Clostridium difficile est une bactérie présente sous formes de spores dans l’environnement qui vont être ingérées par l’hôte puis germer en formes végétatives dans le tube digestif. Les formes végétatives vont coloniser l’hôte grâce à différents facteurs de colonisation. Ensuite, C. difficile va produire des toxines A et B qui vont être responsables des signes cliniques de l’infection.Après ingestion et colonisation par une souche toxinogène, les présentations cliniques sont variables d’un individu à l’autre. Certaines personnes vont rester porteuses asymptomatiques et d’autres peuvent déclarer des formes menaçant le pronostic vital. De plus, un caractère particulier de l’infection à C. difficile (ICD) est la survenue de récidives. Cette variabilité inter-individuelle de réponses de l’hôte à la colonisation par C. difficile est probablement multifactorielle mais elle paraît reposer largement sur le développement d’une réponse immune efficace de l’hôte.De nombreux travaux ont évalué l’intérêt de la réponse immune développée contre les toxines de C. difficile aboutissant à l’élaboration de thérapeutiques par immunisations ciblant les toxines.Cependant, la réponse immune dirigée contre les toxines n’est pas exclusive. Au vu des principaux résultats de l’équipe et de la littérature récente, il semble que le précurseur des protéines de la couche S SlpA et la flagelline FliC soient d’une importance particulière puisque ces protéines interagissent activement avec les cellules de l’immunité innée via les TLR (Toll Like Receptor) et sont immunogènes chez l’Homme.Nous avons donc voulu reposer les bases du développement d’une réponse immune chez un individu naïf en utilisant un modèle murin d’ICD.Nous avons montré qu’après une infection dans ce modèle aussi bien qu’après deux infections itératives, les animaux développaient une réponse de type IgM dirigée contre les toxines avec une commutation de classe en IgG au niveau sérique. Cependant, bien que nous ayons également observé la production d’IgM spécifiquement dirigées contre SlpA ou FliC, les souris n’avaient paradoxalement pas développé d’IgG dirigés contre SlpA ou FliC.Nous avons ensuite décidé de mener des essais d’immunisation chez la souris en se focalisant sur SlpA. Après des immunisations répétées, en présence de la toxine cholérique utilisée comme adjuvant, nous avons mis en évidence une réponse spécifique objectivée par une augmentation des IgG sériques et des IgA mucosales anti-SlpA dans les deux modèles. Cette réponse était associée à une diminution significative des taux de colonisation et un retard au décès des hamsters.Nous avons ensuite montré sur une première cohorte prospective que les patients atteints d’une ICD simple avaient significativement plus d’IgG spécifiques anti-SlpA que les patients récidivant de l’ICD entre 5 et 25 jours après l’infection.Enfin, nous avons également constitué une deuxième cohorte de patients sur la base d’une étude cas-témoins avec des objectifs plus ambitieux notamment de constitution de collections biologiques cliniquement documentée. Parmi les objectifs, l’étude vise à déterminer de la valeur prédictive des anticorps dirigés contre les facteurs de colonisation et les toxines de C. difficile sur l’évolution de l’ICD et notamment les récidives. Les résultats préliminaires concernant les IgG dirigés contre SlpA sur les premiers couples de cas et de leurs témoins permettent de confirmer ceux qui avaient été observées sur la première cohorte. L’ensemble des collections biologiques et des données cliniques associées permettront très rapidement de générer de nombreux résultats pour chacun des antigènes d’intérêt et ouvrent à de nombreuses perspectives en termes de compréhension des processus physiopathologiques et d’études ancillaires sur la réponse immune cellulaire et/ou humorale ou l’étude de marqueurs biologiques prédictifs des formes sévères et/ou récidivantes. / Clostridium difficile is a bacterium found in the environment as spores. It can be ingested by a host and germinate under vegetative forms in the digestive tract. These forms colonize hosts through colonization factors. C. difficile will then produce two toxins (A and B), responsible for clinical signs of infection.Following the ingestion and colonization by a toxigenic strain, a wide spectrum of clinical presentations can occur between individuals. Some will remain asymptomatic carriers when others will develop life-threatening infections. Besides, C. difficile infections (CDI) are specific as they can develop recurrences. These inter-individuals variabilities seem to be multifactorial, though, vastly depending on a host efficient immune response.Studies