Difficile Disease Research Articles

A 10-Year Review of Total Hospital-Onset ICU Bloodstream Infections at an Academic Medical Center

The rates of central line-associated bloodstream infections (CLABSIs) in U.S. ICUs have decreased significantly, and a parallel reduction in the rates of total hospital-onset bacteremias in these units should also be expected. We report 10-year trends for total hospital-onset ICU-associated bacteremias at a tertiary-care academic medical center. This was a retrospective analysis of all positive-result blood cultures among patients admitted to seven adult ICUs for fiscal year 2005 (FY2005) through FY2014 according to Centers for Disease Control and Prevention National Healthcare Safety Network definitions. The rate of change for primary and secondary hospital-onset BSIs was determined, as was the distribution of organisms responsible for these BSIs. Data from three medical, two general surgical, one combined neurosurgical/trauma, and one cardiac/cardiac surgery adult ICU were analyzed. Across all ICUs, the rates of primary BSIs progressively fell from 2.11/1,000 patient days in FY2005 to 0.32/1,000 patient days in FY2014; an 85.0%decrease (P< .0001). Secondary BSIs also progressively decreased from 3.56/1,000 to 0.66/1,000 patient days; an 81.4%decrease (P< .0001). The decrease in BSI rates remained significant after controlling for the number of blood cultures obtained and patient acuity. An increased focus on reducing hospital-onset infections at the academic medical center since 2005, including multimodal multidisciplinary efforts to prevent central line-associated BSIs, pneumonia, Clostridium difficile disease, surgical site infections, and urinary tract infections, was associated with progressive and sustained decreases for both primary and secondary hospital-onset BSIs.

Development of a Novel Vaccine Containing Binary Toxin for the Prevention of Clostridium difficile Disease with Enhanced Efficacy against NAP1 Strains.

Clostridium difficile infections (CDI) are a leading cause of nosocomial diarrhea in the developed world. The main virulence factors of the bacterium are the large clostridial toxins (LCTs), TcdA and TcdB, which are largely responsible for the symptoms of the disease. Recent outbreaks of CDI have been associated with the emergence of hypervirulent strains, such as NAP1/BI/027, many strains of which also produce a third toxin, binary toxin (CDTa and CDTb). These hypervirulent strains have been associated with increased morbidity and higher mortality. Here we present pre-clinical data describing a novel tetravalent vaccine composed of attenuated forms of TcdA, TcdB and binary toxin components CDTa and CDTb. We demonstrate, using the Syrian golden hamster model of CDI, that the inclusion of binary toxin components CDTa and CDTb significantly improves the efficacy of the vaccine against challenge with NAP1 strains in comparison to vaccines containing only TcdA and TcdB antigens, while providing comparable efficacy against challenge with the prototypic, non-epidemic strain VPI10463. This combination vaccine elicits high neutralizing antibody titers against TcdA, TcdB and binary toxin in both hamsters and rhesus macaques. Finally we present data that binary toxin alone can act as a virulence factor in animal models. Taken together, these data strongly support the inclusion of binary toxin in a vaccine against CDI to provide enhanced protection from epidemic strains of C. difficile.

Clostridium difficile rates in asymptomatic and symptomatic hospitalized patients using nucleic acid testing

BackgroundThe Clostridium difficile rate in symptomatic patients represents both those with C. difficile infection (CDI) and those with colonization. To predict the extent of CDI overdiagnosis, we compared the asymptomatic colonization rate to the symptomatic positivity rate in hospitalized patients using nucleic acid testing. MethodsBetween July 2014 and April 2015, formed stool samples were collected from asymptomatic patients after admission to 3 hospital wards at the Stanford Hospital. Stool samples from symptomatic patients with suspected CDI in the same wards were collected for testing per provider order. The GeneXpert C. difficile tcdB polymerase chain reaction (PCR) assay (Cepheid, Sunnyvale, CA, USA) was performed on all stool samples and PCR cycle threshold was used as a measure of genomic equivalents. Chart review was performed to obtain clinical history and medication exposure. ResultsWe found an asymptomatic C. difficile carriage rate of 11.8% (43/365) (95% confidence interval [CI], 8.5–15.1%) and a positivity rate in symptomatic patients of 15.4% (54/351) (95% CI, 11.6–19.2%; P=0.19). The median PCR cycle thresholds was not significantly different between asymptomatic carriers and symptomatic positives (29.5 versus 27.3; P=0.07). Among asymptomatic patients, 11.6% (5/43) of carriers and 8.4% (27/322; P=0.56) of noncarriers subsequently became symptomatic CDI suspects within the same hospitalization. Single and multivariate analysis did not identify any demographic or clinical factors as being significantly associated with C. difficile carriage. ConclusionsAsymptomatic C. difficile carriage rate was similar to symptomatic positivity rate. This suggests the majority of PCR-positive results in symptomatic patients are likely due to C. difficile colonization. Disease-specific biomarkers are needed to accurately diagnose patients with C. difficile disease.

