C. Difficile-associated Disease Research Articles

697. Characteristics of Hospitalized Patients Colonized with Clostridioides difficile at an Academic Medical Center

Abstract Background Clinical spectrum of C. difficile can range from colonization to fulminant colitis. Patients with toxin antigen negative, C. difficile nucleic acid amplification (NAAT)-positive diarrhea are frequently only colonized and do not suffer consequences of C. difficile associated disease (CDAD) but receive treatment for CDAD due to the perceived low risk of oral vancomycin vs. the risk of developing CDAD. Methods We performed a retrospective cohort study of hospitalized adult patients with positive C. difficile NAAT and negative toxin antigen results at University of Iowa Health Care between 9/1/2021 and 9/30/2022. Chart review was conducted to obtain patient age, immunocompromised state, involvement of infectious disease (ID) consultant, prior C. difficile test status and treatment course. Results Of the 295 NAAT-positive C. difficile results, 210 (71%) were toxin antigen negative. Patient characteristics and frequency of common risk factors are shown in Table 1. C. difficile colonization was detected ≥4 days after admission in 111 (53%), with internal medicine and stem cell transplant (SCT)/hematologic malignancies (HM) services having the most patients with colonization (31% and 18%, respectively). Antibiotic use in the prior 30 days was reported in 154 (73%). Of 134 (64%) patients on systemic antibiotics at time of C. difficile testing, antibiotics were discontinued in 29 (22%). Only 43 patients (20%) did not receive any treatment for C. difficile. Median treatment duration was 10 days with 133 (80%) being treated for 10-14 days (Table 2). ID consult was obtained in 48 (23%) and recommended no treatment initially in 11 (23%), 4 of whom were started on treatment in subsequent days. Oral twice a day vancomycin for prophylaxis was given to 28 (13%) patients, 19 (68%) of whom were immunocompromised (16 SCT/HM and 3 solid organ transplant). Conclusion Patients with C. difficile colonization have similar risk factors as patients with CDAD. Understanding treatment patterns for C. difficile colonization can guide educational activities. Most colonized patients received C. difficile treatment and/or prophylaxis, likely due to ongoing systemic antibiotic use and immunosuppression. Benefit of treatment and prophylaxis in colonized patients remains an unresolved issue. Disclosures Kelly M. Percival, PharmD, Gilead Sciences Inc: Advisor/Consultant

Clostridium difficile, the Difficult "Kloster" Fuelled by Antibiotics.

Clostridium difficile is normally present in low numbers in a healthy adult gastro-intestinal tract (GIT). Drastic changes in the microbial population, e.g., dysbiosis caused by extensive treatment with antibiotics, stimulates the growth of resistant strains and the onset of C. difficile infection (CDI). Symptoms of infection varies from mild diarrhea to colitis (associated with dehydration and bleeding), pseudomembranous colitis with yellow ulcerations in the mucosa of the colon, to fulminant colitis (perforation of the gut membrane), and multiple organ failure. Inflamed epithelial cells and damaged mucosal tissue predisposes the colon to other opportunistic pathogens such as Clostridium perfringens, Staphylococcus aureus, Klebsiella oxytoca, Candida spp., and Salmonella spp. This may lead to small intestinal bacterial overgrowth (SIBO), sepsis, toxic megacolon, and even colorectal cancer. Many stains of C. difficile are resistant to metronidazole and vancomycin. Vaccination may be an answer to CDI, but requires more research. Success in treatment with probiotics depends on the strains used. Oral or rectal fecal transplants are partly effective, as spores in the small intestine may germinate and colonize the colon. The effect of antibiotics on C. difficile and commensal gut microbiota is summarized and changes in gut physiology are discussed. The need to search for non-antibiotic methods in the treatment of CDI and C. difficile-associated disease (CDAD) is emphasized.

Characterization of Clostridium difficile Strains Isolated from Patients with C. difficile-associated Disease in Korea.