have assessed the interest of an immune response against C. difficile toxins, leading to immunization therapeutics targeting the toxins.However, immune response against toxins isn’t exclusive. Considering our team findings and recent literature, it seems that the S layer proteins precursor SlpA, as well as the FliC flagellin, have an important role. They indeed actively interact with the innate immunity cells via the TLR (Toll Like Receptor) and are immunogen in Humans.We therefore aimed at laying the foundations of an immune response development in a naïve individual, using a CDI mice model.We demonstrated within this model that further to one or two iterative infections, the animals developed an IgM response against the toxins, with a commutation in IgG at the serum level. However, despite the production of IgM specifically targeting SlpA or FliC, mice didn’t develop IgG against SlpA or FliC.We then decided to conduct immunization assays in mice, focusing on SlpA. After repetitive immunizations with the choleric toxin as an adjuvant, we noticed a specific response, objectified by a growth of serum IgG and anti-SlpA mucosal IgA in both models, as well as a significant decrease in colonization levels and a delay in the hamsters’ death.We showed on a first prospective cohort that patients with simple CDI had significantly more specific anti-SlpA IgG than patients with a CDI recurrence, occurring 5 to 25 days post infection.Finally, we constituted a second cohort of patients with a case-control study. It had more ambitious objectives, including the collection of clinically documented biologic samples. Among the objectives, this study aims at assessing the predictive value of antibodies against C. difficile colonization factors and toxins on the CDI evolution, notably on the recurrences.Preliminary results of IgG against SlpA on the first case-control couples confirm the first cohort observations. The biological collections and associated clinical data will soon enable to generate results for each antigen of interest. It opens new perspectives in terms of understanding of pathophysiological processes, and ancillary studies on the cellular and/or humoral immune response, as well as the study of predictive biological markers of severe forms or recurrences.

La diarrhée associée au Clostridium difficile (ICD) est la première cause de diarrhée nosocomiale au Canada. La vancomycine donnée par voie orale est une composante importante du traitement. Des doses plus élevées sont utilisées chez des patients avec une ICD sévère sans aucune évidence clinique supportant cette pratique. Le but de cette étude était de déterminer si les niveaux fécaux de vancomycine varient selon la sévérité de la diarrhée et le dosage de l'antibiotique. Les objectifs spécifiques étaient de développer une technique de dosage de vancomycine adaptée à des spécimens fécaux et de vérifier si des concentrations sériques étaient détectables avec un traitement oral. Les adultes hospitalisés présentant des selles non formées et recevant de la vancomycine orale pour une suspicion d'ICD depuis < 24 heures étaient inclus. Les selles étaient recueillies jusqu'à 3x/jour les 3 premiers jours et 1 fois par jour pour le reste du suivi. Les dosages sériques de vancomycine étaient mesurés aux jours 1 et 3. Les niveaux fécaux et sériques de vancomycine étaient mesurés avec le système AxSYM fluorescence polarization immunoassay Vancomycin II . Un total de 15 patients avec un âge médian de 63 ans, ont été traités avec de la vancomycine orale 4x/jour (QID) pour une suspicion d'ICD. Une infection au C. difficile a été confirmée chez 9 patients par détection de la cytotoxine ou par endoscopie. Des doses élevées de vancomycine (250 mg ou 500 mg QID) ont mené à des niveaux fécaux élevés (>2000 mg/L). Lorsque la vancomycine était administrée à une dose de 125 mg QID, certains patients présentaient des niveaux en dessous de 50 mg/L durant les premiers jours de traitement. Les patients ayant >4 selles/jour avaient des concentrations plus faibles comparés à des patients avec une diarrhée moins sévère. Les concentrations sériques obtenues auprès de 11 patients se situaient entre 0 et 0,77 mg/L, malgré la présence d'une ICD sévère de doses élevées et/ou d'insuffisance rénale. Les concentrations fécales de vancomycine sont proportionnelles au dosage administré et dépassent largement la CMI[indice inférieur 90] (1,0mg/L), même chez les patients avec une diarrhée sévère. Des patients recevant 125 mg QID ont eu des niveaux fécaux peu élevés au début du traitement. Donc, une dose de charge de 250 mg QID pour les premiers 24 à 48 heures serait à considérer chez certains patients.

