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1.
Gastroenterology ; 136(4): 1206-14, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19162027

RESUMO

BACKGROUND & AIMS: Prevention of recurrent Clostridium difficile infection (CDI) is a substantial therapeutic challenge. A previous prospective study of 63 patients with CDI identified risk factors associated with recurrence. This study aimed to develop a prediction rule for recurrent CDI using the above derivation cohort and prospectively evaluate the performance of this rule in an independent validation cohort. METHODS: The clinical prediction rule was developed by multivariate logistic regression analysis and included the following variables: age>65 years, severe or fulminant illness (by the Horn index), and additional antibiotic use after CDI therapy. A second rule combined data on serum concentrations of immunoglobulin G (IgG) against toxin A with the clinical predictors. Both rules were then evaluated prospectively in an independent cohort of 89 patients with CDI. RESULTS: The clinical prediction rule discriminated between patients with and without recurrent CDI, with an area under the curve of the receiver-operating-characteristic curve of 0.83 (95% confidence interval [CI]: 0.70-0.95) in the derivation cohort and 0.80 (95% CI: 0.67-0.92) in the validation cohort. The rule correctly classified 77.3% (95% CI: 62.2%-88.5%) and 71.9% (95% CI: 59.2%-82.4%) of patients in the derivation and validation cohorts, respectively. The combined rule performed well in the derivation cohort but not in the validation cohort (area under the curve of the receiver-operating-characteristic curve, 0.89 vs 0.62; diagnostic accuracy, 93.8% vs 69.2%, respectively). CONCLUSIONS: We prospectively derived and validated a clinical prediction rule for recurrent CDI that is simple, reliable, and accurate and can be used to identify high-risk patients most likely to benefit from measures to prevent recurrence.


Assuntos
Clostridioides difficile/patogenicidade , Enterocolite Pseudomembranosa/epidemiologia , Enterocolite Pseudomembranosa/prevenção & controle , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/uso terapêutico , Toxinas Bacterianas/imunologia , Enterocolite Pseudomembranosa/sangue , Enterotoxinas/imunologia , Feminino , Humanos , Imunoglobulina G/sangue , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Curva ROC , Fatores de Risco , Prevenção Secundária , Sensibilidade e Especificidade
2.
Clin Gastroenterol Hepatol ; 6(12): 1354-60, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19081526

RESUMO

BACKGROUND & AIMS: Recent studies of Clostridium difficile infection (CDI) have indicated a dramatic increase in metronidazole failure. The aims of this study were to compare current and historical rates of metronidazole failure and to identify risk factors for metronidazole failure. METHODS: Eighty-nine patients with CDI in 2004 to 2006 were followed for 60 days and were compared with a historical cohort of 63 CDI patients studied prospectively in 1998. Metronidazole failure was defined as persistent diarrhea after 10 days of therapy or a change of therapy to vancomycin. Stool samples were analyzed for the presence of the North American pulsed-field gel electrophoresis type-1 (NAP-1) strain. RESULTS: Metronidazole failure rates were 35% in both cohorts. There was no difference in the median time to resolution of diarrhea (8 vs 5 d; P = .52) or the proportion with >10 days of diarrhea (35% vs 29%; P = .51). Risk factors for metronidazole failure included recent cephalosporin use (odds ratio [OR], 32; 95% confidence interval [CI], 5-219), CDI on admission (OR, 23; 95% CI, 3-156), and transfer from another hospital (OR, 11; 95% CI, 2-72). The frequency of NAP-1 infection in patients with and without metronidazole failure was similar (26% vs 21%; P = .67). CONCLUSIONS: We found no difference in metronidazole failure rates in 1998 and 2004 to 2006. Patients with recent cephalosporin use, CDI on admission, and transfer from another hospital were more likely to metronidazole failure. Infection with the epidemic NAP-1 strain was not associated with metronidazole failure in endemic CDI.


