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Antibiotic-induced colitis.

Most cases of antibiotic-associated diarrhea can be classified into two categories: cases in which Clostridium difficile is implicated and cases in which no putative agent or recognized pathophysiological mechanism is recognized. C difficile colonization produces a spectrum of conditions, ranging from asymptomatic carriage to fatal pseudomembranous colitis: it is implicated in virtually all cases of pseudomembranous colitis and up to 25% of cases of antibiotic-associated diarrhea without colitis. Clindamycin is notorious for its propensity to induce C difficile colitis, but in current practice, broad-spectrum penicillins and cephalosporins are the most frequently implicated agents, reflecting their widespread use. Treatment includes cessation or alteration of antimicrobial therapy when possible, provision of supportive care, and specific therapy aimed at eradicating C difficile if symptoms are severe or persistent or if antibiotic therapy cannot be safely discontinued. Oral metronidazole or vancomycin is equally efficacious in uncomplicated disease; optimal therapy for severe disease has not been established. Relapses occur in up to 15% of cases and cannot be accurately predicted or prevented.

Adult↗

Clostridium difficile toxin A stimulates macrophage-inflammatory protein-2 production in rat intestinal epithelial cells.

Neutrophil infiltration of the colonic mucosa is a hallmark of Clostridium difficile toxin A-mediated enterocolitis. Macrophage-inflammatory protein-2 (MIP-2) is a potent neutrophil chemoattractant secreted by rat macrophages and epithelial cells in response to inflammatory stimuli. In this work, we report that administration of toxin A into rat ileal loops increased mucosal levels of MIP-2 before the onset of fluid secretion and mucosal neutrophil infiltration. Administration of rabbit anti-MIP-2 IgG, but not control IgG, reduced toxin A-mediated secretion (by 58%), mucosal permeability (by 80%), and myeloperoxidase activity (by 85%). Immunohistochemical analysis demonstrated increased MIP-2 expression in intestinal epithelial and lamina propria cells 1 h after toxin A administration. Intestinal epithelial cells purified from toxin A-exposed ileal loops also showed increased MIP-2 mRNA expression and MIP-2 protein release that was inhibited by pretreatment of rats with the transcriptional inhibitor actinomycin D. These results indicate that C. difficile toxin A induces MIP-2 release from intestinal epithelial cells and that MIP-2 contributes to neutrophil mucosal influx during toxin A enteritis.

Animals↗

Improvement of Clostridium difficile isolation by heat-shock and typing of the isolated strains by SDS-PAGE.

Clostridium difficile plays an essential role in causing pseudomembranous colitis. We looked for the presence of these bacteria in the stools of 169 hospitalized patients and 38 nurses from wards with cases of diarrhea (207 subjects). The study was divided into three parts. In the first part, we compared three methods for isolating Clostridium difficile from stool samples: pre-selection with heat-shock, direct plating on Cycloserine-Cefotaxime-Fructose Agar (CCFA) and culturing in a selective broth medium. Final identification of Clostridium difficile was achieved by gas-chromatography and ApiZym. From the 207 consecutively obtained stool specimens, Clostridium difficile was isolated in 108 (52%) when pre-treated by heat-shock compared to only 26 (13%) when plated on modified CCFA and 23 (11%) when cultured in selective broth medium. Pre-selection significantly increases the isolation rate for Clostridium difficile and should be used in further epidemiological research. In the second part of our study, a retrospective review of subjects' records showed that the heat-shock method detected Clostridium difficile in all age groups at a higher rate than the other methods. In the third part of our study, we typed the 157 isolates of Clostridium difficile strains by protein patterns using SDS-PAGE, and 16 distinct groups were identified. In 19 cases different Clostridium difficile strains were found in the same subject by SDS-PAGE. Finally, the isolated strains were compared with strains from Brussels and Freiburg. Matching patterns were noted in only three cases.

Adolescent↗

Susceptibility of anaerobic bacteria to PD 131628.