Clostridium difficile is a clinically problematic pathogen and continues to persist within the healthcare system. Presentation of disease symptoms ranges from mild to severe diarrhoea, through to fulminant pseudomembranous colitis. Approximately 20% of patients will suffer from recurrent episodes and of all patients who die from C. difficile related causes, approximately 41% of death certificates mention C. difficile as an underlying cause of death, and this poses a significant burden on healthcare facilities. Three methods of investigation were employed to develop a more comprehensive understanding of both the host and isolate association with the outcomes of C. difficile infection; mortality and recurrence. These methods were; analysing patient clinical data to try and identify host markers of infection outcomes, evaluating C. difficile type association with infection outcomes, and genetically and phenotypically characterising the clinically relevant C. difficile isolates associated to these outcomes. During this study statistical analysis of clinical data revealed that there were four variables; white cell count, serum albumin, C-reactive protein and respiratory rate, which were prognostic of mortality in patients with C. difficile infection. Threshold levels of these variables were used to create a clinical prediction rule to classify patients with C. difficile infection who were more 'at risk' from mortality, with statistical significance in both a derivation and validation cohort. However, analysis was unable to determine variables prognostic of recurrent infection. Due to small sample sizes of some groups of isolates, no groups of C. difficile isolates were significantly associated with increased recurrent infection or mortality during this study. Some groups of isolates were associated with primary only infection and/or low mortality. There was a non-significant trend in particular C. difficile isolate groups being associated with infection outcome; a panel of representative isolates was therefore chosen to be characterised in more detail. Phenotypic and genetic analysis of a panel of sixteen C. difficile isolates revealed isolate specific differences in toxin production, conservation of transposable elements and SNP abundances, which may have played a role in infection outcome. Isolate motility and antibiotic resistance profiles were not statistically significantly different between isolates within a particular group of C. difficile types. One hypothesis from the collective results obtained during this study suggests that the phenotypic and genotypic changes in isolates may have facilitated differences in their interaction with the host. In turn, the host specific inflammatory response to the infecting C. difficile isolate may have played a role in host outcomes. Research conducted during this study has begun to assess which host specific responses may be important in determining the outcome of C. difficile infection, and which C. difficile isolate characteristics may in part also contribute. However, the assessment of both host and isolate association to infection outcomes would benefit from further investigation in a larger cohort, in order to prove or refute conclusively any hypothesises generated in this study.

Clostridium difficile is the most common cause of nosocomial diarrhoea today. Through the changing epidemiology of C. difficile infection, the emergence and decline of different strains of varying virulence and a broad spectrum of disease from asymptomatic carriage and mild infection to severe pseudomembranous colitis have been observed. The main aim of this three-part thesis was to identify bacterial factors that might explain these variations by comparing five C. difficile strains - strain 630, an historic strain, strain VPI 10463, a reference strain, the hypervirulent ribotype 027 and the current locally endemic ribotypes 001 and 106. The first study focussed on the growth-related phenotypic and genotypic expression of virulence factors in C. difficile. Growth was studied over twenty-four hours, with simultaneous assessment of toxin and spore production. Total toxin production was measured by a commercial ELISA, while a quantitative ELISA for toxin A and a quantitative cytotoxicity assay for toxin B were developed for individual toxin levels, and spores were enumerated by viable counts. Ribotype 027 produced large amounts of toxin A and toxin B and was the second highest spore producer after ribotype 106. Growth may not affect virulence, but the ability to produce more toxins and spores could. To study the transcription of the genes involved in these processes, a real-time RT-PCR was developed. The transcription of the pathogenicity locus (tcdA-E) that regulates toxin production in C. difficile, and of spo0A, the initiator of sporulation, was studied. There were three key observations: firstly, the transcription of tcdC, the negative regulator of toxin production, did not decrease over time, suggesting it has a modulatory rather than repressive effect on the process. Secondly, tcdE expression was highest in ribotype 027, which might explain its hypertoxicity by greater toxin release. Thirdly, there was almost steady state expression of spo0A during the exponential growth phase in ribotypes 106 and 027, the highest spore producers, suggesting