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PubMed2006

Multihospital surveillance of nosocomial methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococcus, and Clostridium difficile: analysis of a 4-year data-sharing project, 1999-2002.

BACKGROUND: This study sought to establish a benchmark of resistant organism rates among a cohort of regional hospitals. METHODS: The Centers for Disease Control and Prevention (CDC) definitions were used to standardize the methodology for obtaining rates per 1000 patient days of nosocomial infection and colonization with methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococcus (VRE), and nosocomial infection with Clostridium difficile (CDIF). Only newly acquired nosocomial cases were counted. Data were reported as individual hospital control charts and as cohorted aggregate data. VHA East Coast Infection Control Professionals from 32 hospitals in New Jersey and Pennsylvania were involved. RESULTS: Benchmarks were established with pooled mean rates for each cohort. During the observational period, a statistically significant downward trend was observed for VRE and MRSA (P = .02 and .0007, respectively), and an upward trend was observed for CDIF (P = .0256). CONCLUSION: Benchmarks were established to compare nosocomial MRSA, VRE, and CDIF rates. Although significant changes in rates were observed, no attempt was made to establish a causal relationship between infection control practices and observed rates. However, a secondary gain was achieved through sharing best practices.

Benchmarking↗
PubMed2003

Impact of changes in antibiotic policy on Clostridium difficile-associated diarrhoea (CDAD) over a five-year period in a district general hospital.

The impact of changes in antibiotic policy on Clostridium difficile-associated diarrhoea (CDAD), over a five-year period between 1995 and 2000, were studied in the Preston Acute Hospitals Trust. In 1996 the policy was changed in the Preston Acute Hospitals Trust from cefotaxime to ceftriaxone for initial treatment of severe sepsis or pneumonia in medical patients. Over the next nine months the average number of patients with C. difficile toxin-positive stools per quarter increased from 16 to 39. The predicted use of ceftriaxone exceeded by 65% an estimate based on prior use of cefotaxime. A policy of restricted duration of ceftriaxone was introduced, and although this reduced usage by over 50%, CDAD continued at an average of 9.2 cases per month, despite withdrawal of oral cephalosporins in December 1998. In August 1999 levofloxacin was substituted for ceftriaxone in the policy. The incidence of CDAD fell progressively to five cases per month by 2000. It would appear that a short (typically three dose) course of third-generation cephalosporin poses a similar risk for CDAD as a more prolonged course. The six-month delay in the decline of CDAD after virtual withdrawal of cephalosporins may reflect a slowly diminishing environmental reservoir.

Anti-Bacterial Agents↗
PubMed1999

Incidence of Clostridium difficile infection: a prospective study in an Indian hospital.

Clostridium difficile is the commonest cause of hospital-acquired diarrhoea. A prospective study comprising of 156 patients and 54 healthy controls was undertaken to assess C. difficile associated diarrhoea (CDAD) incidence in an Indian hospital. Methods used included C. difficile culture and enzyme linked immunosorbent assay (ELISA) for Toxin A. Attempts were made to type isolates by antibiogram and SDS-PAGE. Of the 210 stool samples tested, 12 gave positive results in at least one assay. Of these, 11 were positive by the ELISA method, eight by culture, and seven by both methods. Neither the organisms nor the toxin was found in healthy controls or neonates. The average disease incidence of CDAD estimated by using both methods was 15%. Two antibiotypes of the isolates were obtained and of the isolates characterized by SDS-PAGE, two had identical patterns. This study shows that CDAD is an emerging problem in Indian hospitals. Monitoring should enable the development and implementation of policies and procedures that minimize the risk of this nosocomial pathogen.

Adolescent↗
PubMed2005

Prospective multicenter evaluation of a new immunoassay and real-time PCR for rapid diagnosis of Clostridium difficile-associated diarrhea in hospitalized patients.