ObjectivesStudies on Clostridium difficile are rare in Korea. We investigated the epidemiological characteristics of C. difficile isolates from patients with C. difficile-associated disease (CDAD) in Korea.MethodsMultiplex polymerase chain reaction was performed to detect the presence of tcdA and tcdB toxin genes. Antimicrobial susceptibility test was carried out by the disk-dilution method. C. difficile strains were subtyped by automated repetitive-element palindromic PCR (rep-PCR).ResultsAmong patients with CDAD, 73 (25.8%), 32 (11.3%), 32 (11.3%), and 26 (9.2%) suffered from pneumonia, cancer or neoplasm, diabetes, and colitis, respectively. Of all stool samples, 43 samples (15.2%) were positive for C. difficile strains. We observed two expression patterns of toxin genes: tcdA+/tcdB+ (86% isolates) and tcdA−/tcdB+ (14% isolates), with all isolates expressing tcdB. Furthermore, some isolates were resistant to clindamycin (65%), ampicillin (56%), and cefazolin (40%), but all were susceptible to vancomycin and metronidazole. The tested samples were classified into diverse clusters using automated rep-PCR.ConclusionOur findings revealed the characteristics and antibiotic resistance of C. difficile isolates from patients in Korea. The epidemiological data may provide valuable insight into development of treatment strategies for C. difficile infections in Korea.

Modeling new immunoregulatory therapeutics as antimicrobial alternatives for treating Clostridium difficile infection.

The current treatment paradigm in Clostridium difficile infection is the administration of antibiotics contributing to the high rates of recurrent infections. Recent alternative strategies, such as fecal microbiome transplantation and anti-toxin antibodies, have shown similar efficacy in the treatment of C. difficile associated disease (CDAD). However, barriers exist for either treatment or other novel treatments to displace antibiotics as the standard of care. To aid in the comparison of these and future treatments in CDAD, we developed an in silico pipeline to predict clinical efficacy with nonclinical results. The pipeline combines an ordinary differential equation (ODE)-based model, describing the immunological and microbial interactions in the gastrointestinal (GI) mucosa, with machine learning algorithms to translate simulated output quantities (i.e. time of clearance, quantity of commensal bacteria, T cell ratios) into clinical predictions based on prior preclinical, translational and clinical trial data. As a use case, we compare the efficacy of lanthionine synthetase C-like 2 (LANCL2), a novel immunoregulatory target with promising efficacy in inflammatory bowel disease (IBD), activation with antibiotics, fecal microbiome transplantation and anti-toxin antibodies in the treatment of CDAD. We further validate the potential of LANCL2 pathway activation, in a mouse model of C. difficile infection in which it displays an ability to decrease weight loss and inflammatory cell types while protecting against mortality. The computational pipeline can serve as an important resource in the development of new treatment modalities.

Development of a dose assay for a Clostridium difficile vaccine using a tandem ion exchange high performance liquid chromatography method

Clostridium difficile is a gram-positive intestine bacterium that causes a severe diarrhea and could eventually be lethal. The main virulence factor is related to the release of two major exotoxins, toxin A (TcdA) and toxin B (TcdB). Recent C. difficile-associated disease (CDAD) outbreaks have been caused by hypervirulent strains which secrete an additional binary toxin (CDTa/CDTb). Vaccination against these toxins is considered the best way to combat the CDAD. Recently, a novel tetravalent C. difficile vaccine candidate containing all four toxins produced from a baculovirus expression system has been developed. A dose assay to release this tetravalent C. difficile vaccine was developed using tandem ion-exchange HPLC chromatography. A sequential weak cation exchange (carboxyl group) and weak anion exchange (tertiary amine group) columns were employed. The four C. difficile vaccine antigen pIs range from 4.4 to 8.6. The final optimized separation employs salt gradient elution at two different pHs. The standard analytical parameters such as LOD, LOQ, linearity, accuracy, precision and repeatability were evaluated for this method and it was deemed acceptable as a quantitative assay for vaccine release. Furthermore, the developed method was utilized for monitoring the stability of the tetravalent C. difficile vaccine in final container.

Neutrophil-mediated inflammation in the pathogenesis of Clostridium difficile infections

Clostridium difficile is the most important cause of nosocomial infectious diarrhea in the western world. C. difficile infections are a major healthcare burden with approximately 500,000 new cases every year and an estimated annual cost of nearly $1 billion in the U.S. Furthermore, the infections are no longer restricted to health care facilities, and recent studies indicate spread of C. difficile infection to the community as well. The clinical spectrum of C. difficile infection ranges from asymptomatic colonization to severe diarrhea, fulminant colitis and death. This spectrum results from a complex interplay between bacterial virulence factors, the colonic microbiome and the host inflammatory response. The overall vigor of host inflammatory response is believed to be an important determinant of C. difficile disease severity, and a more robust immune response is associated with worse outcomes. Neutrophils are the primary cells that respond to C. difficile invasion and neutrophilic inflammation is the hallmark of C. difficile-associated disease. In this review, we will focus on the role of neutrophils (infiltration to infected tissue, pathogen clearance and resolution of inflammation) in the immuno-pathogenesis of C. difficile-associated disease (CDAD).

