrhea; in a small Phase II clinical trial, a single monoclonal antibody infusion in combination with vancomycin or metronidazole therapy was more effective than antibiotic therapy alone in preventing CDI relapse. Other emerging approaches to CDI treatment and prophylaxis include the use of vaccines against C. difficile toxins (several C. difficile-targeted vaccines are under development in Europe and the United States); microbe-based strategies such as fecal microbiota transplants, "microbial ecosystem therapeutics," and probiotic supplements; and an investigational encapsulated form of β-lactamase designed to prevent C. difficile colonization from progressing to CDI. The current antibiotic therapies for CDI, mainly vancomycin and (off-label) metronidazole and the newer agent fidaxomicin, have limitations with respect to efficacy, recurrence rates, and adverse effects, but a variety of promising approaches are emerging. Copyright © 2015 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

The Risks of Incident and Recurrent Clostridium difficile-Associated Diarrhea in Chronic Kidney Disease and End-Stage Kidney Disease Patients: A Systematic Review and Meta-Analysis

Article

May 2015
DIGEST DIS SCI

The objective of this systematic review and meta-analysis was to assess the risks of incident and recurrent Clostridium difficile-associated diarrhea in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) requiring dialysis. A literature search was performed from inception to February 2015. Studies that reported relative risks, odds ratios, or hazard ratios comparing the risks of C. difficile-associated diarrhea in patients with CKD or ESRD versus those without CKD or ESRD were included. Pooled risk ratios (RRs) and 95 % confidence intervals (CIs) were calculated using a random-effect, generic inverse variance method. Twenty studies (nine case-control, seven cohort, and four cross-sectional studies with 162,218,041 patients) were included in the meta-analysis. Pooled RRs of C. difficile-associated diarrhea in patients with CKD and ESRD were 1.95 (95 % CI 1.81-2.10) and 2.63 (95 % CI 2.04-3.38), respectively. When meta-analysis was limited only to cohort and case-control studies with confounder-adjusted analysis, the pooled RRs of C. difficile-associated diarrhea in patients with CKD and ESRD were 1.89 (95 % CI 1.75-2.05) and 2.50 (95 % CI 1.49-4.17), respectively. The pooled RR of recurrent C. difficile-associated diarrhea in patients with CKD was 2.61 (95 % CI 1.53-4.44). Data on the risk of recurrent C. difficile-associated diarrhea were limited. This meta-analysis demonstrates significantly increased risks of incident and recurrent C. difficile-associated diarrhea in patients with CKD. Furthermore, the magnitude of increased risk of C. difficile-associated diarrhea in ESRD patients is even higher.

Fecal Microbiota Transplantation for Clostridium difficile Infection: A Systematic Review

Article

May 2015
ANN INTERN MED

The role of fecal microbiota transplantation (FMT) for Clostridium difficile infection (CDI) is not well-known. To assess the efficacy, comparative effectiveness, and harms of FMT for CDI. MEDLINE (1980 to January 2015), Cochrane Library, and ClinicalTrials.gov, followed by hand-searching references from systematic reviews and identified studies. Any study of FMT to treat adult patients with CDI; case reports were only used to report harms. Data were extracted by 1 author and verified by another; 2 authors independently assessed risk of bias and strength of evidence. Two randomized, controlled trials (RCTs); 28 case-series studies; and 5 case reports were included. Two RCTs and 21 case-series studies (516 patients receiving FMT) reported using FMT for patients with recurrent CDI. A high proportion of treated patients had symptom resolution; however, the role of previous antimicrobials is unclear. One RCT comparing FMT with 2 control groups (n = 43) reported resolution of symptoms in 81%, 31%, and 23% of the FMT, vancomycin, or vancomycin-plus-bowel lavage groups, respectively (P < 0.001 for both control groups vs. FMT). An RCT comparing FMT route (n = 20) reported no difference between groups (60% in the nasogastric tube group and 80% in the colonoscopy group; P = 0.63). Across all studies for recurrent CDI, symptom resolution was seen in 85% of cases. In 7 case-series studies of patients with refractory CDI, symptom resolution ranged from 0% to 100%. Among 7 patients treated with FMT for initial CDI, results were mixed. Most studies were uncontrolled case-series studies; only 2 RCTs were available for analysis. Fecal microbiota transplantation may have a substantial effect with few short-term adverse events for recurrent CDI. Evidence is insufficient on FMT for refractory or initial CDI treatment and on whether effects vary by donor, preparation, or delivery method. U.S. Department of Veterans Affairs.