The in vitro activity of PD 131628 against anaerobic cocci, Propionibacterium acnes, Clostridium perfringens, Clostridium difficile, Bacteroides fragilis, Bacteroides spp. and fusobacteria was determined by the agar dilution method. This activity was compared with that of ciprofloxacin, piperacillin, cefoxitin, imipenem, clindamycin, metronidazole and chloramphenicol. PD 131628, imipenem, clindamycin, metronidazole and chloramphenicol were the most active agents tested.

Anti-Infective Agents↗

Clostridium difficile-associated diarrhea and colitis: clinical manifestations, diagnosis, and treatment.

PURPOSE: This review examines the pathogenesis, clinical manifestations, diagnosis, and current medical and operative strategies in the treatment of Clostridium difficile diarrhea and colitis. Prevention and future avenues of research are also investigated. METHODS: A review of the literature was conducted with the use of MEDLINE. RESULTS: C. difficile is a gram-positive, spore-forming bacterium capable of causing toxigenic colitis in susceptible patients, usually those receiving antibiotics. Overgrowth of toxigenic strains may result in a spectrum of disease, including becoming an asymptomatic carrier, diarrhea, self-limited colitis, fulminant colitis, and toxic megacolon. Diagnosis requires a high index of suspicion and depends on clinical data, laboratory stool studies (enzyme-linked immunoabsorbent assay and cytotoxin test), and endoscopy in selected cases. Protocols for treatment of primary and relapsing infections are provided in algorithm format. Discontinuation of antibiotics may be enough to resolve symptoms. Medical management with oral metronidazole or vancomycin is the first-line therapy for those with symptomatic colitis. Teicoplanin, Saccharomyces spp. and Lactobacillus spp., and intravenous IgG antitoxin are reserved for more recalcitrant cases. Refractory or relapsing infections may require vancomycin given orally or other newer modalities. Fulminant colitis and toxic megacolon warrant subtotal colectomy. Cost, in terms of extended hospital stay, medical and surgical management, and, in some cases, ward closure, is thought to be formidable. Review of perioperative antibiotic policies and analysis of hospital formularies may contribute to prevention and decreased costs. CONCLUSION: C. difficile diarrhea and colitis is a nosocomial infection that may result in significant morbidity, mortality, and medical costs. Standard laboratory studies and endoscopic evaluation assist in the diagnosis of clinically suspicious cases. Appropriate perioperative antibiotic dosing, narrowing the antibiotic spectrum when treating infections, and discontinuing antibiotics at appropriate intervals prevent toxic sequelae.

Clostridioides difficile↗

Usefulness of simultaneous detection of toxin A and glutamate dehydrogenase for the diagnosis of Clostridium difficile-associated diseases.

The aim of this study was to evaluate an immunoassay (Triage; Biosite Diagnostics, BMD, France) for detecting both a specific antigen of Clostridium difficile (glutamate dehydrogenase [GDH]) and toxin A. Evaluation of the test was carried out in 304 fecal samples from patients suspected of having Clostridium difficile-associated diseases. The results with GDH and toxin A were compared with those of a culture and cytotoxicity assay (toxin B). The prevalence rates for toxin B-positive and culture-positive fecal samples were 11.2% and 25%, respectively. The sensitivity of the Triage immunoassay was 90.8% for GDH and 79.4% for toxin A. A negative result with both toxin A and GDH was very reliably able to eliminate a diagnosis of Clostridium difficile-associated disease (negative predictive value 99.6%). Triage is a very rapid (20 min) and easy-to-perform test. It could be useful for diagnostic purposes and also for detecting nontoxigenic strains in epidemiogical studies.

Bacterial Proteins↗

Blood pressure cuffs: friend or foe?