prolonged activation of sporulation. Thus, distinct inter-strain differences exist between C. difficile strains in vitro, which could mirror their virulence in vivo, and several traits contribute synergistically to the hypervirulence of ribotype 027. The second study aimed to identify suitable laboratory disinfectants against C. difficile. The efficacy of four commonly-used disinfectants and one decontaminant was tested; one disinfectant was a chlorine-based agent commonly used in hospitals. In conventional susceptibility tests, all five agents were effective against vegetative cells and spores of C. difficile. However, only the chlorine-based disinfectant was effective against spores dried onto surfaces, but this too required more than two minutes of treatment. The presence of organic matter significantly impaired the efficacy of the non-chlorine agents. The spores of epidemic strains were destroyed less effectively and exposure to sub-MIC levels of disinfectant increased sporulation, especially in ribotype 001, a common outbreak strain. Environmental sampling of the laboratory and surrounding areas showed considerable dissemination of C. difficile, highlighting the need for effective decontamination in conjunction with basic hygiene methods like hand-washing. The third study examined the biological activity of C. difficile. Macrophages were challenged in vitro with S-layer proteins, flagella, heat-shock proteins and culture supernatants of the five strains and cytokine production was measured by specially developed ELISAs. No significant inter-strain differences were observed, although the epidemic strains generally elicited a slightly greater cytokine response. Using epithelial cell lines it was observed that epidemic strains showed greater adherence; from inhibition assays, flagella and S-layer proteins were found to contribute equally to this. Through these studies, inter-strain differences between epidemic and historic isolates were identified with respect to virulence factors, survival in the environment and possible behaviour within the host. A sum of these observations suggests increased virulence in contemporary versus historical C. difficile strains. Finally, a supplementary study characterising a collection of ribotype 027 strains isolated in Scotland and the Netherlands by typing schemes, gene sequencing, susceptibility testing and phenotypic studies was performed. In agreement with other studies, the clonality of these hypervirulent strains was observed.

MESQUITA, Ana Maria Ribeiro Cardoso. Diarreia nosocomial e doença associada ao clostridium difficile em pacientes imunossuprimidos de hospital universitário em Fortaleza-CE. 2014. 84 f. Tese (Doutorado em Farmacologia) - Universidade Federal do Ceará. Faculdade de Medicina, Fortaleza, 2014. / Submitted by denise santos (denise.santos@ufc.br) on 2014-08-27T16:21:17Z No. of bitstreams: 1 2014_tese_amrcmesquita.pdf: 2666784 bytes, checksum: fb31c21ded00b7d822d2e31e8dc09359 (MD5) / Approved for entry into archive by denise santos(denise.santos@ufc.br) on 2014-08-27T16:24:51Z (GMT) No. of bitstreams: 1 2014_tese_amrcmesquita.pdf: 2666784 bytes, checksum: fb31c21ded00b7d822d2e31e8dc09359 (MD5) / Made available in DSpace on 2014-08-27T16:24:52Z (GMT). No. of bitstreams: 1 2014_tese_amrcmesquita.pdf: 2666784 bytes, checksum: fb31c21ded00b7d822d2e31e8dc09359 (MD5) Previous issue date: 2014 / Nosocomial diarrhea (ND) is a healthcare - associated infections (HAI) with increasing incidence and severity. It is proposed to determine the incidence of ND, the associated risk factors and the incidence of disease associated to Clostridium difficile (C. difficile). For this, a case - control study, pairing patients by age, sex, length of admission, and clinical diagnosis was conducted 06 / Feb/12 to 05/Fev/13 in the University Hospital of the UFC. Cases: patients with DN and controls: patients without ND. Nosocomial diarrhea is defined as watery stools, three or more times within 24 hours, over 12 hours without further diagnostic procedures or inflammatory causes. ND was detected by active surveillance, visiting the patients of Hematology, Liver and Renal Transplant. DN was defined as loose stools, 3 or more times in 24 hours, with duration longer than 12 hours, without other inflammatory causes or diagnostic procedures. The ELISA TOX A / B II test was used to detect toxin A and/or B and to diagnose C. difficile associated disease. Others HAI were investigated by the notification records of nosocomial infection (NI). The overall rate of Nosocomial infection was 7.17 %. The incidence of DN in the wards of Hematology, Liver and Renal Transplant was 4.80% (44/925) and C. difficile associated with DN was 0.12 % (01/925). Toxins A/B were detected in the case of C. difficile [1/43 (2.32%)] and controls [3/72 (4.17%)]. DN was significantly associated with previous use > 6 antimicrobials per patient, beyond the prior use of ciprofloxacin, metronidazole, polymyxin B and enteral feeding (p ≤ 0.05). Patients with ND remained in hospital longer, had more vomiting, cramps and fever, verifying high statistical significance (p ≤ 0.05). Other identified HAI were mainly urinary infection 54% (15/28), followed by bacterial bloodstream infection 32% (8/28), surgical site infection 11% (3/28) and soft tissue infection 4% (1/28). ND entails