In a prospective multicenter study, 367 fecal samples from 300 patients with diarrhea were tested for Clostridium difficile-associated diarrhea (CDAD) with a new immunochromatography assay for toxins A and B (ICTAB), a real-time PCR on the toxin B gene, and the cell cytotoxicity assay. Twenty-three (6.2%) of the 367 fecal samples were positive by the cell cytotoxicity assay. With the cell cytotoxicity assay as the "gold standard," the sensitivity, specificity, positive predictive value, and negative predictive value for the ICTAB assay and real-time PCR were 91, 97, 70, and 99%, and 87, 96, 57 and 99%, respectively. In conclusion, both the ICTAB and the real-time PCR can be implemented as rapid screening methods for patients suspected of having CDAD.

Academic Medical Centers↗
PubMed2005

Three surveillance strategies for vancomycin-resistant enterococci in hospitalized patients: detection of colonization efficiency and a cost-effectiveness model.

OBJECTIVE: To evaluate the cost-effectiveness and detection sensitivity associated with three active surveillance strategies for the identification of patients harboring vancomycin-resistant enterococci (VRE) to determine which is the most medically and economically useful. DESIGN: Culture for VRE from 200 consecutive stool specimens submitted for Clostridium difficile culture. Following this, risk factors were assessed for patients whose culture yielded VRE, and a cost-effectiveness evaluation was performed using a decision analytic model with a probabilistic analysis. SETTING: A 688-bed, tertiary-care facility in Chicago, Illinois, with approximately 39,000 annual admissions, 7,000 newborn deliveries, 56,000 emergency department visits, and 115,000 home care and 265,000 outpatient visits. SUBJECTS: All stool specimens submitted to the clinical microbiology laboratory for C. difficile culture from hospital inpatients. RESULTS: From 200 stool samples submitted for C. difficile testing, we identified 5 patients with VRE in non-high-risk areas not screened as part of our routine patient surveillance. Medical record review revealed that all 5 had been hospitalized within the prior 2 years. Three of 5 had a history of renal impairment. The strategy that would involve screening the greatest number of patients (all those with a history of hospital admission in the prior 2 years) resulted in highest screening cost per patient admitted (dollars 2.48), lower per patient admission costs (dollars 480), and the best survival rates. CONCLUSION: An expanded VRE surveillance program that encompassed all patients hospitalized within the prior 2 years was a cost-effective screening strategy compared with a more traditional one focused on high-risk units.

Carrier State↗
PubMed1999

Local and systemic neutralizing antibody responses induced by intranasal immunization with the nontoxic binding domain of toxin A from Clostridium difficile.

Fourteen of the 38 C-terminal repeats from Clostridium difficile toxin A (14CDTA) were cloned and expressed either with an N-terminal polyhistidine tag (14CDTA-HIS) or fused to the nontoxic binding domain from tetanus toxin (14CDTA-TETC). The recombinant proteins were successfully purified by bovine thyroglobulin affinity chromatography. Both C. difficile toxin A fusion proteins bound to known toxin A ligands present on the surface of rabbit erythrocytes. Intranasal immunization of BALB/c mice with three separate 10-microg doses of 14CDTA-HIS or -TETC generated significant levels of anti-toxin A serum antibodies compared to control animals. The coadministration of the mucosal adjuvant heat labile toxin (LT) from Escherichia coli (1 microg) significantly increased the anti-toxin A response in the serum and at the mucosal surface. Importantly, the local and systemic antibodies generated neutralized toxin A cytotoxicity. Impressive systemic and mucosal anti-toxin A responses were also seen following coadministration of 14CDTA-TETC with LTR72, an LT derivative with reduced toxicity which shows potential as a mucosal adjuvant for humans.

Administration, Intranasal↗
PubMed2001

Role of inducible cyclooxygenase and prostaglandins in Clostridium difficile toxin A-induced secretion and inflammation in an animal model.