Antimicrobial susceptibility of Clostridium difficile isolated from food animals on farms

Clostridium difficile is commonly associated with a spectrum of disease in humans referred to as C. difficile-associated disease (CDAD) and use of antimicrobials is considered a risk factor for development of disease in humans. C. difficile can also inhabit healthy food animals and transmission to humans is possible. As a result of the complexity and cost of testing, C. difficile is rarely tested for antimicrobial susceptibility. A total of 376 C. difficile strains (94 each from swine and dairy feces, and 188 from beef cattle feces) were isolated from healthy food animals on farms during studies conducted by the National Animal Health Monitoring System. Using the Etest (AB Biodisk, Solna, Sweden), samples were tested for susceptibility to nine antimicrobials implicated as risk factors for CDAD (linezolid, amoxicillin-clavulanic acid, ampicillin, clindamycin, erythromycin, levofloxacin, metronidazole, rifampicin, and vancomycin). Vancomycin was active against all isolates of C. difficile (MIC90=3.0μg/ml) while almost all isolates (n=369; 98.1%) were resistant to levofloxacin. With the exception of vancomycin, resistance varied by animal species as follows: linezolid (8.5% resistance among swine versus 2.1 and 1.1% resistance among dairy and beef, respectively), clindamycin (56.4% resistance among swine versus 80% and 90.9% resistance among dairy and beef, respectively), and rifampicin (2.1% and 0% resistance among swine and dairy cattle isolates, respectively versus 14.3% resistance among beef isolates). Regardless of species, multiple drug resistance was observed most often to combinations of clindamycin and levofloxacin (n=195; 51.9%) and ampicillin, clindamycin and levofloxacin (n=41; 10.9%). The reason for the variability of resistance between animal species is unknown and requires further research.

Toxigenic Clostridium difficile colonization in children

Clostridium difficile is a Gram positive, spore-forming organism that has become a significant cause of nosocomial infection in hospitalized adults. Colonization with this organism results in a wide spectrum of clinical conditions, including an asymptomatic carrier state, mild self-limited diarrhea, pseudomembranous colitis, and fulminant colitis. It’s role in disease in children remains controversial. This is a prospective study in which we evaluated all the patients hospitalized in the infectious diseases ward of Mofid Children’s Hospital, Tehran during 12 months (between September 2006 and September 2007). Stool samples from 250 patients were cultured for C. difficile and specimens analyzed for detection of toxin A and B. Data were analyzed by SPSS software version 11.5. Stool culture was positive for C. difficile in 113 (45.2%) patients, 10 (4%) of these were positive for both toxins A and B by enzyme-linked immunosorbent assay (ELISA). ELISA was negative in all patients with negative culture. None of the variables tested (age and antibiotic exposure) was significantly correlated with colonization. This is the first study about colonization rates of C. difficile in children in Iran. We conclude that although the C. difficile colonization rate in our children is high (45.2%), the rate of toxigenic strains is low (4%). This may explain the low rate of C. difficile associated disease (CACD) in our population.

Factors associated with Clostridium difficile diarrhea in a hospital in Beijing, China

Clostridium difficile is the most common cause of hospital-acquired diarrhea in patients treated with antibiotics, chemotherapeutic agents, and other drugs that alter the normal equilibrium of the intestinal flora. A better understanding of the risk factors for C. difficile-associated disease (CDAD) could be used to reduce the incidence of CDAD and the costs associated with its treatment. The aim of this study was to identify the risk factors for CDAD in a cohort of Chinese patients in a Beijing hospital. Medical charts of a total of 130 inpatients (62 males and 68 females) with hospital-acquired diarrhea (45 with CDAD; 85 without CDAD) were retrospectively reviewed. C. difficile toxins A and B were detected in fecal samples using enzyme-linked fluorescence assays. The drugs used by patients with and without CDAD before the onset of diarrhea were compared. Factors that differed significantly between the two groups by univariate analysis were analyzed by multivariate analysis using a logistic regression model. Multivariate analysis showed that cephalosporin treatment was associated with a significantly higher risk of CDAD in hospitalized patients, while treatment with glycopeptides was significantly associated with a reduction in CDAD (P<0.001 for cephalosporin; P=0.013 for glycopeptides). Our data confirmed previous findings that empirical treatment with cephalosporins is positively associated with CDAD compared to individuals using other CDAD-related drugs. Additionally, we showed that treatment with glycopeptides was negatively associated with CDAD, compared to individuals using other CDAD-related drugs.