European Society of Clinical Microbiology and Infectious Diseases: Update of the Treatment Guidance Document for Clostridium difficile Infection

Article

Mar 2014

In 2009 the first European Society of Clinical Microbiology and Infection (ESCMID) treatment guidance document for Clostridium difficile infection (CDI) was published. The guideline has been applied widely in clinical practice. In this document an update and review on the comparative effectiveness of the currently available treatment modalities of CDI is given, thereby providing evidence-based recommendations on this issue. A computerized literature search was carried out to investigate randomized and non-randomized trials investigating the effect of an intervention on the clinical outcome of CDI. The Grades of Recommendation Assessment, Development and Evaluation (GRADE) system was used to grade the strength of our recommendations and the quality of the evidence. The ESCMID and an international team of experts from 11 European countries supported the process. To improve clinical guidance in the treatment of CDI, recommendations are specified for various patient groups, e.g. initial non-severe disease, severe CDI, first recurrence or risk for recurrent disease, multiple recurrences and treatment of CDI when oral administration is not possible. Treatment options that are reviewed include: antibiotics, toxin-binding resins and polymers, immunotherapy, probiotics, and faecal or bacterial intestinal transplantation. Except for very mild CDI that is clearly induced by antibiotic usage antibiotic treatment is advised. The main antibiotics that are recommended are metronidazole, vancomycin and fidaxomicin. Faecal transplantation is strongly recommended for multiple recurrent CDI. In case of perforation of the colon and/or systemic inflammation and deteriorating clinical condition despite antibiotic therapy, total abdominal colectomy or diverting loop ileostomy combined with colonic lavage is recommended.

Clostridium difficile Infection

Article

Apr 2015
NEW ENGL J MED

Despite concerted efforts to improve the prevention and treatment of C. difficile infection, this infection remains common and serious in both hospitals and the community. In recent years, fecal microbial transplantation has emerged as a safe and very effective strategy for the treatment of recurrent infection. With further refinement, fecal microbial transplantation will most likely become the standard of care for recurrent infection. Newer antibiotics with clinical activity against C. difficile are now available, but widespread use has been limited by their cost, which is higher than the cost of vancomycin. Although antibiotic stewardship and decontamination in health care settings remain essential for infection control, effective probiotics and vaccination will most likely become important tools for the prevention of C. difficile infection in the future. Until such time, C. difficile infection will continue to be a common and highly morbid consequence of antibiotic use.

How to eradicate Clostridium difficile from the environment

Article

Jan 2015
J HOSP INFECT

Frédéric Barbut

During the last decade, Clostridium difficile has emerged as a major cause of healthcare-associated diarrhoea and death. Transmission of this spore-forming bacterium is thought to occur via the hands of healthcare providers or via the contaminated environment. Therefore, enhanced environmental cleaning/disinfection of the rooms housing C. difficile-infected patients is warranted. Guidelines from various scientific bodies have been published. They recommend performing environmental decontamination of rooms of patients with C. difficile infection (CDI) using hypochlorite (diluted 1/10) or a sporicidal product. Compliance with cleaning and disinfection is a critical point and is often suboptimal. Novel 'no-touch' methods for room disinfection have recently been introduced. Ultraviolet (UV) light or hydrogen peroxide systems are most widely used. In-vitro studies suggest that hydrogen peroxide vapour (from 30% hydrogen peroxide) methods achieve a >6 log10 reduction in C. difficile spores placed on carriers, and that aerosolized hydrogen peroxide systems (from 5% to 6% hydrogen peroxide) achieve ∼4 log10 reduction, whereas UV-based methods achieve ∼2 log10 reduction. Very few studies have assessed the impact of these devices on the transmission of C. difficile. Major limitations of these devices include the fact that they can only be used after the patient's discharge, because patients and staff must be removed from the room. The new no-touch methods for room disinfection supplement, but do not replace, daily cleaning. Copyright © 2015 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.