Cyclooxygenase (Cox)-2 expression and inhibition were investigated in a rabbit ileal loop model of Clostridium difficile colitis and diarrhea. Intestinal tissue stimulated with C. difficile toxin A showed up-regulation of Cox-2 expression in lamina propria macrophages and elevated prostaglandin levels. Toxin A-stimulated loops exhibited severe inflammation and increased secretory volume. Celecoxib, a specific Cox-2 inhibitor, significantly reduced toxin A-induced prostaglandin production. Furthermore, celecoxib (> or =0.02 mg/mL) blocked both histologic damage (mean histologic grade, 1.25 vs. 3.44 in rabbits receiving toxin A alone; P<.0005) and secretion (volume:length ratio, 0.18 vs. 0.72 in those receiving toxin A alone; P=.002) in toxin A-stimulated loops in a dose-related manner. Thus, toxin A induced expression of Cox-2 in the host, and prostaglandins produced through Cox-2 were involved in the mediation of the increased secretion of electrolytes and water and the inflammatory response induced by toxin A.

Animals↗
PubMed1999

Clostridium difficile-associated diarrhea and colitis.

Clostridium difficile-induced diarrhea (CDAD) and colitis (CDAC) are important nosocomial (hospital)-acquired infections resulting almost exclusively from antibiotic therapy and certain host factors. The severity of these disorders may range from simple diarrhea that can be resolved easily with antibiotic cessation to fulminant pseudomembranous colitis with fever, severe dehydration, abdominal pain and distention, and plaque formation over part or all of the colon. Community-acquired CDAD and CDAC are far less problematic but nevertheless may affect 20,000 or more people in the United States every year. Knowledge of the risk factors for CDAD and CDAC, including certain antibiotics, and recognition of the entire spectrum of signs and symptoms of this disorder are imperative for good dental practice. Likewise the prevention of recurrence of CDAD by judicious use of antibiotics in its immediate posttreatment period is an important consideration.

Anti-Bacterial Agents↗
PubMed1995

Toxigenicity of Clostridium difficile strains isolated in the surgical ward.

We report the use of the polymerase chain reaction (PCR) for the detection of toxigenic Clostridium difficile strains. PCR was performed as described (McMillin et al., 1991). The results obtained by PCR were compared with those of cytotoxicity assays and of the latex agglutination test. Twenty seven strains cultured from stool specimens of patients and five strains isolated from hospital environment in a surgical ward were investigated. Twenty five of 32 strains produced cytotoxin as shown on the McCoy cell-line (CA). Positive reaction in the latex test was observed in 20 strains supernatants. In 24 strains PCR revealed toxin B gene fragments (1.0 kb). In the 5 strains PCR did not detect toxin B fragments, and these strains were not cytotoxic on McCoy cells. We observed 2 strains toxin B gene fragment negative, which had a low cytotoxic activity on McCoy cells, and were toxin A gene fragment positive.

Base Sequence↗
PubMed2000

Activation of MMP-2 by Clostridium difficile toxin B in bovine smooth muscle cells.

Matrix metalloproteinase-2 (MMP-2) plays critical roles in cell migration through the breakdown of the extracellular matrix. Cell movements require dynamic actin reorganization, which is controlled by Rho family GTPases. In order to examine the relation between MMP-2 regulation and actin reorganization, we used several inhibitors of Rho family GTPases. Treatment of smooth muscle cells with Clostridium difficile toxin B known to inactivate Rho family GTPases activated MMP-2. However, neither C3 transferase, a Rho inhibitor, nor Y-27632, a specific inhibitor of Rho-kinase, induced MMP-2 activation. Treatment with C3 transferase and Y-27632 caused morphological changes into the round and stellate shape, respectively, by inhibition of actin stress fiber formation. In addition, toxin B treatment induced expression and processing of MT1-MMP, a major activator of MMP-2. Taken together, we suggest the involvement of Rho family GTPases, although inhibition of neither Rho nor Rho-kinase is sufficient, in the activation of MMP-2 through expression and activation of MT1-MMP.

ADP Ribose Transferases↗
PubMed1999

Deletions in the repeating sequences of the toxin A gene of toxin A-negative, toxin B-positive Clostridium difficile strains.