Lactobacillus rhamnosus L34 and Lactobacillus casei L39 suppress Clostridium difficile-induced IL-8 production by colonic epithelial cells.

BackgroundClostridium difficile is the main cause of hospital-acquired diarrhea and colitis known as C. difficile-associated disease (CDAD).With increased severity and failure of treatment in CDAD, new approaches for prevention and treatment, such as the use of probiotics, are needed. Since the pathogenesis of CDAD involves an inflammatory response with a massive influx of neutrophils recruited by interleukin (IL)-8, this study aimed to investigate the probiotic effects of Lactobacillus spp. on the suppression of IL-8 production in response to C. difficile infection.ResultsWe screened Lactobacillus conditioned media from 34 infant fecal isolates for the ability to suppress C. difficile-induced IL-8 production from HT-29 cells. Factors produced by two vancomycin-resistant lactobacilli, L. rhamnosus L34 (LR-L34) and L.casei L39 (LC-L39), suppressed the secretion and transcription of IL-8 without inhibiting C. difficile viability or toxin production. Conditioned media from LR-L34 suppressed the activation of phospho-NF-κB with no effect on phospho-c-Jun. However, LC-L39 conditioned media suppressed the activation of both phospho-NF-κB and phospho-c-Jun. Conditioned media from LR-L34 and LC-L39 also decreased the production of C. difficile-induced GM-CSF in HT-29 cells. Immunomodulatory factors present in the conditioned media of both LR-L34 and LC-L39 are heat-stable up to 100°C and > 100 kDa in size.ConclusionsOur results suggest that L. rhamnosus L34 and L. casei L39 each produce factors capable of modulating inflammation stimulated by C. difficile. These vancomycin-resistant Lactobacillus strains are potential probiotics for treating or preventing CDAD.

Timing and type of surgical treatment of Clostridium difficile-associated disease: a practice management guideline from the Eastern Association for the Surgery of Trauma.

Clostridium difficile infection is the leading cause of nosocomial diarrhea in the United States; however, few patients will develop fulminant C. difficile-associated disease (CDAD), necessitating an urgent operative intervention. Mortality for patients who require operative intervention is very high, up to 80% in some series. Since there is no consensus in the literature regarding the best operative treatment for this disease, we sought to answer the following:PICO [population, intervention, comparison, and outcome] Question 1: In adult patients with CDAD, does early surgery compared with late surgery, as defined by the need for vasopressors, decrease mortality?PICO Question 2: In adult patients with CDAD, does total abdominal colectomy (TAC) compared with other types of surgical intervention decrease mortality? A subcommittee of the Practice Management Guideline Committee of the Eastern Association for the Surgery of Trauma conducted a systematic review and meta-analysis for the selected questions. RevMan software was used to generate forest plots. Grading of Recommendations, Assessment, Development and Evaluations methodology was used to rate the quality of the evidence, using GRADEpro software to create evidence tables. Reduction in mortality was significantly associated with early surgery, with a risk ratio (RR) of 0.5 (95% confidence interval [CI], 0.35-0.72). The quality of evidence was rated "moderate." Considering only the first procedure performed, mortality seemed to trend higher for TAC, with an RR of 1.11 (95% CI, 0.69-1.80). Considering only the actual procedure performed, the point estimate switched sides, showing a trend toward decreased mortality with TAC (RR, 0.86; 95% CI, 0.56-1.31). The quality of evidence was rated "very low." We strongly recommend that adult patients with CDAD undergo early surgery, before the development of shock and need for vasopressors. We conditionally recommend total or subtotal colectomy (vs. partial colectomy or other surgery) when the diagnosis of The Centers for Disease Control and Prevention is known.

