Transplantes de microbiota fecal para tratamento da colite pseudomembranosa (1958-2013): prioridade de descoberta e estilos de pensamento na literatura acadêmica / Fecal microbiota transplants in the treatment of pseudomembranous colitis (1958-2013): priority of discovery and thought styles in the academic literature

Resumo Em 1958, Eiseman e colaboradores publicaram o primeiro artigo científico relatando o uso de transplante de microbiota fecal para tratar casos graves de colite pseudomembranosa. A relevância desse trabalho inovador só foi reconhecida em 1990. A literatura acadêmica sobre o tema caracteriza-se por sucessivas reconstruções. Sugerimos que tais reconstruções foram orientadas por questões de atribuição de prioridade de descoberta científica nos termos propostos por Merton. A retomada do uso de transplantes de microbiota fecal é interpretada como processo de gênese de um fato científico, conforme Fleck: ocorre a mudança de um estilo de pensamento baseado no uso de antibióticos no tratamento de doenças infecciosas para outro que considera as relações ecológicas entre hospedeiros, vetores e agentes etiológicos de doenças.

Abstract In 1958, Eiseman and contributors published the first scientific paper reporting the use of fecal microbiota transplant for treating pseudomembranous colitis. The relevance of this innovative paper was only acknowledged in 1990. The academic literature on the theme is characterized by a narrative that has undergone successive revisions. We suggest that such revisions were based on claims of priority of scientific discoveries, as described by Merton. The revival of fecal microbiota transplants is interpreted as a process of genesis of a scientific fact, as defined by Fleck: there is a switch from a thought style based on the use of antibiotics to treat infectious diseases to another that accepts the ecological relations between hosts, vectors and parasites.

Factors associated with Clostridium difficile diarrhea in a hospital in Beijing, China

Clostridium difficile is the most common cause of hospital-acquired diarrhea in patients treated with antibiotics, chemotherapeutic agents, and other drugs that alter the normal equilibrium of the intestinal flora. A better understanding of the risk factors for C. difficile-associated disease (CDAD) could be used to reduce the incidence of CDAD and the costs associated with its treatment. The aim of this study was to identify the risk factors for CDAD in a cohort of Chinese patients in a Beijing hospital. Medical charts of a total of 130 inpatients (62 males and 68 females) with hospital-acquired diarrhea (45 with CDAD; 85 without CDAD) were retrospectively reviewed. C. difficile toxins A and B were detected in fecal samples using enzyme-linked fluorescence assays. The drugs used by patients with and without CDAD before the onset of diarrhea were compared. Factors that differed significantly between the two groups by univariate analysis were analyzed by multivariate analysis using a logistic regression model. Multivariate analysis showed that cephalosporin treatment was associated with a significantly higher risk of CDAD in hospitalized patients, while treatment with glycopeptides was significantly associated with a reduction in CDAD (P<0.001 for cephalosporin; P=0.013 for glycopeptides). Our data confirmed previous findings that empirical treatment with cephalosporins is positively associated with CDAD compared to individuals using other CDAD-related drugs. Additionally, we showed that treatment with glycopeptides was negatively associated with CDAD, compared to individuals using other CDAD-related drugs.

Infección por Clostridium difficile: enfrentamiento de la crisis grave y recurrencia / Clostridium difficile infection: management of severe and recurrent disease

Clostridium difficile has become an important healthcare-associated infection due to increased frequency, mortality and recurrence rate. These facts, associated in part to the appearance of epidemic strains have driven changes in diagnostic and therapeutic approaches. The clinical spectrum of C. difficile infection (CDI) ranges from mild diarrhea without systemic compromise to life-threatening pseudomembranous colitis. Metronidazole is the first line treatment in mild CDI; however, the response rate is lower in severe disease, therefore in patients with clinical markers of unfavorable outcome, the first line treatment is oral vancomicin. On the other hand, the increased recurrence rate seen in the last decade with its clinical and economic consequences has forced the development of new therapies that allow change the course of this disease. In this line, the fecal microbiota transplantation and new antibiotics as fidaxomicin has proved to decrease the recurrences.