The repeating sequences of the toxin A gene from toxin A-negative, toxin B-positive (toxin A-, toxin B+) strains of Clostridium difficile which were isolated in geographically separated facilities in Japan and Indonesia were determined. All six strains tested had identical repeating sequences with two deletions (1548 and 273 nucleotides in size) in the toxin A gene. A PCR method was designed to detect the deletions and the deletions were confirmed in all 50 toxin A-, toxin B+ strains examined by this method. Western immunoblot analysis revealed that polyclonal antiserum against native toxin A did not react with the concentrated culture filtrates of the toxin A-, toxin B+ strains. These results may suggest that toxin A-, toxin B+ strains have deletions of the two thirds of the repeating regions of the toxin A gene, which encodes the epitopes fully responsible for the reaction with the polyclonal antiserum.

Adult↗
PubMed1998

Neurokinin-1 (NK-1) receptor is required in Clostridium difficile- induced enteritis.

Toxin A, a 308,000-Mr enterotoxin from Clostridium difficile, mediates antibiotic-associated diarrhea and colitis in humans. Injection of toxin A into animal intestine triggers an acute inflammatory response characterized by activation of sensory neurons and immune cells of the intestinal lamina propria, including mast cells and macrophages, and migration of circulating neutrophils in the involved intestinal segment. In this study we show that mice genetically deficient in the neurokinin-1 receptor are protected from the secretory and inflammatory changes as well as from epithelial cell damage induced by toxin A. The protective effect of neurokinin-1R deletion correlates with diminished intestinal levels of the cytokine TNF-alpha and its mRNA and the leukocyte enzyme myeloperoxidase. These results demonstrate a major requirement for substance P receptors in the pathogenesis of acute inflammatory diarrhea.

Animals↗
PubMed1993

Evaluation of four commercially available enzyme immunoassays for laboratory diagnosis of Clostridium difficile-associated diseases.

Four commercial enzyme immunoassays (EIAs) for the detection of Clostridium difficile toxin A have recently been developed and marketed (Premier, Meridian Diagnostics, Cincinnati, Ohio; VIDAS, bioMerierux Vitek, Inc., Hazelwood, Mo.; Tox-A-Test, TechLab, Blacksburg, Va.; and Bartels, Baxter Diagnostics, McGaw Park, Ill.). The performances of these EIAs were compared with those of the tissue culture cytotoxicity assay and a definition of C. difficile-associated disease based on both laboratory and clinical criteria for 329 clinical specimens. Two EIAs (Premier and VIDAS) showed good overall agreement (96 and 95%, respectively) with the cytotoxicity assay. However, they were less sensitive (84 and 71%, respectively) than the Bartels (94%) or Tox-A-Test (93%) EIAs. The Bartels and Tox-A-Test assays were much less specific, resulting in poor positive predictive values (56%) of the two assays when compared with that of the cytotoxicity assay. Tox-A-Test had the added drawback of having a significant number of indeterminate results (6.4%). These data indicate that the four EIAs all have specific shortcomings. When using these EIAs, testing strategies that take these shortcomings into consideration should be developed.

Adult↗
PubMed2004

[Characterization of an extracellular protease from Clostridium difficile].

Clostridium difficile is an intestinal pathogen, which produces two main virulence factors, the exotoxins A and B. Other bacterial structures have been implicated in the colonization of the gastrointestinal tract, which is the first step of the pathogenic process. C. difficile expresses adherence factors and also, displays some surface-associated proteolytic activity, which could play a role in the physiopathology of this bacterium. The aim of this work was to study the protein named Cwp84 which displays significant homologies with many cysteine proteases. The coding catalytic domain of this protein has been cloned in the expression system pGEX-6P-1, as an in-frame fusion with the gluthatione S-transferase, and subsequently purified. The purified fraction showed proteolytic activity on gelatine and BAPNA, but not on azocoll, suggesting a highly selective substrate specificity. The results obtained from inhibition experiments confirmed that Cwp84 belongs to the cysteine protease family. Cwp84 could play a role in degrading some specific host proteins or in the maturation of surface-associated bacterial proteins.

Amino Acid Sequence↗
PubMed2003

Antibiotics and hospital-acquired Clostridium difficile-associated diarrhoea: a systematic review.