A study to assess the level of bacterial contamination of blood pressure cuffs in use on hospital wards was performed. Viable organisms were recovered from all the 24 cuffs sampled at a density of between 1000 and >25 000 colony-forming units/100 cm2. Potential pathogens were isolated from 14 cuffs (58%). Eleven cuffs grew a single pathogen and three cuffs grew a mixture, yielding a total of 18 isolates. Meticillin-susceptible Staphylococcus aureus was isolated from eight (33%) cuffs, meticillin-resistant S. aureus was isolated from two (8%) cuffs and Clostridium difficile was isolated from eight (33%) cuffs. This study serves as a reminder that hands are not the only fomite to go from patient to patient on hospital wards, and that measures should be taken to reduce the risks posed by blood pressure cuffs.

Bacterial Infections↗

[Diarrhea associated with Clostridium difficile: experience at a secondary hospital].

BACKGROUND AND OBJECTIVE: Our purpose was to know the incidence, clinical profile, evolution and mortality of Clostridium difficile-associated diarrhea. PATIENTS AND METHOD: Retrospective study. Inpatients were included who had a positive toxin on stools or a diagnostic colonoscopy (pseudomembranous colitis) after ruling out other causes (n=113). RESULTS: We observed a growing annual incidence (1.05, 1.7, and 2.6 per 1000 admissions in 1999, 2000 and 2001, respectively). Hyponatremia (OR=5.16) and vomiting (OR=3.09) were found to be worse-prognosis factors. Hyponatremia (OR=2.72) and chronic renal disease (OR=4.45) increased the mortality risk. CONCLUSIONS: The incidence of C. difficile-associated diarrhea is growing, probably in relation to increased clinical suspicion, wide antibiotics utilization, and old age of inpatients. Hyponatremia could be a predictive factor of both illness and worse-prognosis.

Adult↗

The lack of therapeutic effect of Saccharomyces boulardii in the prevention of antibiotic-related diarrhoea in elderly patients.

Diarrhoea is a common side effect of antibiotic therapy, especially in the elderly. Saccharomyces boulardii is a non-pathogenic yeast which has been demonstrated to reduce the frequency of diarrhoea in patients due to a variety of causes. We set out to assess its role in preventing antibiotic-related diarrhoea. Consecutive patients over the age of 65 admitted to medical wards, and who were being prescribed antibiotics, were randomized to receive either S. boulardii 113 g twice daily or placebo for as long as they received antibiotics. Bowel habit was monitored using a record of interdefaecatory intervals (IDI) and stool form graded 1-4 (hard to liquid). Stool samples were tested every fourth day for Clostridium difficile toxin. Of the 72 patients randomized, 69 completed the study. There was no difference in sex, age, duration of antibiotic use, length of hospital stay, IDI, stool form, the proportion of patients receiving laxatives, the number of patients experiencing watery stools (seven vs. five), or the presence of C. difficile toxin (five vs. three). No side effects were attributable to S. boulardii. There was no evidence that the concomitant use of S. boulardii with antibiotics alters patients' bowel habits or prevents the appearance of C. difficile toxin in the stool. Thus, S. boulardii cannot be recommended as a 'natural' way to prevent antibiotic-related diarrhoea. This highlights the need for proper evaluation of probiotics before their unrestricted use in medical practice.

Aged↗

Clostridium difficile: an update on its epidemiology and role in hospital outbreaks in England and Wales.

Data from the surveillance system of general outbreaks of infectious intestinal disease and from laboratory reports collated by the Communicable Disease Surveillance Centre (CDSC) and requests for outbreak investigation by the PHLS Anaerobe Reference Unit were used to evaluate the current epidemiology of Clostridium difficile infection in England and Wales. Between January 1992 and December 1996, CDSC received 10,220 laboratory reports of C difficile isolation from patient's faeces and 26,873 of toxin in faeces. Over 75% of all reports were of people aged 64 years and over. The surveillance system captured a minimum data set on 694 hospital outbreaks of infectious intestinal disease. C. difficile was responsible for 109 (15%) outbreaks affecting 1625 people, of whom 1152 were found to have a C. difficile toxin producing strain. The median duration of outbreaks was 11 days. Fingerprinting by Pyrolysis Mass Spectrometry (PMS) was performed by the PHLS Anaerobe Reference Unit in 60 outbreaks, and typing by Polymerase Chain Reaction ribotyping (PCR) in 14.