Clostridium difficile es actualmente una de las principales infecciones asociadas a la atención de salud debido al aumento de su frecuencia, letalidad y capacidad de recurrencia. Estos hechos en parte asociados al surgimiento de cepas conocidas como epidémicas han determinado grandes cambios en el enfrentamiento diagnóstico y terapéutico. El espectro clínico de la infección por C. difficile (ICD) abarca desde una diarrea leve sin compromiso sistémico hasta cuadros de colitis pseudomembranosa que pueden ocasionar la muerte. Metronidazol es el tratamiento de elección de la ICD leve; sin embargo, la tasa de respuesta es inferior en cuadros graves, por lo tanto, en pacientes con marcadores de mal pronóstico vancomicina oral es la terapia de primera elección. Por otro lado, la mayor tasa de recurrencia observada en la última década con sus consecuencias clínicas y económicas ha obligado al desarrollo de nuevas terapias que permitan alterar el curso de la enfermedad. En esta línea, el trasplante de microbiota fecal y nuevos antibióticos como fidaxomicina han mostrado efectividad en reducir las recurrencias.

Recent changes in Clostridium difficile infection / Recentes mudanças da infecção por Clostridium difficile

Clostridium difficile is the main cause of nosocomial diarrhea. Diarrhea associated with C. difficile has increased incidence, morbidity, and mortality in the last few years. The major related risk factors include use of antibiotics, elderly patients and prolonged hospital stay. Many patients receive combinations of antibiotics or multiple antibiotics, which represents the main risk to develop diarrhea associated to C. difficile or its recurrence. Therefore, interventions to improve antibiotic prescribing, as well as compliance with infection control measures can reduce hospital-acquired C. difficile infections. This review addresses the epidemiological changes in C. difficile disease and its treatment.

Clostridium difficile é a principal causa de diarreia hospitalar. A diarreia por C. difficile aumentou sua incidência e sua morbiletalidade nos últimos anos. Os principais fatores de risco relacionados são uso de antibióticos, idosos e permanência hospitalar prolongada. Muitos pacientes recebem combinação de antibióticos ou múltiplos antibióticos, constituindo-se, assim, o principal fator de risco para o desenvolvimento de infecção ou de recorrência de diarreia associada ao C. difficile. Por isso, intervenções que otimizem a prescrição de antibióticos associado à aderência de medidas de controle de infecção podem reduzir aquisição dessa infecção. Assim, esta revisão aborda a mudança da epidemiologia da infecção por C. difficile e seu tratamento.

Effect of Lactobacillus acidophilus & epidermal growth factor on experimentally induced Clostridium difficile infection.

Background & objectives: Clostridium difficile-associated disease (CDAD) remains an important nosocomial ailment. Antimicrobial therapy used for CDAD gives inconsistent results. This experimental study was planned to investigate the beneficial effects of Lactobacillus acidophilus and epidermal growth factor (EGF) for CDAD management. Methods: Among 10 groups of BALB/c mice (6 in each), group 1 served as controls receiving no inoculum. Animals in groups 2-10 received C. difficile, those in groups 3, 6 and 9 received L. acidophilus and those in groups 4, 7 and 10 received EGF after C. difficile inoculation. Animals in groups 5-7 were pre-treated with ampicillin and those in groups 8-10 with lansoprazole prior to C. difficile. The animals were killed and investigated for colonisation by C. difficile and toxin production, myeloperoxidase (MPO) activity and histopathology. Results: Colonisation by C. difficile was found to be significantly different (P<0.001) in the various groups. C. difficile toxin titres and MPO activity were significantly lower in animals given L. acidophilus and EGF after ampicillin (groups 6 and 7) and lansoprazole (groups 9 and 10). The severity of acute inflammation was also significantly less (P<0.05) in caecal and colonic segments of animals in groups 6 and 7 compared to those in group 5. Although the severity of acute inflammation was less in the caecal and colonic segment of animals in groups 9 and 10, the reduction was not significant compared to group 8. Interpretation & conclusions: Our findings showed that the administration of L. acidophilus and EGF reduced the severity of C. difficile infection in the experimental animals.

The management of Clostridium difficile-associated diarrhoea in a community hospital / Tratamiento de diarreas asociadas con Clostridium difficile en un hospital comunitario