risks to the already debilitated patients. The data demonstrate the presence of endemic C. difficile. The updated of the local epidemiology guide control measures NI, such as judicious use of antibiotics, enteral feeding precautions and contact precautions for patients with nosocomial diarrhea. / Diarreia nosocomial (DN) é uma infecção relacionada à assistência à saúde (IRAS) com incidência e severidade crescentes. Propõe-se determinar a incidência da DN, os fatores de risco e a incidência da doença associada a Clostridium difficile (C. difficile). Para isso, um estudo caso – controle, pareando pacientes por idade, sexo, período de admissão, clínica e diagnóstico, foi conduzido, de 06/ fev/12 a 05/fev/13, no Hospital Universitário da UFC. Casos ̶ pacientes com DN e Controles ̶ pacientes sem DN. Definiu-se DN como fezes líquidas, três ou mais vezes em 24 horas, com duração superior a 12 horas, sem outras causas inflamatórias ou procedimentos diagnósticos. DN foi detectada mediante busca ativa, visitando-se os pacientes das Unidades de Hematologia, Transplante Hepático e Renal. O teste ELISA TOX A/B II foi utilizado para detectar as toxinas A e/ou B e diagnosticar doença associada ao C. difficile. Demais IRAS foram investigadas por intermédio de fichas de notificação de infecção hospitalar (IH). O índice geral de IH foi de 7,17%. A incidência da DN nas enfermarias de Hematologia, Transplante Hepático e Renal foi 4,80% (44/925) e da DN associada ao C. difficile 0,12% (01/925). Detectaram-se toxinas A/B de C. difficile em caso [1/43 (2,32%)] e controles [3/72 (4,17%)]. DN foi significantemente associada ao uso prévio > 6 antimicrobianos por paciente, além do uso prévio de ciprofloxacina, metronidazol, polimixina B e dieta enteral (p≤ 0,05). Pacientes com DN permaneceram mais tempo internados, tiveram mais vômitos, cólicas e febre, verificando-se alta significância estatística (p≤ 0,05). Outras IRAS identificadas, nos casos e controles, foi infeção do trato urinário 54% (15/28), seguida da corrente sanguínea 32% (8/28), do sítio cirúrgico 11% (3/28) e de infecção de partes moles 4% (1/28). DN impõe riscos aos pacientes já debilitados. Os dados demonstram a presença endêmica do C. difficile. A atualização da epidemiologia local orienta medidas de controle da IH, como uso judicioso de antibióticos, cautelas com a dieta enteral e precauções de contato, para os pacientes com diarreia nosocomial.

Class of 2012 Abstract / Specific Aims: The incidence of non-response, recurrence, relapse, and rate of complications of Clostridium difficile infections treated with combination of metronidazole and vancomycin versus vancomycin or metronidazole alone over a one-year period by treatment and strain type (i.e. NAP1/BI/027) were evaluated. The incidence of mortality in patients with moderate to severe Clostridium difficile associated diarrhea prescribed metronidazole, vancomycin, or combination metronidazole plus vancomycin as initial therapy was also determined. Additionally, significant factors associated with the use of combination vancomycin-metronidazole as initial therapy for moderate to severe CDAD were characterized. Methods: T This retrospective medical record review has been approved by the Institutional Review Board. Adult patients with stool specimens tested for detection of Clostridium difficile toxin B by PCR between April 2010 and March 2011 at a tertiary care, academic medical center were evaluated. Patients were included in the study if diagnosed with moderate to severe disease and received either monotherapy with metronidazole, monotherapy with oral vancomycin, or combination therapy with metronidazole and oral vancomycin for at least 80% of the first 10 days of treatment. Patients who are discharged alive within 72 hours of admission or who received therapy for less than 48 hours were excluded. Main Results: All patients (N=411) with laboratory evidence of Clostridium difficile during the study time period were evaluated. A total of 26 subjects who received oral vancomycin monotherapy and 56 subjects who received oral vancomycin along with metronidazole for at least 80% of the first 10 days of treatment were identified. Of the subjects who received oral vancomycin monotherapy during the first ten days of therapy, 5 (19%) were classified has a treatment failure or died within the first 21 days of therapy and 5 (19%) had either a recurrence or reappearance of Clostridium difficile associated diarrhea between 22 and 65 days post start of therapy. Of the subjects who received a combination of oral vancomycin and metronidazole during the first 10 days of therapy, 14 (25%) were classified has a treatment failure or died within the first 21 days of therapy and 22 (39%) had either a recurrence or reappearance of Clostridium difficile associated diarrhea between 22 and 65 days post start of therapy. In the combination therapy group, 5 (9%) were reported to have an ileus, toxic megacolon, or necrotic bowel during the first 10 days of therapy. Conclusions: In this study, the subjects who received a combination of oral vancomycin and metronidazole had higher rates of clinical failure, death, and recurrence than subjects who received monotherapy. Current guideline statements recommend combination therapy only in patients with an ileus with Clostridium difficile-associated diarrhea.