A DNA vaccine targeting TcdA and TcdB induces protective immunity against Clostridium difficile

Background Clostridium difficile-associated disease (CDAD) constitutes a great majority of hospital diarrhea cases in industrialized countries and is induced by two types of large toxin molecules: toxin A (TcdA) and toxin B (TcdB). Development of immunotherapeutic approaches, either active or passive, has seen a resurgence in recent years. Studies have described vaccine plasmids that express either TcdA and/or TcdB receptor binding domain (RBD). However, the effectiveness of one vector encoding both toxin RBDs against CDAD has not been evaluated.MethodsIn the study, we constructed highly optimized plasmids to express the receptor binding domains of both TcdA and TcdB from a single vector. The DNA vaccine was evaluated in two animal models for its immunogenicity and protective effects.ResultsThe DNA vaccine induced high levels of serum antibodies to toxin A and/or B and demonstrated neutralizing activity in both in vitro and in vivo systems. In a C. difficile hamster infection model, immunization with the DNA vaccine reduced infection severity and conferred significant protection against a lethal C. difficile strain.ConclusionsThis study has demonstrated a single plasmid encoding the RBD domains of C. difficile TcdA and TcdB as a DNA vaccine that could provide protection from C. difficile disease.

A Clostridium difficile Cell Wall Glycopolymer Locus Influences Bacterial Shape, Polysaccharide Production and Virulence.

Clostridium difficile is a diarrheagenic pathogen associated with significant mortality and morbidity. While its glucosylating toxins are primary virulence determinants, there is increasing appreciation of important roles for non-toxin factors in C. difficile pathogenesis. Cell wall glycopolymers (CWGs) influence the virulence of various pathogens. Five C. difficile CWGs, including PSII, have been structurally characterized, but their biosynthesis and significance in C. difficile infection is unknown. We explored the contribution of a conserved CWG locus to C. difficile cell-surface integrity and virulence. Attempts at disrupting multiple genes in the locus, including one encoding a predicted CWG exporter mviN, were unsuccessful, suggesting essentiality of the respective gene products. However, antisense RNA-mediated mviN downregulation resulted in slight morphology defects, retarded growth, and decreased surface PSII deposition. Two other genes, lcpA and lcpB, with putative roles in CWG anchoring, could be disrupted by insertional inactivation. lcpA - and lcpB - mutants had distinct phenotypes, implying non-redundant roles for the respective proteins. The lcpB - mutant was defective in surface PSII deposition and shedding, and exhibited a remodeled cell surface characterized by elongated and helical morphology, aberrantly-localized cell septae, and an altered surface-anchored protein profile. Both lcpA - and lcpB - strains also displayed heightened virulence in a hamster model of C. difficile disease. We propose that gene products of the C. difficile CWG locus are essential, that they direct the production/assembly of key antigenic surface polysaccharides, and thereby have complex roles in virulence.

Dysbiosis in Intensive Care

The composition of the human microbiome has been recognized to have a substantial effect on multiple aspects of human health. Alterations in the microbiome are associated with diseases as diverse as Clostridium difficile disease, obesity, juvenile rheumatoid arthritis, and colon cancer, as well as an increased risk for colonization with multidrug-resistant bacteria. Noting the frequent use of antibiotic therapy and other interventions in …

Disparate prevalence of toxigenic and nontoxigenic Clostridium difficile among distinct adult patient populations in a single institution.