OBJECTIVES: To review the management of patients with Clostridium difficile-associated diarrhoea (CDAD). METHODS: A retrospective study was conducted on 26 patients with clinical symptoms of CDAD and positive tests for C difficile toxins A and/or B in stool samples, over a 12- month period. Demographic and clinical data on the patients including use ofproton pump inhibitors (PPI), management of CDAD, and compliance with local Infection Prevention and Control Guidelines were examined. RESULTS: The majority ofpatients were over 45 years of age (24/26, 92.4%) and 42% (11/26) were over 80 years of age. At least 50% (13/26) of the patients had acquired CDAD in hospital, 15% (4/26) were community acquired and symptomatic at admission while the onset of diarrhoea following admission to hospital was not documented in 35% (9/26). Three (11%) patients had used PPI. Fifteen per cent (4/26) of patients had no history of previous antibiotic therapy; 40% (10/26) were treated with a cephalosporin, fluoroquinolone or a combination of at least two different classes of antibiotics; one (3%) patient was on augmentin and the antibiotic regime used was not documented in 42% (11/26) who also had previous antibiotic therapy. The conditions for which antibiotics were prescribed could not be ascertained in 58% (15/26) but among the remaining cases antibiotics had been prescribed for urinary tract infection, wound respiratory tract infections and sepsis. Metronidazole (18/26, 70%) was the preferred drug of choice for first line therapy in patients with CDAD. None of the patients in the study received the recommended 10 to 14 days of antimicrobial therapy for CDAD. Recurrent CDAD was observed in 40% of those who were treated with metronidazole. The study also showed that there was timely reporting oflaboratory results and good compliance with the hospital Infection Prevention and Control Guidelines. CONCLUSION: The findings of this study can be used as a process improvement measure in the management of patients with CDAD.

OBJETIVO: Revisar el tratamiento de pacientes con diarrea asociada con Clostridium difficile (DACD). MÉTODO: Se llevó a cabo un estudio retrospectivo de 26 pacientes aquejados por síntomas clínicos de DACD. Dichos pacientes resultaron positivos a pruebas de detección de toxinas A y/o B de C difficile en muestras de heces fecales por un período de 12 meses. Se examinaron los datos demográficos y clínicos de los pacientes, incluyendo el uso de inhibidores de la bomba de protones (IBP), tratamiento de la DACD, y el cumplimiento con las guías para el control de la infección local. RESULTADOS: La mayoría de los pacientes tenían más de 45 años de edad (24/26, 92.4%) y 42% (11/26) estaban por encima de los 80 años de edad. Al menos 50% (13/26) de los pacientes habían adquirido DACD en el hospital; el 15 % (4/26) la adquirió en la comunidad y presentaba síntomas al momento del ingreso; el comienzo de la diarrea tras el ingreso al hospital no se documentó en 35% (9/26) de los casos. Tres pacientes (11%) habían usado IBP. El 15% (4/26) de los pacientes no tenían antecedente alguno de terapia con antibióticos; un 40% (10/26) fue tratado con cefalosporina, fluoroquinolona, o una combinación por lo menos dos clases diferentes del antibióticos; un paciente (3%) se hallaba bajo tratamiento con augmentina y el régimen antibiótico usado no se documentó en el 42% (11/26) de los casos, que también tuvieron terapia antibiótica previa. No pudieron determinarse las condiciones para las que se prescribieron los antibióticos en el 58% (15/26), pero entre los casos restantes, se habían prescrito antibióticos para la infección de las vías urinarias, heridas, infecciones de las vías respiratorias, y sepsis. El metronidazol (18/26, 70%) fue el medicamento de opción preferida para la terapia de primera línea en los pacientes con DACD. Ninguno de los pacientes en el estudio recibió los 10 a 14 días de terapia antimicrobiana, recomendados para la DACD. Se observó DACD recurrente en 40% de aquéllos que fueron tratados con metronidazol. El estudio también mostró que hubo reportes oportunos de resultados de laboratorio y buen cumplimiento de las guías hospitalarias para el control de las infecciones. CONCLUSIÓN: Los hallazgos de este estudio pueden usarse como medida para mejorar el proceso encaminado a tratar a los pacientes con DACD.

Emergence of Clostridium difficile Ribotype 027 in Korea / 대한진단검사의학회지

BACKGROUND: Clostridium difficile infection (CDI) has markedly risen and is associated with hypervirulent ribotype 027 outbreaks in North America and Europe since 2003. The aims of this study were to determine the prevalence of ribotype 027 among C. difficile isolates in Korea, to characterize the ribotype 027 isolates, and to determine the clinical severity of CDI in patients infected with these isolates. METHODS: A total of 1,251 isolates of C. difficile recovered from stool specimens of suspected CDI patients at two tertiary-care hospitals and one commercial laboratory between 2002 and 2009. Genes for toxin A (tcdA), toxin B (tcdB), and binary toxin (cdtA and cdtB) were detected by PCR. Mutation in the tcdC gene was detected by sequencing after PCR amplification. For molecular genotyping, we performed PCR-ribotyping, pulsed-field gel electrophoresis (PFGE), and multilocus variable-number tandem-repeat analysis (MLVA). Minimum inhibitory concentrations of moxifloxacin were determined using Etest strips (AB bioMerieux, Sweden). RESULTS: We identified 7 isolates as ribotype 027. These isolates had the same tcdC mutation as the epidemic strain, and 6 of them were resistant to moxifloxacin. The isolates were categorized into 3 different PFGE types and 7 different MLVA types. All the 7 cases had occurred sporadically. CONCLUSIONS: C. difficile ribotype 027 is uncommon, but it has emerged in Korea. The spread of this ribotype should be closely monitored in order to avoid an outbreak of CDI in Korea.