Die CDI ist weltweit die häufigste Ursache der antibiotikaassoziierten nosokomialen Diarrhoe. Sie geht mit steigender Inzidenz, Hospitalisierung und hohen Behandlungskosten in Milliardenhöhe einher. Auch im ambulanten Sektor werden steigende Infektionszahlen gemeldet, die nicht nur ein Problem für die Krankenhäuser, sondern auch für die Pflegeeinrichtungen darstellen. Ziel dieser Arbeit war es, retrospektiv die CDI-Fälle des Klinikums Aschaffenburg-Alzenau (ausgenommen Kinderklinik) im Zeitraum 01.01.2013 - 25.05.2015 zu erfassen und die antibiotische Initialtherapie zu ermitteln. Für die Diagnose einer CDI wurde ein positiver Toxinnachweis in der Stuhlkultur vorausgesetzt. Im weiteren Fokus standen die Rezidivhäufigkeit, die antibiotische Folgetherapie, die Komplikationen bis hin zu den Todesursachen sowie Präventionsmaßnahmen. Im o.g. Zeitraum waren 299 Patienten und Patientinnen mit einer CDI hospitalisiert. Das mittlere Alter lag bei 73,8 Jahren. Es handelte sich in der Mehrzahl um multimorbide und immunsupprimierte Patienten und Patientinnen. 61% waren antibiotisch vorbehandelt. Am häufigsten verwendet wurden Breitbandpenicilline (36%), Cephalosporine der 3. Generation (12%) und Fluorchinolone (10%). Über 1/3 der Patienten und Patientinnen wurde mit Mehrfachkombinationen behandelt und bei 2% war eine zytostatische Behandlung vorausgegangen. In der Initialtherapie der CDI kam bei fast der Hälfte Erkrankten (47%) Metronidazol zur Anwendung. Die Rezidivrate lag bei 20%, Mehrfachrezidive traten bei 5,7% auf. Die antibiotische Folgetherapie der CDI erfolgte bei 39% der Patienten und Patientinnen mit Vancomycin oder Fidaxomicin entsprechend den damals geltenden Empfehlungen leitlinienkonform. Rund ¼ aller Erkrankten verstarben, davon 17% CDI-assoziiert. Der fäkale Stuhltransfer, der ab dem 2. Rezidiv empfohlen wird, und die Genotypisierung bei Mehrfachrezidiven wurde in keinem Fall durchgeführt. 2021 wurde die CDI-Behandlungsleitlinie der ESCMID aktualisiert. Statt dem Einsatz von Metronidazol werden nun Fidaxomicin oder Vancomycin, in Rezidivsituationen die Standardantibiose um den Antikörper Bezlotoxumab ergänzt. 06/2023 erschien die Konsultationsfassung der S2k-Leitlinie “Gastrointestinale Infektionen und Morbus Whipple” der DGVS. Die Empfehlungen gleichen sich. Es kann festgehalten werden, dass die CDI auch im Klinikum Aschaffenburg-Alzenau ein ernstes Problem darstellt, das Präventionsmaßnahmen bedarf. Die Rezidiv- und Todesraten sind hoch. In dieser Arbeit konnte bestätigt werden, dass der unbedachte Einsatz von Antibiotika ein wichtiger Hauptrisikofaktor für die Entstehung einer CDI ist. Daher sollte die Indikation für eine antibiotische Therapie streng gestellt werden. Die Daten zeigen ferner, dass die Umsetzung aktueller Leitlinienempfehlungen nicht oder zeitlich verzögert erfolgte. Seit der Etablierung und Umsetzung des ABS 2017 am Klinikum Aschaffenburg-Alzenau konnte ein Rückgang der CDI um 21% verzeichnet werden. Ein ABS ist eine Möglichkeit die konsequente Anwendung aktueller Empfehlungen im klinischen Alltag umzusetzen und so zu einer höheren Erfolgsrate der Behandlung und einer niedrigeren Rezidivrate beizutragen. Die Umsetzung einer gezielten frühen Diagnostik, Schutz- und Isoliermaßnahmen, Surveillance und regelmäßige Fort- und Weiterbildung der Mitarbeiter*innen sind weitere wichtige Bausteine, die zur Prävention der CDI beitragen. / CDI is the most common cause of antibiotic-associated nosocomial diarrhea worldwide. It is accompanied by rising incidence, hospitalization and high treatment costs in the billions. Rising numbers of infections are also reported in the outpatient sector, posing a problem not only for hospitals, but also for care facilities. The aim of this study was to retrospectively record the CDI cases of the Aschaffenburg-Alzenau Hospital (except for the Children's Hospital) in the period 01.01.2013 - 25.05.2015 and to determine the initial antibiotic therapy. For the diagnosis of CDI, a positive toxin detection in the stool culture was required. The focus was also on the frequency of recurrence, antibiotic follow-up therapy, complications and causes of death, and preventive measures. In the above-mentioned period, 299 patients with CDI were hospitalized. The median age was 73.8 years. The majority of them were multimorbid and immunosuppressed patients. 