Clostridium difficile (CD) disease remains a costly and important hospital-associated infection. Although nontoxigenic CD is detected by some CD testing methods, can interfere with some detection algorithms and has been suggested as a treatment for CD disease, little is known about the relative occurrence of toxigenic and nontoxigenic CD in a single institution.We used both chromogenic and selective agar media to recover CD isolates and a molecular method to detect the toxin B gene from over 2400 fresh unformed stool specimens with isolates further tested for the toxin B gene. We recovered 74 nontoxigenic and 306 toxigenic CD isolates for which a collection site could be assigned.The frequency of recovery of toxigenic and nontoxigenic CD for each hospital location and the ratio of toxigenic to nontoxigenic CD were calculated. Although the overall prevalence of toxigenic and nontoxigenic CD was 12.7 % and 3.1 %, respectively, on some wards, 48 % of all CD were nontoxigenic, while on other wards, ≤5 % were nontoxigenic.The disparate ratios of nontoxigenic CD to toxigenic CD presented here for the various 'groups' within the adult veteran population are important to the ongoing discussion and reexamination of other published work on the occurrence of toxigenic and nontoxigenic CD, for evaluating the performance of CD detection tests, for designing infection control strategies and in ultimately understanding both CD carriage and disease.

Importance of Glutamate Dehydrogenase (GDH) in Clostridium difficile Colonization In Vivo.

Clostridium difficile is the principal cause of antibiotic-associated diarrhea. Major metabolic requirements for colonization and expansion of C. difficile after microbiota disturbance have not been fully determined. In this study, we show that glutamate utilization is important for C. difficile to establish itself in the animal gut. When the gluD gene, which codes for glutamate dehydrogenase (GDH), was disrupted, the mutant C. difficile was unable to colonize and cause disease in a hamster model. Further, from the complementation experiment it appears that extracellular GDH may be playing a role in promoting C. difficile colonization and disease progression. Quantification of free amino acids in the hamster gut during C. difficile infection showed that glutamate is among preferred amino acids utilized by C. difficile during its expansion. This study provides evidence of the importance of glutamate metabolism for C. difficile pathogenesis.

Analysis of risk factors and clinical manifestations associated with Clostridium difficile disease in Serbian hospitalized patients.

Clostridium difficile is the leading cause of infectious diarrhoea in hospitalized patients. The aim of this study was to determine the risk factors important for the development of hospital-acquired Clostridium difficile-associated disease and clinical manifestations of Clostridium difficile-associated disease. The clinical trial group included 37 hospitalized patients who were selected according to the inclusion criteria. A control group of 74 hospitalized patients was individually matched with cases based on hospital, age (within 4 years), sex and month of admission.Clostridium difficile-associated disease most commonly manifested as diarrhoea (56.76%) and colitis (32%), while in 8.11% of patients, it was diagnosed as pseudomembranous colitis, and in one patient, it was diagnosed as fulminant colitis. Statistically significant associations (p < 0.05) were found with the presence of chronic renal failure, chronic obstructive pulmonary disease, cerebrovascular accident (stroke) and haemodialysis. In this study, it was confirmed that all the groups of antibiotics, except for tetracycline and trimethoprim–sulfamethoxazole, were statistically significant risk factors for Clostridium difficile-associated disease (p < 0.05). However, it was difficult to determine the individual role of antibiotics in the development of Clostridium difficile-associated disease. Univariate logistic regression also found that applying antibiotic therapy, the duration of antibiotic therapy, administration of two or more antibiotics to treat infections, administering laxatives and the total number of days spent in the hospital significantly affected the onset of Clostridium difficile-associated disease (p < 0.05), and associations were confirmed using the multivariate model for the application of antibiotic therapy (p = 0.001), duration of antibiotic treatment (p = 0.01), use of laxatives (p = 0.01) and total number of days spent in the hospital (p = 0.001). In this study of patients with hospital-acquired diarrhoea, several risk factors for the development of Clostridium difficile-associated disease were identified.

A human gut ecosystem protects against C. difficile disease by targeting TcdA.