Intestinal Alkaline Phosphatase Prevents Antibiotic-Induced Susceptibility to Enteric Pathogens

To determine the efficacy of oral supplementation of the gut enzyme intestinal alkaline phosphatase (IAP) in preventing antibiotic-associated infections from Salmonella enterica serovar Typhimurium (S. Typhimurium) and Clostridium difficile. The intestinal microbiota plays a pivotal role in human health and well-being. Antibiotics inherently cause dysbiosis, an imbalance in the number and composition of intestinal commensal bacteria, which leads to susceptibility to opportunistic bacterial infections. Previously, we have shown that IAP preserves the normal homeostasis of intestinal microbiota and that oral supplementation with calf IAP (cIAP) rapidly restores the normal gut flora. We hypothesized that oral IAP supplementation would protect against antibiotic-associated bacterial infections. C57BL/6 mice were treated with antibiotic(s) ± cIAP in the drinking water, followed by oral gavage of S. Typhimurium or C. difficile. Mice were observed for clinical conditions and mortality. After a defined period of time, mice were killed and investigated for hematological, inflammatory, and histological changes. We observed that oral supplementation with cIAP during antibiotic treatment protects mice from infections with S. Typhimurium as well as with C. difficile. Animals given IAP maintained their weight, had reduced clinical severity and gut inflammation, and showed improved survival. Oral IAP supplementation protected mice from antibiotic-associated bacterial infections. We postulate that oral IAP supplementation could represent a novel therapy to protect against antibiotic-associated diarrhea (AAD), C. difficile-associated disease (CDAD), and other enteric infections in humans.

Analysis of the Intestinal Microbiome of a Recovered Clostridium difficile Patient after Fecal Transplantation

Background:Clostridium difficile infections upon antibiotic disruption of the gut microbiota are potentially lethal. Fecal microbiota transplantation (FMT) is a promising treatment option for recurrent C. difficile-associated disease (CDAD). Here, we present a patient with recurrent CDAD that received FMT, leading to full recovery for what has now been 3 years. We performed metagenomic sequencing on stool samples to assess if there are indications for recolonization with C. difficile and changes in the gut microbiota after FMT. Methods: DNA from the stool of the donor and recipient was subjected to illumina sequencing. Obtained read sets were assembled to contiguous sequences and open reading frames were predicted. Deduced proteins were taxonomically assigned. Results: We detected complex and apparently healthy microbiomes in the donor's and recipient's intestines after FMT, but no indications for C. difficile colonization. Conclusions: Metagenomic analysis proved suitable to analyze the intestinal microbiome after FMT. Discussion of our evaluation procedure and data management may be helpful for future studies. We demonstrated restoration of a healthy and diverse gut microbiome with chimeric composition from donor and recipient, and long-lasting clearance of C. difficile. The procedure is simple, cheap, caused no side effects, and was stable over 3 years.

Pathology and Diagnostic Criteria ofClostridium difficileEnteric Infection in Horses

Clostridium difficile is commonly associated with diarrhea and colitis in humans and other mammals, including horses. To this date, the epidemiologic, microbiologic, clinical, and diagnostic aspects of C. difficile-associated disease (CDAD) in horses have been thoroughly described. However, reports describing the enteric pathology of this disease in horses are limited. This study presents a comprehensive description of the pathologic characteristics of CDAD in 21 horses and discusses the criteria for the diagnosis of the disease. Case selection was based on C. difficile A/B toxins detection (enzyme-linked immunosorbent assay) in intestinal content samples accompanied by compatible gross and microscopic enteric lesions. Grossly, multifocal, segmental, or diffuse hemorrhage; congestion; and/or marked gelatinous edema of the intestinal wall with abundant bloody or green watery contents were observed. Histologically, the most common lesion was severe necrotizing or necrohemorrhagic enteritis, colitis, or typhlocolitis, with mucosal and/or submucosal thrombosis and marked submucosal edema. The pathology of CDAD in horses is similar to that caused by other equine enteric pathogens; therefore, a definitive diagnosis requires detection of C. difficile A/B toxins in the intestinal contents.

Modulation of mucosal immune responses to Clostridium difficile by probiotic bacteria (P3073)

