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1.
J Pharm Sci ; 105(7): 2032-41, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27233688

RESUMO

A recombinant Clostridium difficile expression system was used to produce genetically engineered toxoids A and B as immunogens for a prophylactic vaccine against C. difficile-associated disease. Although all known enzymatic activities responsible for cytotoxicity were genetically abrogated, the toxoids exhibited residual cytotoxic activity as measured in an in vitro cell-based cytotoxicity assay. The residual cytotoxicity was eliminated by treating the toxoids with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide. Mass spectrometry and amino acid analysis of the EDC-inactivated toxoids identified crosslinks, glycine adducts, and ß-alanine adducts. Surface plasmon resonance analysis demonstrated that modifications resulting from the chemical treatment did not appreciably affect recognition of epitopes by both toxin A- and B-specific neutralizing monoclonal antibodies. Compared to formaldehyde-inactivated toxoids, the EDC/N-hydroxysuccinimide-inactivated toxoids exhibited superior stability in solution with respect to reversion of cytotoxic activity.


Assuntos
Clostridioides difficile/química , Clostridioides difficile/genética , Engenharia de Proteínas/métodos , Toxoides/química , Toxoides/genética , Animais , Proteínas de Bactérias/química , Toxinas Bacterianas/química , Vacinas Bacterianas , Sobrevivência Celular/efeitos dos fármacos , Estabilidade de Medicamentos , Enterotoxinas/química , Epitopos , Etildimetilaminopropil Carbodi-Imida/química , Imunização , Mesocricetus , Proteínas Recombinantes , Succinimidas/química , Ressonância de Plasmônio de Superfície
2.
Infect Control Hosp Epidemiol ; 26(3): 273-80, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15796280

RESUMO

BACKGROUND AND OBJECTIVE: Fluoroquinolones have not been frequently implicated as a cause of Clostridium difficile outbreaks. Nosocomial C. difficile infections increased from 2.7 to 6.8 cases per 1000 discharges (P < .001). During the first 2 years of the outbreak, there were 253 nosocomial C. difficile infections; of these, 26 resulted in colectomy and 18 resulted in death. We conducted an investigation of a large C. difficile outbreak in our hospital to identify risk factors and characterize the outbreak. METHODS: A retrospective case-control study of case-patients with C. difficile infection from January 2000 through April 2001 and control-patients matched by date of hospital admission, type of medical service, and length of stay; an analysis of inpatient antibiotic use; and antibiotic susceptibility testing and molecular subtyping of isolates were performed. RESULTS: On logistic regression analysis, clindamycin (odds ratio [OR], 4.8; 95% confidence interval [CI95], 1.9-12.0), ceftriaxone (OR, 5.4; CI95, 1.8-15.8), and levofloxacin (OR, 2.0; CI95, 1.2-3.3) were independently associated with infection. The etiologic fractions for these three agents were 10.0%, 6.7%, and 30.8%, respectively. Fluoroquinolone use increased before the onset of the outbreak (P < .001); 59% of case-patients and 41% of control-patients had received this antibiotic class. The outbreak was polyclonal, although 52% of isolates belonged to two highly related molecular subtypes. CONCLUSIONS: Exposure to levofloxacin was an independent risk factor for C. difficile-associated diarrhea and appeared to contribute substantially to the outbreak. Restricted use of levofloxacin and the other implicated antibiotics may be required to control the outbreak


Assuntos
Clostridioides difficile/isolamento & purificação , Infecção Hospitalar/microbiologia , Surtos de Doenças , Enterocolite Pseudomembranosa/prevenção & controle , Fluoroquinolonas/uso terapêutico , Antibacterianos/efeitos adversos , Antibacterianos/uso terapêutico , Estudos de Casos e Controles , Causas de Morte , Clindamicina/efeitos adversos , Clindamicina/uso terapêutico , Infecção Hospitalar/epidemiologia , Diarreia/induzido quimicamente , Diarreia/microbiologia , Enterocolite Pseudomembranosa/mortalidade , Feminino , Fluoroquinolonas/efeitos adversos , Hospitais de Ensino , Humanos , Levofloxacino , Modelos Logísticos , Masculino , Ofloxacino/efeitos adversos , Ofloxacino/uso terapêutico , Pennsylvania/epidemiologia , Estudos Retrospectivos , Fatores de Risco
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