Assuntos
Clostridioides difficile/classificação , Enterocolite Pseudomembranosa/tratamento farmacológico , Metronidazol/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Técnicas de Tipagem Bacteriana , Clostridioides difficile/genética , Clostridioides difficile/isolamento & purificação , Estudos de Coortes , Eletroforese em Gel de Campo Pulsado , Enterocolite Pseudomembranosa/microbiologia , Feminino , Seguimentos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Falha de Tratamento , Adulto Jovem
3.
Vaccine ; 26(27-28): 3404-9, 2008 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-18502001

RESUMO

BACKGROUND: Recent data suggest that Clostridium difficile-associated diarrhea is becoming more severe and difficult to treat. Antibody responses to C. difficile toxin A are protective against symptomatic disease and recurrence. We examined the safety and pharmacokinetics (pk) of a novel neutralizing human monoclonal antibody against C. difficile toxin A (CDA1) in healthy adults. METHODS: Five cohorts with 6 subjects each received a single intravenous infusion of CDA1 at escalating doses of 0.3, 1, 5, 10, and 20 mg/kg. Safety evaluations took place on days 1, 2, 3, 7, 14, 28, and 56 post-infusion. Samples for pk analysis were obtained before and after infusion, and at each safety evaluation. Serum CDA1 antibody concentrations and human anti-human antibody (HAHA) titers were measured with enzyme-linked immunosorbent assays. A noncompartmental model was used for pk analysis. RESULTS: Thirty subjects were enrolled. The median age was 27.5 yrs. There were no serious adverse events (AE) related to CDA1. Twenty-one of the 48 reported non-serious adverse events were possibly related to CDA1, and included transient blood pressure changes requiring no treatment, nasal congestion, headache, abdominal cramps, nausea, and self-limited diarrhea. Serum CDA1 concentrations increased with escalating doses: mean C(max) ranged from 6.82 microg/ml for the 0.3 mg/kg cohort to 511 microg/ml for the 20 mg/kg cohort. The geometric mean values of the half-life of CDA1 ranged between 25.3 and 31.8 days, and the volume of distribution approximated serum. No subject formed detectable HAHA titers. CONCLUSION: Administration of CDA1 as a single intravenous infusion was safe and well tolerated. C(max) increased proportionally with increasing doses. A randomized study of CDA1 in patients with C. difficile associated diarrhea is underway.


Assuntos
Anticorpos Antibacterianos/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Antitoxinas/efeitos adversos , Toxinas Bacterianas/antagonistas & inibidores , Enterotoxinas/antagonistas & inibidores , Adulto , Anticorpos Anti-Idiotípicos/sangue , Anticorpos Antibacterianos/administração & dosagem , Anticorpos Antibacterianos/sangue , Anticorpos Monoclonais/administração & dosagem , Antitoxinas/administração & dosagem , Antitoxinas/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Meia-Vida , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade
4.
Clin Gastroenterol Hepatol ; 5(6): 707-13, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17544998

RESUMO

BACKGROUND & AIMS: Individuals who mount a significant serum immunoglobulin (Ig)G response to toxin A are protected against recurrent Clostridium difficile-associated disease (CDAD). We investigated whether humoral immune deficiencies and/or specific IgG subclass responses are associated with recurrent CDAD. METHODS: We compared the clinical characteristics and humoral immune responses of 13 patients with recurrent CDAD with 13 matched controls with a single CDAD episode. We measured the serum IgG titers to tetanus and diphtheria toxoids, as well as total and toxin A- and toxin B-specific serum IgG, IgA, and IgG subclass concentrations. RESULTS: There were no differences between the single and recurrent CDAD subjects in terms of age, sex, ethnicity, or other potential confounding variables. The total duration of diarrhea in patients with recurrent CDAD was greater (median, 62 vs 17 days; P = .005). IgG titers to tetanus and diphtheria toxoids, total IgG, and IgG subclass levels were similar in both groups. The total IgA was somewhat lower in those with recurrent CDAD (204 vs 254 mg/dL; P = .05). IgA, IgG, IgG1, and IgG4 anti-toxin A and anti-toxin B levels were similar in both groups. However, IgG2 and IgG3 anti-toxin A levels were significantly lower in the recurrent group (P = .01 and .001, respectively). CONCLUSIONS: Subjects with recurrent CDAD did not show evidence of widespread humoral immune deficiency or of IgG subclass deficiency. Their low serum IgG anti-toxin A concentrations reflected selectively reduced IgG2 and IgG3 subclass responses. Measurement of specific IgG2/3 anti-toxin A may be useful in selecting patients for treatment with agents to prevent recurrent CDAD.