Adolescent↗

Lack of care giver hand contamination with endemic bacterial pathogens in a nursing home.

Prevalences of Clostridium difficile and multiply resistant Staphylococcus aureus (MRSA) were determined in nursing staff and residents of a 233-bed long-term care facility. Twenty of 38 (52.6%) patients in the long-term care ward and three of 69 (4.3%) in the skilled-nursing ward were colonized with MRSA; 16 of 48 (33%) patients in the long-term care ward and seven of 52 (13%) in the nursing home ward were colonized with C. difficile. None of the 79 staff members whose hands were cultured had chronic C. difficile hand carriage and MRSA was present on only three of 79 (3.9%). Over a 6-month period, 128,000 pairs of gloves were worn. Since C. difficile and MRSA are rarely present on washed hands of care providers, appropriate handwashing and gloving should make a significant contribution to reducing the spread of these agents in long-term care facilities.

Adult↗

Regulation of toxin synthesis in Clostridium difficile by an alternative RNA polymerase sigma factor.

Clostridium difficile, a causative agent of antibiotic-associated diarrhea and its potentially lethal form, pseudomembranous colitis, produces two large protein toxins that are responsible for the cellular damage associated with the disease. The level of toxin production appears to be critical for determining the severity of the disease, but the mechanism by which toxin synthesis is regulated is unknown. The product of a gene, txeR, that lies just upstream of the tox gene cluster was shown to be needed for tox gene expression in vivo and to activate promoter-specific transcription of the tox genes in vitro in conjunction with RNA polymerases from C. difficile, Bacillus subtilis, or Escherichia coli. TxeR was shown to function as an alternative sigma factor for RNA polymerase. Because homologs of TxeR regulate synthesis of toxins and a bacteriocin in other Clostridium species, TxeR appears to be a prototype for a novel mode of regulation of toxin genes.

Bacterial Toxins↗

Predominance of a single restriction endonuclease analysis group with intrahospital subgroup diversity among Clostridium difficile isolates at two Chicago hospitals.

OBJECTIVE: To determine the epidemiology and relatedness of Clostridium difficile isolates in two geographically separated hospitals in a large metropolitan area, each with unique patients and personneL DESIGN: Observational descriptive molecular epidemiology of clinical C. difficile isolates. SETTING: Two tertiary-care hospitals in Chicago. METHODS: Consecutive C. difficile isolates from the clinical laboratory of a Veterans Affairs hospital during a 13-month period were typed by restriction endonuclease analysis (REA). During an overlapping 3-month period, stool specimens that tested positive for C. difficile toxin from patients at a nearby county hospital were cultured and the recovered isolates typed by the same method. RESULTS: Nineteen (68%) of 28 nosocomial isolates at the smaller, Veterans Affairs hospital belonged to REA group K. Within this group of closely related strains, 9 distinct REA types were recognized. Twenty-one (72%) of 29 nosocomial isolates at the larger, county hospital also belonged to group K. However, the predominant REA types within group K differed markedly at each institution. CONCLUSIONS: These findings demonstrate a high degree of similarity among nosocomial C. difficile strains from different hospitals in the same city and suggest the possibility of an extended outbreak of a prototype group K strain with subsequent genetic drift at the two different institutions.

Chicago↗

Tolevamer, a novel nonantibiotic polymer, compared with vancomycin in the treatment of mild to moderately severe Clostridium difficile-associated diarrhea.