Abstract Commensal bacteria play a critical role in maintaining intestinal epithelium and mucosal immune homeostasis. Alterations in intestinal microflora predispose mammalian hosts to infection with pathogens such as Clostridium difficile, which has recently re-emerged as a pathogen causing nosocomial diarrhea, colitis and death. We investigated the mechanisms by which the probiotic VSL#3 ameliorates C. difficile-associated disease (CDAD) in mice. Oral VSL#3 administration reduced disease activity, body weight loss, and colonic inflammatory lesions after infection. Probiotic treatment also decreased Th17 and IL-17-producing TCRγδ cell populations at the colonic lamina propria as well as production of IL-17 and IL-1β in the colonic mucosa. Increased numbers of regulatory T cells (Treg) were seen in spleens of VSL#3-treated mice, which correlated to increased peroxisome proliferator-activated receptor γ (PPARγ) activity. PPARγ is a transcription factor and nuclear receptor that modulates immune responses and whose activation is essential for the maintenance of innate antimicrobial immunity in the colon. Mice treated with VSL#3 had an upregulation of calprotectin antimicrobial peptides S100A8 and S100A9 in the colon correlating to decreased fecal clostrial burden at day 4 post-infection. VSL#3 probiotic bacteria regulate colitis by increasing PPARγ activity and decreasing IL-17 responses and increase clostridial clearance by upregulating antimicrobial peptides in mice with CDAD.

Clostridium difficile infection in horses: A review

Clostridium difficile is considered one of the most important causes of diarrhea and enterocolitis in horses. Foals and adult horses are equally susceptible to the infection. The highly resistant spore of C. difficile is the infectious unit of transmission, which occurs primarily via the fecal-oral route, with sources of infection including equine feces, contaminated soil, animal hospitals, and feces of other animals. Two major risk factors for the development of C. difficile associated disease (CDAD) in adult horses are hospitalization and antimicrobial treatment, although sporadically, cases of CDAD can occur in horses that have not received antimicrobials or been hospitalized. The most common antibiotics associated with CDAD in horses are erythromycin, trimethoprim/sulfonamides, β-lactam antimicrobials, clindamycin, rifampicin, and gentamicin. Clinical signs and intestinal lesions of CDAD infection are not specific and they cannot be used to distinguish infections by C. difficile from infections by other agents, such as Clostridium perfringens or Salmonella sp. The distribution of lesions throughout the intestinal tract seems to be age-dependent. Small intestine is invariably affected, and colon and cecum may or may not have lesions in foals<1-month old. Naturally acquired disease in older foals and adult horses has a more aboral distribution, affecting colon and sometimes cecum, but rarely the small intestine. Detection of toxin A, toxin B or both in intestinal contents or feces is considered the most reliable diagnostic criterion for CDAD in horses. Isolation of toxigenic strains of C. difficile from horses with intestinal disease is highly suggestive of CDAD. A better understanding of pathogenesis, reservoirs of infection, and vaccines and other methods of control is needed. Also further studies are recommended to investigate other possible predisposing factors and/or etiological agents of enteric diseases of horses.

Epidemiological characteristics of nosocomial diarrhea caused by Clostridium difficile in a tertiary level hospital in Serbia

Among the most important causes of diarrhea in modern hospitals is Clostridium difficile (C. difficile). A wide spectrum of diseases caused by this bacterium is now known as C. difficile associated disease (CDAD). The development of CDAD is usually preceded by the administration of antimicrobial therapy and fecal-oral infections with C. difficile. Over the last years epidemiology of CDAD has significantly changed. Recently, a hypervirulent BI/NAP1/027 strain, the cause of severe epidemics in North America and Western Europe, has been identified. The aim of this study was to identify risk factors for CDAD in patients operated on at the Military Medical Academy (MMA). The study included all patients who underwent surgery at the MMA during 2010. Nested case-control study design was used. The subjects were divided into groups of operated patients with and without CDAD. The patients were under prospective follow-up, while their data were collected using a questionnaire during a routine epidemiological control. During 2010 the incidence rate of CDAD was 3.3 per 10,000 hospital days. Univariate regression analysis showed that the length of administration of one or two antibiotics, as well as concurrent administration of two antibiotics, were far more frequently observed in the patients with than in the patients without CDAD. Independent risk factor for the development of CDAD was the length of the administration of one antibiotic. Reduction in the incidence rate of CDAD can be achieved by using reliable measures of prevention and control; the rational use of antibiotics, early diagnosis and therapy of infected patients, contact isolation of infected persons, proper disinfection, and continued education of medical and nonmedical personnel.