Diagnosis and Management of Clostridium difficile Infection

Article

Oct 2013
CLIN GASTROENTEROL H

Dupont Herbert

Clostridium difficile infection (CDI) is increasing in frequency and severity in and out of the hospital, with a high probability of recurrence after treatment. The recent literature on CDI was reviewed using PubMed to include recent publications dealing with diagnosis and therapy. Real-time polymerase chain reaction is a sensitive and useful diagnostic test for CDI but there are growing concerns of false-positive test results if the rate of CDI is low in the patient population providing samples and/or if the population being studied commonly includes people with C difficile colonization. Recommended therapy of CDI includes oral metronidazole for milder cases of CDI and oral vancomycin or fidaxomicin for more severe cases, each given for 10 days. Colectomy is being performed more frequently in patients with fulminant CDI. For treatment of first recurrences the drug used in the first bout can be used again and for second recurrences longer courses of vancomycin often are given in a tapered dose or intermittently to allow gut flora reconstitution, or other treatments including fidaxomicin may be used. Bacteriotherapy with fecal transplantation is playing an increasing role in therapy of recurrent cases. Metagenomic studies of patients with CDI during successful therapy are needed to determine how best to protect the flora from assaults from antibacterial drugs and to develop optimal therapeutic approaches. Immunotherapy and immunoprophylaxis offer opportunities to prevent CDI, to speed up recovery from CDI, and to eliminate recurrent infection. Humanized monoclonal antitoxin antibodies and active immunization with vaccines against C difficile or its toxins are both in development and appear to be of potential value.

The Epidemiology of Clostridium difficile Infection Inside and Outside Health Care Institutions

Article

Jan 2015
INFECT DIS CLIN N AM

This article describes the global changes in Clostridium difficile epidemiology since the late twentieth century and into the twenty-first century when the new epidemic strain BI/NAP1/027 emerged. The article provides an overview of how understanding of C difficile epidemiology has rapidly evolved since its initial association with colitis in 1974. It also discusses how C difficile has spread across the globe, the role of asymptomatic carriers in disease transmission, the increased recognition of C difficile outside health care settings, the changes in epidemiology of C difficile infection in children, and the risk factors for disease. Published by Elsevier Inc.

Environmental Interventions to Control Clostridium difficile

Article

Jan 2015
INFECT DIS CLIN N AM

Vivian G Loo

The control of Clostridium difficile infection is paramount. C difficile spores are difficult to eradicate and can survive on surfaces for prolonged periods of time. Hand washing with either plain or antimicrobial soap is effective in removing C difficile spores from hands. Patients should be placed in private rooms and under contact precautions to prevent transmission to other patients. Regular hospital germicides are not sporicidal and hypochlorite solutions are required for surface disinfection. In outbreak situations, a multifaceted approach is required. Copyright © 2015 Elsevier Inc. All rights reserved.

Practice Parameters for the Management of Clostridium difficile Infection

Article

Jan 2015
DIS COLON RECTUM

Ertapenem Prophylaxis Associated With an Increased Risk of Clostridium difficile Infection Among Surgical Patients

Conference Paper

Oct 2014
INFECT CONT HOSP EP

Background: We observed high rates of Clostridium difficile infections (CDI) among 2 surgical units at UCSF despite improvements in hand hygiene, adherence to contact precautions, and environmental cleaning. Our objective was to identify risk factors for CDI among surgical patients at our institution. Methods: We designed a case-control study that included 46 patients with hospital-onset CDI who were directly admitted to 2 surgical units between July 2012 and Sept 2013. Each case was matched to 2 controls without CDI selected from the same unit and calendar quarter by incidence density sampling. We used conditional logistical regression for bivariate analysis and included risk factors with a p-value less than 0.2 into a final multivariate model to identify independent risk factors for CDI (p-value < 0.05). Results: Cases and controls were similar in demographics, underlying comorbidities, need for emergency surgery, total parenteral nutrition, enteral feeding, use of bowel prep and gastric acid suppressants. Multivariate analysis revealed that receipt of ertapenem (OR=4.41, p=0.003; 95% CI 1.7-11.7), cystectomy (OR 5.29, p=.03; 95% CI 1.1-24.5) and Whipple procedure (OR 5.58, p=.048, OR 1.02-30.6) were associated with a significantly increased risk of CDI. The median ertapenem duration among the cases and controls was 1 day of therapy (DOT), interquartile range 0.5 DOT to 1 DOT. We noted that ertapenem prophylaxis was highly associated with CDI risk on bivariate analysis (OR 4.2, p=.003, 95% CI 1.64-10.8) and this also held true when included in multivariate analysis (OR = 3.89, p=.009, 95% CI 1.41-10.8). Conclusion: Surgical procedures with prolonged operative time such as cystectomies and Whipple procedures may be independent risk factors for CDI, although numbers were small in our study. Ertapenem, particularly its use as prophylaxis, was associated with an increased risk of CDI among surgical patients, which may offer an appropriate target to improve antibiotic stewardship among the surgical patient population.

Clostridium difficile disease: Diagnosis, pathogenesis, and treatment update

Abstract

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