BACKGROUND: Current antibiotic therapies for Clostridium difficile-associated diarrhea have limitations, including progression to severe disease, recurrent C. difficile-associated diarrhea, and selection for nosocomial pathogens. Tolevamer, a soluble, high-molecular weight, anionic polymer that binds C. difficile toxins A and B is a unique nonantibiotic treatment option. METHODS: In this 3-arm, multicenter, randomized, double-blind, active-controlled, parallel-design phase II study, patients with mild to moderately severe C. difficile-associated diarrhea were randomized to receive 3 g of tolevamer per day (n = 97), 6 g of tolevamer per day (n = 95), or 500 mg of vancomycin per day (n = 97). The primary efficacy parameter was time to resolution of diarrhea, defined as the first day of 2 consecutive days when the patient had hard or formed stools (any number) or < or = 2 stools of loose or watery consistency. RESULTS: In the per-protocol study population, resolution of diarrhea was achieved in 48 (67%) of 72 patients receiving 3 g of tolevamer per day (median time to resolution of diarrhea, 4.0 days; 95% confidence interval, 2.0-6.0 days), in 58 (83%) of 70 patients receiving 6 g of tolevamer per day (median time to resolution of diarrhea, 2.5 days; 95% confidence interval, 2.0-3.0 days), and in 73 (91%) of 80 patients receiving vancomycin (median time to resolution of diarrhea, 2.0 days; 95% confidence interval, 1.0-3.0 days). Tolevamer administered at a dosage of 6 g per day was found to be noninferior to vancomycin administered at a dosage of 500 mg per day with regard to time to resolution of diarrhea (P = .02) and was associated with a trend toward a lower recurrence rate. Tolevamer was well tolerated but was associated with an increased risk of hypokalemia. CONCLUSIONS: Tolevamer, a novel polystyrene binder of C. difficile toxins A and B, effectively treats mild to moderate C. difficile diarrhea and merits further clinical development.

Adult↗

Nosocomial diarrhoea due to a single strain of Clostridium difficile: a prolonged outbreak in elderly patients.

An outbreak of diarrhoea occurred in an acute geriatric ward of a hospital (A). It affected six patients initially and was found to be due to a single strain of Clostridium difficile. There was little evidence for asymptomatic carriage of this strain or others in the hospital patients. The following three months saw an increase in the number of symptomatic cases of C. difficile disease in two peripheral hospitals, B and C. Patients had been moved from the outbreak ward to these hospitals. Of 18 cases in hospital B all 15 isolates saved for typing were of the 'outbreak' strain. Of three cases occurring in hospital C, only one was the 'outbreak' strain (a relapsed patient who was part of the original episode). There were seven further cases in geriatric and medical wards of hospital A. All six typed isolates were also the outbreak strain. By chance, four isolates from hospital A and four from hospital B pre-dating the outbreak were also available for typing and seven of these were found to be identical to the outbreak strain. This suggests that one strain of C. difficile was endemic in geriatric and medical facilities on two sites and was responsible for nosocomial diarrhoea over at least one year. The problems of optimal management and infection control in this situation are discussed.

Aged↗

Etiological agents of infectious diarrhea: implications for requests for microbial culture.

Gastrointestinal infections remain a frequent disease worldwide. In order to increase our knowledge of the epidemiology for our patient population, we retrospectively analyzed the results obtained for stool samples received at the clinical microbiology laboratory of the University Hospital of Geneva during a 4-year period. A total of 13,965 specimens from 7,124 patients (1.96 specimens per patient) were cultured, yielding 369 (2.6%) Salmonella spp., 408 (2.9%) Campylobacter spp., and 79 (0.6%) Shigella spp. The cumulative positivity rate of 6.1% decreased to 2.7% when patients received antimicrobial agents (P < 0.001). The positivity rate for 5,912 specimens obtained from patients hospitalized for < or = 3 days was 12.6%, whereas it dropped to 1.4% for patients hospitalized for > 3 days (P < 0.001). Of 3,837 stool samples originating from pediatric patients, 8.8% were positive, and 5.1% of 10,128 samples from adults were positive (P < 0.001). The cytotoxin of Clostridium difficile was detected in 379 of 3,723 samples analyzed (10.2%), and rotaviruses were detected in 190 of 1,601 samples (11.9%). We recommend that the use of cultures for enteric bacterial pathogens be restricted to patients hospitalized for < or = 3 days, with the exceptions of follow-up samples, specimens from immunocompromised patients, and patients whose first sample was culture negative or in the rare event of nosocomial food-borne outbreaks. For patients under antimicrobial therapy, testing for cytotoxin of C. difficile should primarily be requested; this analysis should also be accepted for samples from patients not receiving antimicrobial agents at the time of specimen collection. By applying these restrictions, we could have saved at least $5,000 annually.