Diarrea por clostridium difficile / Clostridium difficile-associated diarrhea

Clostridium difficile (CD), es un bacilo gram positivo, anaerobio formador de esporas identificado como la principal causa de diarrea asociado al uso de antibióticos en pacientes hospitalizados. Los dos factores de riesgo más importantes para adquirir esta infección son el uso reciente de terapia antimicrobiana y la exposición al microorganismo productor de toxinas. La epidemiología de la enfermedad asociada a Clostridium difficile (EACD) ha cambiado sustancialmente en la última década, con un incremento sostenido en la incidencia y aparición de casos más severos, refractarios y recurrentes. La EACD abarca un amplio espectro de manifestaciones clínicas, que van de la portación asintomática, pasando por un cuadro de diarrea leve, hasta el desarrollo de colitis fulminante con una elevada tasa de mortalidad. El tratamiento antibiótico estándar es el metronidazol y vancomicina oral, con tasas de respuesta cercanas a un 95 por ciento por ; sin embargo, luego de la aparición de cepas “hipervirulentas” en el año 2003, la tasa de respuesta al metronidazol ha disminuido en forma significativa. Por ello, en los últimos años, se han comunicado una serie de estrategias y estudios con nuevos antimicrobianos con resultados alentadores. La terapia inmunológica pareciera tener un rol importante en la prevención de recurrencias así como en el manejo de pacientes con enfermedad severa. Se revisan aquellos aspectos más importantes relacionados con la infección asociada a CD.

Clostridium difficile (CD) is an anaerobic, gram-positive, spore-forming, toxin-producing bacillus. This is the leading cause of nosocomial diarrhea associated with antibiotic therapy in hospitalized patients. The two major risk factors for C. Difficile associated disease (CDAD) are recent exposure to an antibiotic and exposure to a toxin producing strain of the microorganism. Epidemiology of CDAD has changed substantially in the last decade, with an increase of incidence and occurrence of more severe, refractory and recurrent episodes. CDAD clinical spectrum varies from asymptomatic carriers, going from mild diarrhea to fulminant colitis with a high mortality rate. The standard antibiotic treatment is oral metronidazole and vancomycin, with response rates close to 90 percent, but after the appearance of “hypervirulent” strains in 2003, the response rate has decreased significantly. Therefore, in recent years many trials have reported a series of strategies and studies with new antimicrobial agents with promising results. Immunotherapy appears to play an important role in preventing recurrence and in the management of patients with a severe disease. The present article will review the most important aspects related to the infection associated with CD.

O Clostridium difficile como agente indutor de diarréia inflamatória / Clostridium difficile as an inflammatory diarrhea inducer agent

O Clostridium difficile tem sido apontado como um importante agente causador de doenças diarreicas associadas ao uso de antimicrobianos. Contudo, em razäo da sua complexidade a fisiopatologia dessas doenças ainda se encontra apenas parcialmente esclarecida, muito embora, uma série de trabalhos cienfíficos demonstrem a importância das toxinas A e B na patogênese da diarréia inflamatória induzida por esse microrganismo. Os mecanismos inflamatórios envolvidos nas atividades biológicas dessas toxinas säo bastante complexos. Existem alguns estudos relatando que a toxina B é desprovida de efeitos enterotóxicos, in vivo. No entanto, essa toxina provoca, de forma dose-dependente, alteraçöes eletrofisiológicas e morfológicas na mucosa colônica humana, in vitro. Ademais, a toxina B estimula a síntese de potentes mediadores inflamatórios, por monócitos e macrófagos. Os efeitos provocados pela toxina A sobre a mucosa intestinal säo bastante evidentes e caracterizam-se por uma intensa secreçäo de fluidos e por um grande acúmulo de células inflamatórias, do tipo macrófagos, mastócitos, linfócitos e neutrófilos, com a conseqüente liberaçäo de seus mediadores, tais como prostaglandinas, leucotrienos, fator de agregaçäo plaquetária, óxido nítrico e citocinas

Diarreas inducidas por antibioticos: adquisiciones recientes sobre clostridium difficile / Antibiotics induced diarrhea-recent knowledge about clostridium difficile

From the beginning of the antibiotherapy, diarrhea frequently ocurred as a side effect of the treatment. The spectrum of diarrheal disease associated with antibiotic therapy ranges from antibiotic associated diarrhea and colitis, to the more severe pseudomembranous colitis, wich is always associated with Clostridium difficile (CD). Because most of the antibiotics are not active against this sporulated Gram positive anaerobe. The pathogenic process accurs only by production of toxins. CD is now recognized as one of the most important hospital infections. Although therapy is available for the majority of patients with CD infection, pseudomembranous colitis is a serious disease which, if untreated, can lead to major complications.