A defined Microbial Ecosystem Therapeutic (MET-1, or "RePOOPulate") derived from the feces of a healthy volunteer can cure recurrent C. difficile infection (rCDI) in humans. The mechanisms of action whereby healthy microbiota protect against rCDI remain unclear. Since C. difficile toxins are largely responsible for the disease pathology of CDI, we hypothesized that MET-1 exerts its protective effects by inhibiting the effects of these toxins on the host. A combination of in vivo (antibiotic-associated mouse model of C. difficile colitis, mouse ileal loop model) and in vitro models (FITC-phalloidin staining, F actin Western blots and apoptosis assay in Caco2 cells, transepithelial electrical resistance measurements in T84 cells) were employed. MET-1 decreased both local and systemic inflammation in infection and decreased both the cytotoxicity and the amount of TcdA detected in stool, without an effect on C. difficile viability. MET-1 protected against TcdA-mediated damage in a murine ileal loop model. MET-1 protected the integrity of the cytoskeleton in cells treated with purified TcdA, as indicated by FITC-phalloidin staining, F:G actin assays and preservation of transepithelial electrical resistance. Finally, co-incubation of MET-1 with purified TcdA resulted in decreased detectable TcdA by Western blot analysis. MET-1 intestinal microbiota confers protection against C. difficile and decreases C. difficile-mediated inflammation through its protective effects against C. difficile toxins, including enhancement of host barrier function and degradation of TcdA. The effect of MET-1 on C. difficile viability seems to offer little, if any, contribution to its protective effects on the host.

Development of SYN-004, an oral beta-lactamase treatment to protect the gut microbiome from antibiotic-mediated damage and prevent Clostridium difficile infection

The gut microbiome, composed of the microflora that inhabit the gastrointestinal tract and their genomes, make up a complex ecosystem that can be disrupted by antibiotic use. The ensuing dysbiosis is conducive to the emergence of opportunistic pathogens such as Clostridium difficile. A novel approach to protect the microbiome from antibiotic-mediated dysbiosis is the use of beta-lactamase enzymes to degrade residual antibiotics in the gastrointestinal tract before the microflora are harmed. Here we present the preclinical development and early clinical studies of the beta-lactamase enzymes, P3A, currently referred to as SYN-004, and its precursor, P1A. Both P1A and SYN-004 were designed as orally-delivered, non-systemically available therapeutics for use with intravenous beta-lactam antibiotics. SYN-004 was engineered from P1A, a beta-lactamase isolated from Bacillus licheniformis, to broaden its antibiotic degradation profile. SYN-004 efficiently hydrolyses penicillins and cephalosporins, the most widely used IV beta-lactam antibiotics. In animal studies, SYN-004 degraded ceftriaxone in the GI tract of dogs and protected the microbiome of pigs from ceftriaxone-induced changes. Phase I clinical studies demonstrated SYN-004 safety and tolerability. Phase 2 studies are in progress to assess the utility of SYN-004 for the prevention of antibiotic-associated diarrhea and Clostridium difficile disease.

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).

Mo1669 A Human Gut Ecosystem Protects Against C. difficile Disease and Decreases Inflammation by Targeting C. difficile Toxin tcdA

Mo1669 A Human Gut Ecosystem Protects Against C. difficile Disease and Decreases Inflammation by Targeting C. difficile Toxin tcdA

Detection and characterisation of Clostridium difficile in Australian Thoroughbred foals

Diarrhoea is a common disease in young foals that is labour intensive and costly to manage. A large number of infectious agents have been detected in foals with diarrhoea, but the pathogenic importance of many of these agents is poorly understood. Clostridium difficile has been associated with severe necrotising enteritis in foals, but has also been isolated from healthy foals. Hypervirulent strains of C. difficile, such as ribotypes 027 and 078, commonly associated with human hospital outbreaks of diarrhoea, have also been detected in some animal populations. There are limited data on C. difficile disease in Australian horses. In a prospective case control investigation of diarrhoea in foals, faecal samples were collected on five Thoroughbred breeding farms in New South Wales, Australia, from foals with diarrhoea and age-matched control foals (agematched pair). In addition, faeces were collected from foals with diarrhoea at an equine referral hospital. Foal faeces were tested for the presence of C. difficile using a quantitative polymerase chain reaction assay (qPCR) targeting the gene encoding triose phosphate isomerase. Anaerobic culture for C. difficile was performed on samples that tested positive by qPCR and isolates were further characterised by ribotyping. In total, 117 age

Immunogenicity and protective efficacy of recombinant Clostridium difficile flagellar protein FliC

Clostridium difficile is a Gram-positive bacillus and is the leading cause of toxin-mediated nosocomial diarrhea following antibiotic use. C. difficile flagella play a role in colonization, adherence, biofilm formation, and toxin production, which might contribute to the overall virulence of certain strains. Human and animal studies indicate that anti-flagella immune responses may play a role in protection against colonization by C. difficile and subsequent disease outcome. Here we report that recombinant C. difficile flagellin (FliC) is immunogenic and protective in a murine model of C. difficile infection (CDI) against a clinical C. difficile strain, UK1. Passive protection experiments using anti-FliC polyclonal serum in mice suggest this protection to be antibody-mediated. FliC immunization also was able to afford partial protection against CDI and death in hamsters following challenge with C. difficile 630Δerm. Additionally, immunization against FliC does not have an adverse effect on the normal gut flora of vaccinated hamsters as evidenced by comparing the fecal microbiome of vaccinated and control hamsters. Therefore, the use of FliC as a vaccine candidate against CDI warrants further testing.