Assuntos
Toxinas Bacterianas/imunologia , Enterocolite Pseudomembranosa/imunologia , Enterotoxinas/imunologia , Imunoglobulina G/imunologia , Idoso , Idoso de 80 Anos ou mais , Formação de Anticorpos , Proteínas de Bactérias/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptores Fc/imunologia , Recidiva
5.
Dig Dis Sci ; 52(2): 396-401, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17219071

RESUMO

Although there are several methods to detect Helicobacter pylori infection, there is no simple validated test to quantify the density of infection, which is believed to play a major role in the pathogenesis of H. pylori-associated gastritis and peptic ulceration. The aim of this study was to evaluate and compare noninvasive and invasive tests for assessing the level of H. pylori infection so as to facilitate the development and clinical testing of new antibiotic treatments. Healthy volunteers (n=323) were screened for H. pylori infection by serology and, if positive (n=86), invited to undergo (13)C urea breath testing (UBT) (n=55). An increase of >2.4 parts per thousand (13)CO(2) at 15 min compared to baseline was considered a positive test. Total cumulative urease activity (mumol) at 60 min was also calculated. UBT-positive subjects underwent endoscopy and nine biopsies were obtained from defined sites for quantitative culture and histological grading using the modified Sydney System. A total of 19 subjects were studied, 4 of whom underwent repeat testing. All subjects were positive for H. pylori by serology, UBT, culture, and histology. The increase in (13)CO(2) at 30 min correlated with the total cumulative urease activity at 60 min (r (2)=0.92, P< 0.0001). Bacterial counts (log cfu/biopsy; mean+/-SD) were 3.9+/-0.5, 3.9+/-0.4, and 3.9+/-0.6 at the lesser curve antrum, greater curve antrum, and corpus, respectively. There was no significant correlation between UBT results and bacterial counts at any biopsy site. Nor was there any significant correlation between the histology grading and either the UBT or the bacterial counts at any site. This study indicates that there is little correlation among the three methods used to measure bacterial burden in H. pylori infection. Thus, decrements in bacterial numbers during single-agent therapy cannot be measured reliably by UBT and therefore cannot be used to evaluate the potential efficacy of novel agents to treat gastric H. pylori infection.


Assuntos
Testes Respiratórios , Contagem de Colônia Microbiana , Endoscopia Gastrointestinal , Infecções por Helicobacter/diagnóstico , Helicobacter pylori/isolamento & purificação , Urease/metabolismo , Adulto , Anticorpos Antibacterianos/sangue , Dióxido de Carbono/metabolismo , Duodenoscopia , Duodeno/microbiologia , Duodeno/patologia , Feminino , Gastroscopia , Infecções por Helicobacter/enzimologia , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/patologia , Helicobacter pylori/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reprodutibilidade dos Testes , Estômago/microbiologia , Estômago/patologia , Fatores de Tempo
6.
Curr Opin Gastroenterol ; 20(6): 592-7, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15703688

RESUMO

PURPOSE OF REVIEW: Helicobacter pylori is a ubiquitous bacterial pathogen that has evolved to chronically infect the gastric mucosal surface, evade host immune clearance, and cause peptic ulcer disease or gastric neoplasia in a significant minority of infected individuals. Understanding the colonization, persistence, and virulence determinants of the bacterium as well as the innate and adaptive immune responses of the host are critically important if we are to develop novel treatment strategies for eradication of infection and prevention of H. pylori-induced gastroduodenal disease. RECENT FINDINGS: Substantial progress has been made in understanding the role of CagA in altering gastric epithelial cell signaling pathways. Intracellular CagA has been shown to activate the Ras/MEK/ERK mitogen activated protein kinase cascade and to associate with epithelial tight-junction scaffolding protein ZO-1. CagA was shown to regulate cellular responses and possibly contribute to gastritis by phosphorylation-dependent pathways. A phosphorylation-independent mechanism for CagA intracellular effects has also been proposed. The potential for CagA to disrupt the apical junctional barrier and for the outer membrane protein oipA to promote IL-8 secretion and gastric inflammation have also been explored. A number of different mechanisms by which H. pylori escapes and evades host immune attack to cause chronic indolent inflammation have been uncovered. Meanwhile, the examination and development of new adjuvants and vaccine delivery mechanisms to induce mucosal immune responses against key bacterial antigens has been a continuing focus of investigation in both animal and human studies. SUMMARY: H. pylori induces gastritis through production of a variety of antigens, virulence factors, and soluble mediators. The bacterium also dysregulates, disarms, and evades host immune responses to maintain chronic colonization of the gastric mucosa. Understanding the mechanisms of its growth and survival in the human stomach are essential for the development of an effective vaccine and other novel eradication strategies.

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