A systematic review of studies that investigated the association of antibiotics with hospital-acquired Clostridium difficile-associated diarrhoea (CDAD) was undertaken to summarize the strength of the evidence for this relationship. The results from the studies identified were considered after critically reviewing the design and conduct of each study. Although the majority of studies found an association with various antibiotics, antibiotic classes or components of antibiotic administration, most were limited in their ability to establish a causal relationship by the use of incorrect control groups, the presence of bias, inadequate control of confounding and small sample sizes. The limitations identified in this review prevented the pooling of results in a meta-analysis. Two studies of reasonable quality suggested an association between clindamycin, cephalosporins, penicillins and CDAD. Well-designed studies grounded in epidemiological principles are needed to identify true risk factors for CDAD and to provide reliable estimates of the strength of association.

Anti-Bacterial Agents↗
PubMed2002

Clostridium difficile infection associated with levofloxacin treatment.

Nine cases of Clostridium difficile (CD) infection were observed in the period of six months at a nursing home. Eight of them occurred during or after antibiotic treatment. Levofloxacin was used alone in three cases and in combination with another antibiotic in three other cases. CD infection occurred with other antibiotics in two cases. In one case, CD infection occurred without any antibiotic treatment. It is generally accepted that quinolones rarely cause CD infection. Levofloxacin, a new antibiotic of a quinolone group, appears to be an exception. Considering the endemic level of CD infection and the high mortality and morbidity among elderly residents in the long-term care facilities, CD infection should be considered one of the major adverse effects of antibiotic therapy. Physicians are cautioned to prescribe antibiotics judiciously and to anticipate CD infection during and after antibiotic treatment.

Aged↗
PubMed1999

Characterization of surface layer proteins from Clostridium difficile by liquid chromatography/electrospray ionization mass spectrometry.

Surface layers (S-layers) are regularly ordered protein subunits found as the outermost cell envelope component of many bacteria. Most S-layers are composed of a single protein or glycoprotein species with a molecular weight varying between 40 and 200 kDa. Clostridium difficile is the most common cause of antibiotic associated diarrhea (AAD) and pseudomembranous colitis (PMC) in humans. Detection of the S-layer in some C. difficile strains, and preliminary characterization of two glycoproteins, P36 and P47, involved in the composition of the S-layer of one of these strains (C. difficile C253), led us to investigate the most appropriate conditions for purification and chemical characterization of these proteins. This work describes the results obtained when liquid chromatography (LC) coupled to mass spectrometry (MS) using electrospray ionization was applied to the analysis of C. difficile S-layer proteins (SLPs). In this way the molecular weights of the two SLP components, P36 and P47, were detected to be 34,258 +/- 2 and 39,545 +/- 3 Da, respectively. These data deviate from sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) results by 1.85 and 7.5 kDa. To confirm the LC-MS results, an alternative molecular weight analysis was performed: the two S-layer proteins were isolated by semipreparative high performance liquid chromatography (HPLC), concentrated, and analyzed by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF). The two SLP subunits were digested with protease V8, and the peptide maps were determined by LC-MS using a C18 column. Finally, preliminary results about peptide glycosylation were obtained.

Bacterial Outer Membrane Proteins↗
PubMed1992

In vitro self-assembly of the S layer subunits from Clostridium difficile GAI 0714 into tetragonal arrays.

Regularly arrayed surface component (S layer) of Clostridium difficile strain GAI 0714 was isolated with 4 M guanidine hydrochloride from the cell wall of the organism, and examined for self-assembly in vitro. The S layer was composed of two different protein subunits with molecular weights of 32 kDa and 45 kDa. Optical diffraction analysis revealed that the morphological units of both native and self-assembled S layer were essentially identical and composed of a rhombus possessing each side of 8.1 nm and interior angle of 88 degrees. The self-assembly of S layer subunits were induced in the presence of divalent cations such as Ca2+ or Zn2+, but Ba2+ or monovalent cations including K+, Na+ and Li+ failed to induce self-assembly. These results suggest that Ca+2 or Zn+2 may act as bridges to link negatively charged surface subunits.

Bacterial Outer Membrane Proteins↗