Disruption of the Gut Microbiome: Clostridium difficile Infection and the Threat of Antibiotic Resistance.

Clostridium difficile is well recognized as the leading cause of antibiotic-associated diarrhea, having a significant impact in both health-care and community settings. Central to predisposition to C. difficile infection is disruption of the gut microbiome by antibiotics. Being a Gram-positive anaerobe, C. difficile is intrinsically resistant to a number of antibiotics. Mobile elements encoding antibiotic resistance determinants have also been characterized in this pathogen. While resistance to antibiotics currently used to treat C. difficile infection has not yet been detected, it may be only a matter of time before this occurs, as has been seen with other bacterial pathogens. This review will discuss C. difficile disease pathogenesis, the impact of antibiotic use on inducing disease susceptibility, and the role of antibiotic resistance and mobile elements in C. difficile epidemiology.

Reducing the Risk of Pet-Related Infections to Children

Owning a pet can have many health, emotional and social benefits for children, but pets can also serve as source of zoonotic diseases. OWNING A PET can have many health, emotional and social benefits for children, but pets can also serve as source of zoonotic diseases. A zoonotic disease is a disease that can be passed between humans and animals. Most healthy people will not pick up bacteria or pathogens from contact with a pet. However, young children, pregnant women, seniors and people with weakened immune system, including those undergoing treatment for cancer, are more vulnerable. A recent review aims to raise awareness among healthcare providers about the health risks associated with owning popular pets, including dogs, cats, rodents like hamsters, and reptiles or amphibians such as lizards, turtles or frogs (Stull, Brophy, & Weese, 2015). According to the authors of the study, companion animals are a potential source for more than 70 human diseases including salmonella, antibiotic-resistant bacteria such as clostridium difficile, campylobacter jejuni and other diseases. In addition, pets can expose humans to parasites such as hookworms, roundworms and toxoplasma, a parasite sometimes spread through contact with a cat's litter box that can be especially hazardous to pregnant women and their fetuses. Although patient surveys and epidemiologic studies suggest that the occurrence of pet-associated disease is low overall, the number is likely underestimated, owing to the relative absence of reportable pathogens and complicating factors (e.g., non-pet exposure pathways, frequent subclinical shedding by pets). The proportion of human disease in high-risk populations attributable to pets is unknown,

Obscure Overt GI Bleed: A Case of CMV Ileitis in an Immunocompetent Patient

Obscure GI bleeding is an unidentified source of GI bleeding after a negative EGD, colonoscopy and barium small bowel follow-through. Up to 75% of these patients have a bleeding source in the small intestine. We present a patient with recurrent severe hematochezia, with negative upper endoscopy, colonoscopy and visceral angiogram, who was found to have bleeding Ileal ulcers on video capsule endoscopy with retrograde balloon enteroscopy showing bleeding vessels and pathology consistent with Cytomegalovirus. A 52-year-old male with history of Granulomatosis with Polyangiitis (GPA) and end stage renal disease (ESRD) presented with five episodes of Hematochezia. He was off immunosuppression for more than four years. Colonoscopy showed large amount of blood in the colon with moderate diverticuli but no active bleeding. A subsequent EGD was negative. Over the next 2 days, patient had multiple episodes of hematochezia. He underwent a tagged RBC scan, which showed blood in the terminal ileum but the visceral angiogram was negative for active bleeding. A video capsule endoscopy showed ulcerations in proximal to mid ileum. Retrograde balloon push enteroscopy showed ulcers at 135 cm from entry site in Ileum and two bleeding vessels were clipped. Results of ulcer biopsy showed intracellular inclusion bodies suggestive of Cytomegalovirus (CMV), which was confirmed with Immunostains and patient was started on oral Valganciclovir. CMV is known to cause severe infections in immunocompromised patients, but is usually mild and self-limiting in immunocompentent patients. CMV can involve any segment of the gastrointestinal tract, but most commonly involves the colon and small bowel involvement is rare. Most common presenting symptoms include fever, abdominal pain, diarrhea and bleeding per rectum, however massive transfusion dependent GI bleeding, intestinal perforation and intestinal obstruction have been reported. Diagnosis of CMV enteritis is usually made by histopathology which shows intracellular granules combined with Immunostains positive for CMV. Viral cultures and PCR are also helpful. Differential diagnosis of CMV enteritis involves colitis caused by C. difficile, ischemia, colonic malignancies and inflammatory bowel diseases. Treatment involves administration of IV Ganciclovir or oral Valganciclovir. It has been suggested that immunocompetent patients usually tend to recover spontaneously and do not need treatment. However it is hard to define the criteria of immunocompetency. In our case the patient was off immunosuppressant's for over four years, although it can be argued that presence of comorbidities like GPA and ESRD creates a state of relative immunosuppression. Our case highlights the diagnostic dilemma in patients with obscure GI bleed and additionally, is a rare presentation of CMV ileitis in a immunocompetent patient.Figure 1Figure 2Figure 3