Adult↗

Isolation and molecular characterization of Clostridium difficile strains from patients and the hospital environment in Belarus.

Toxigenic Clostridium difficile is the most common etiologic agent of hospital-acquired diarrhea in developed countries. The role of this pathogen in nosocomial diarrhea in Eastern Europe has not been clearly established. The goal of this study was to determine the prevalence of C. difficile in patients and the hospital environment in Belarus and to characterize these isolates as to the presence of toxin genes and their molecular type. C. difficile was isolated from 9 of 509 (1.8%) patients analyzed and recovered from 28 of 1,300 (2. 1%) environmental sites cultured. A multiplex PCR assay was used to analyze the pathogenicity locus (PaLoc) of all isolates, and strain identity was determined by an arbitrarily primed PCR (AP-PCR). The targeted sequences for all the genes in the PaLoc were amplified in all C. difficile strains examined. A predominantly homogeneous group of strains was found among these isolates, with five major AP-PCR groups being identified. Eighty-three percent of environmental isolates were classified into two groups, while patient isolates grouped into three AP-PCR types, two of which were also found in the hospital environment. Although no data on the role of C. difficile infection or epidemiology of C. difficile-associated diarrhea (CDAD) in this country exist, the isolation of toxigenic C. difficile from the hospital environment suggests that this pathogen may be responsible for cases of diarrhea of undiagnosed origin and validates our effort to further investigate the significance of CDAD in Eastern Europe.

Adolescent↗

Clostridium difficile-associated diarrhea in 200 Canadian children.

OBJECTIVE: Clostridium difficile-associated diarrhea is a major problem in adults. The present study was conducted to assess risk factors and outcomes in children with C difficile-associated diarrhea. METHODS: Laboratory records at a university-affiliated pediatric hospital were reviewed for all C difficile toxin-positive stools (cell culture cytotoxin assay) between 2000 and 2003. Charts on identified patients were reviewed. RESULTS: Two hundred patients with a diagnosis of C difficile-associated diarrhea were identified between February 2000 and November 2003. There were 107 males and 93 females (mean age 5.4 years; median age 2.6 years). Underlying factors were identified in 19% (12 patients underwent chemotherapy; seven patients had Crohn's disease; six were transplantation recipients; seven an immunodeficiency; four with Hirschsprung disease; two diagnoses of 'other'). Of the 200 identified patients, 149 (74.5%) had documentation of antibiotics in the previous two months (32 penicillins; 38 cephalosporins; three clindamycin, nine other single-agent, 59 multiple; eight not specified), and 111 (55.5%) had been hospitalized in the previous month. The symptoms of C difficile-associated diarrhea included bloody stools in 12.5% and frequent watery stools in 79%. Hospitalization was required in 27 of 116 outpatients; stay was prolonged in seven of the 84 patients already hospitalized. Fifty-five per cent received metronidazole, 34% were not treated, and treatment data were not available for the remainder. Recurrence occurred in 31% of those treated and retreatment consisted of vancomycin (15%), probiotics (15%) and cholestyramine (6%). No colectomies were required but two deaths occurred. CONCLUSIONS: The majority of pediatric patients developing symptomatic C difficile-associated diarrhea had antibiotic exposure or hospitalization within the previous one to two months. This is higher than previously reported. One-third had spontaneous symptom resolution. For those treated, recurrence rates were high. Mortality was significantly lower than described in adults, in agreement with prior literature.

Child↗