Enteropatía neutropénica asociada a mieloma múltiple / Neutropenic enteropathy associated with multiple myeloma

La enteropatía neutropénica (EN) es una entidad de inicio súbito y con frecuencia grave. La mayoría de casos informados se han identificado al complicar el curso clínico de niños neutropénicos bajo tratamiento para leucemias y linfomas. Con menor frecuencia es observada en adultos neutropénicos con tratamientos para enfermedades autoinmunes, anemia aplásica netopenia cíclica benigna o neoplasias sólidas. Unicamente existen dos casos publicados en los que se encontró asociada a mieloma múltiple (MM). El presente caso corresponde a un hombre de 62 años de edad con diagnóstico de MM de diez meses de evolución y en tratamiento con quimioterapia de rescate. Tres día antes del fallecimiento presentó dolor abdominal, náusea, vómito, diarrea y rectorragia. El estudio de autopsia reveló lesiones ulceradas con engrosamiento de la pared colónica en 40 por ciento de la superficie y en 5 por ciento del ileon terminal. Histológicamente se identificó necrosis isquémica de mucosa y submucosa con invasión bacteriana y ausencia de inflamación aguda. Al igual que los casos informados, recibió vincristina y esteroides pocos días antes de presentar neutropenia grave. El presente trabajo ilustra las características clínicas y morfológicas del tercer caso de asociación de EN con MM, y el primero informado en nuestro medio

Neonatal necrotizing enterocolitis: a clinical study.

Necrotizing enterocolitis was found in 77 infants over a 5 year period. Diagnosis of NEC was established on 4.9 + 4.8 days in babies with birth weight of 1667 + 577 grams and the gestational age of 33.3 + 2.6 weeks. Definite disease occurred in 33 (42.9%) babies while there was strong suspicion in another 44 (57.1%) babies. Prefeed gastric residue (98.7%), abdominal distension (97.3%), lethargy (78.7%), hypotonia (60%) and jaundice (48%) were the main presenting features. However, blood in stools and abdominal wall erythema were found in 38.7% babies. About one third of infants had a positive blood culture. Pneumatosis intestinalis was present in 83.9% of babies and pneumoperitoneum was seen in 35.5% of neonates with NEC. Ileo-ceco-colic region was the commonest site of involvement. Overall survival was 61% and survival with Stage III was only 13%. Birth weight less than 1500 g, gestational age less than 32 weeks, erythema of the abdominal wall, intra-abdominal mass, portal venous gas in abdominal X-ray and Gram negative septicemia were associated with higher mortality.

Comparison of selective media for optimal recovery of Clostridium difficile from diarrhoeal stools.

Five selective media were compared for their efficacy in the recovery of C. difficile from stool specimens. Of 341 diarrhoeic stool samples, 38 (11%) yielded C. difficile. Eighty per cent of the isolates were detected on modified taurocholate cycloserine cefoxitin fructose agar (MTCCFA) and 73 per cent were detected on taurocholate cycloserine cefoxitin fructose agar (TCCFA). MTCCFA was also found superior to the other four media as it supported better growth of C. difficile colonies, by effectively suppressing the competing microflora. These results suggest that the recovery rate of C. difficile could be enhanced when routine media, incorporated with taurocholate and lower concentration of cycloserine and cefoxitin, is used for the isolation of C. difficile from diarrhoeic stool.

Clostridium difficile associated disease in Thailand.

Over a twenty-six month period 383 fecal specimens from 269 diarrheal patients and 114 control patients were examined for Clostridium difficile and its cytotoxin. C. difficile was isolated from 13 (4.8%) of overall age group of diarrheal patients and from 3 (2.6%) of controls. Fecal cytotoxin was detected in 106 (52.5%) of 203 diarrheal patients and in 17 (22.4%) of 76 controls. Sixty-one percent of antibiotic-associated diarrheal patients (less than 3 years) and 51% of non-antibiotic associated diarrhea patients had fecal cytotoxin. Enteric pathogens other than C. difficile were detected in 0.7-7.4% of the patients studied. These data suggest that C. difficile associated disease may be frequently encountered in such a developing region studied. Routine diagnosis for C. difficile in diarrheal patients appears to be warranted.