Clostridium difficile-associated disease: Adherence with current guidelines at a tertiary medical center

To assess adherence with the the Society for Healthcare Epidemiology of America (SHEA)/ the Infectious Diseases Society of America (IDSA) guidelines for management of Clostridium difficile (C. difficile)-associated disease (CDAD) at a tertiary medical center. All positive C. difficile stool toxin assays in adults between May 2010 and May 2011 at the University of Maryland Medical Center were identified. CDAD episodes were classified as guideline adherent or non-adherent and these two groups were compared to determine demographic and clinical factors predictive of adherence. Logistic regression analysis was performed to assess the effect of multiple predictors on guideline adherence. 320 positive C. difficile stool tests were identified in 290 patients. Stratified by disease severity criteria set forth by the SHEA/IDSA guidelines, 42.2% of cases were mild-moderate, 48.1% severe, and 9.7% severe-complicated. Full adherence with the guidelines was observed in only 43.4% of cases. Adherence was 65.9% for mild-moderate CDAD, which was significantly better than in severe cases (25.3%) or severe-complicated cases (35.5%) (P < 0.001). There was no difference in demographics, hospitalization, ICU exposure, recurrence or 30-d mortality between adherent and non-adherent groups. A multivariate model revealed significantly decreased adherence for severe or severe-complicated episodes (OR = 0.18, 95%CI: 0.11-0.30) and recurrent episodes (OR = 0.46, 95%CI: 0.23-0.95). Overall adherence with the SHEA/IDSA guidelines for management of CDAD at a tertiary medical center was poor; this was most pronounced in severe, severe-complicated and recurrent cases. Educational interventions aimed at improving guideline adherence are warranted.

Modeling the Role of Peroxisome Proliferator-Activated Receptor γ and MicroRNA-146 in Mucosal Immune Responses to Clostridium difficile

Clostridium difficile is an anaerobic bacterium that has re-emerged as a facultative pathogen and can cause nosocomial diarrhea, colitis or even death. Peroxisome proliferator-activated receptor (PPAR) γ has been implicated in the prevention of inflammation in autoimmune and infectious diseases; however, its role in the immunoregulatory mechanisms modulating host responses to C. difficile and its toxins remains largely unknown. To characterize the role of PPARγ in C. difficile-associated disease (CDAD), immunity and gut pathology, we used a mouse model of C. difficile infection in wild-type and T cell-specific PPARγ null mice. The loss of PPARγ in T cells increased disease activity and colonic inflammatory lesions following C. difficile infection. Colonic expression of IL-17 was upregulated and IL-10 downregulated in colons of T cell-specific PPARγ null mice. Also, both the loss of PPARγ in T cells and C. difficile infection favored Th17 responses in spleen and colonic lamina propria of mice with CDAD. MicroRNA (miRNA)-sequencing analysis and RT-PCR validation indicated that miR-146b was significantly overexpressed and nuclear receptor co-activator 4 (NCOA4) suppressed in colons of C. difficile-infected mice. We next developed a computational model that predicts the upregulation of miR-146b, downregulation of the PPARγ co-activator NCOA4, and PPARγ, leading to upregulation of IL-17. Oral treatment of C. difficile-infected mice with the PPARγ agonist pioglitazone ameliorated colitis and suppressed pro-inflammatory gene expression. In conclusion, our data indicates that miRNA-146b and PPARγ activation may be implicated in the regulation of Th17 responses and colitis in C. difficile-infected mice.

Recurrent Clostridium difficile colitis in cystic fibrosis: An emerging problem

ObjectiveTo examine the incidence of recurrent Clostridium difficile infection in patients with cystic fibrosis (CF), including patients who had undergone lung transplantation, and review clinical findings in hospitalized patients with C. difficile colitis. MethodsA retrospective chart review was performed to examine the clinical presentation and management of patients with cystic fibrosis (CF) who received care at the University of Wisconsin Hospital and Clinics (UWHC) from 1994 to 2011 and were prospectively identified with C. difficile colitis. ResultsTen cases of C. difficile associated disease (CDAD) occurred in patients with CF followed by our Adult CF Center over a period of 17years, and 4 patients were bilateral lung transplant recipients. Two of the lung transplant recipients had recurrent CDAD that lead to fulminant pancolitis, surgical intervention, and shock. Two patients in the non-transplant group experienced recurrent C. difficile infection that led to fulminant pancolitis with associated systemic inflammatory response syndrome and required colectomy. ConclusionsC. difficile colitis can cause life threatening illness in patients with CF, and symptoms may be subtle and/or atypical and lead to significant delay in diagnosis. Patients with recurrent C. difficile colitis are at high risk of fatal outcome, and empiric therapy should be considered for patients with previous C. difficile colitis even in the absence of disease when broad-spectrum antibiotics are given to treat bacterial infection.