Humanized microbiota mice as a model of recurrent Clostridium difficile disease.

BackgroundClostridium difficile disease is the leading antibiotic-associated cause of diarrhea and nosocomial acquired infection in the western world. The per annum burden in the USA alone amounts to 250,000 cases with 14,000 ascribed deaths and medical costs in excess of a billion dollars. Novel models for the study of C. difficile infection are therefore pertinent.ResultsGerm free C57BL/6 mice gavaged with a healthy human fecal microbiota maintained a stable “humanized” microbiota over multiple generations when housed under specific pathogen-free (SPF) conditions. As with mice containing a conventional microbiota, treatment with a five-antibiotic cocktail followed by a single dose of clindamycin renders the animals susceptible to C. difficile infection (CDI). Interestingly, after recovery from the initial CDI infection, a single intraperitoneal injection of clindamycin is sufficient to induce CDI relapse. Relapse of CDI can be induced up to 35 days postinfection after recovery from the initial infection, and multiple episodes of relapse can be induced.ConclusionsThis model enables the study of recurrent C. difficile disease in a host containing a human-derived microbiota. Probiotic treatments using human-derived microbes, either prophylactic or curative, can be tested within the model. The identification and testing of human-derived microbial communities within a humanized microbiota mouse model may enable a higher rate of successful transfer of bacteria-based treatments from the lab to human patients due to the microbes involved initiating from, and being adapted to, the human GI tract.Electronic supplementary materialThe online version of this article (doi:10.1186/s40168-015-0097-2) contains supplementary material, which is available to authorized users.

Increased Risk of Functional Gastrointestinal Sequelae After Clostridium difficile Infection Among Active Duty United States Military Personnel (1998–2010)

Some acute enteric infections are associated with the development of functional gastrointestinal disorders, most commonly irritable bowel syndrome but also other functional and organic gastrointestinal sequelae. Clostridium difficile infection has increased in incidence and severity, however, few studies have evaluated functional disorders after this infection. We evaluated the epidemiology and sequelae of C difficile in the US military population by using the US Department of Defense's Armed Forces Health Surveillance Center Defense Medical Ecounter Database. We then performed a retrospective cohort study of 891 active-duty US military personnel who developed C difficile from 1998to 2010 and 3231 matched subjects who had not been exposed to C difficile. Subjects were identified based on International Classification of Diseases, 9th revision, Clinical Modification codes for C difficile disease. C difficile was associated independently with increased rate ratios (RRs) for incident irritable bowel syndrome (RR, 6.1; 95% confidence interval [CI], 2.9-12.9), gastroesophageal reflux disease (GERD) (RR, 1.9; 95% CI, 1.4-2.6), dyspepsia (RR, 3.3; 95%, 1.4-7.7), and constipation (RR, 2.2; 95% CI, 1.3-3.7). Approximately 14.1%of subjects with C difficile later were identified with one of these functional gastrointestinal disorders (FGDs), compared with 6% of controls. Community- and health care-associated Cdifficile were associated at similar rates with these sequelae. Patients were at increased risk for FGDs within 3 months of a Cdifficile episode, with one additional case of FGD developing for every 12 diagnoses of C difficile. The incidence of community- and health care-associated C difficile has increased in the US military population from 1998 through 2010. As for other gastrointestinal infections, C difficile disease is associated with clinically relevant functional sequelae in this military population.