61% were pre-treated with antibiotics. The most commonly used antibiotics were broad-spectrum penicillins (36%), 3rd generation cephalosporins (12%) and fluoroquinolones (10%). In the initial therapy of CDI, metronidazole was used in almost half of the patients (47%). The recurrence rate was 20%, multiple recurrences occurred at 5.7%. Follow-up antibiotic therapy of CDI was carried out in 39% of patients with vancomycin or fidaxomicin in accordance with the guidelines in force at the time. About 1/4 of all patients died, 17% of them CDI-associated. Fecal microbiota transplantation, which is recommended from the 2nd recurrence, and genotyping in case of multiple recurrences was not performed in any case. In 2021, ESCMID's CDI treatment guideline, was updated. Instead of the use of metronidazole, fidaxomicin or vancomycin are now supplemented, and in relapse situations, the standard antibiosis is supplemented by the antibody bezlotoxumab. 06/2023, the consultation version of the S2k guideline "Gastrointestinal Infections and Whipple's Disease" of the DGVS was published. The recommendations are similar. It can be stated that CDI is also a serious problem at the Aschaffenburg-Alzenau Hospital, which requires preventive measures. The recurrence and Death rates are high. This study confirmed that the careless use of antibiotics is an important main risk factor for the development of CDI. Therefore, the indication for antibiotic therapy should be set strictly. The data also show that the implementation of current guideline recommendations did not take place or was delayed. Since the establishment and implementation of the ABS in 2017 at the Aschaffenburg-Alzenau Hospital, a 21% decline in CDI has been recorded. An ABS is a way to implement the consistent application of current recommendations in everyday clinical practice and thus contribute to a higher success rate of treatment and a lower recurrence rate. The implementation of targeted early diagnostics, protective and isolation measures, surveillance and regular further education and training of employees are further important building blocks that contribute to the prevention of CDI.

No description available.

Clostridium difficile ist einer der führenden Nosokomialkeime in Bezug auf postoperative Diarrhoe. Die Inzidenz ist steigend und der Verlauf bei fulminanter Infektion häufig fatal. Es besteht der Anspruch der Vermeidung schwerer Verläufe und der horizontalen Verbreitung des Erregers. Ziel der Arbeit war, für den prä-, intra- und postoperativen Zeitraum Risikofaktoren zu identifizieren, welche Einfluss auf Ausprägung und Schwere der Infektion hatten. Die vorliegende klinische Studie umfasst 2.823 Patienten mit Diarrhoe nach kardiochirurgischem Eingriff, darunter 1.256 Patienten mit Clostridium-difficile-Nachweis, welche im Herzzentrum Leipzig von April 1999 bis April 2011 operativ versorgt worden sind. Die Datenanalyse erfolgte retrospektiv an zuvor festgelegten Parametern, die mittels statistischer Verfahren analysiert wurden. Besonderes Augenmerk wurde auf die Entwicklung gastrointestinaler Komplikationen und die Mortalität gelegt. Risikofaktoren für eine fulminante CDI waren u.a. männliches Geschlecht, kardiopulmonale Komorbiditäten, Diabetes mellitus Typ II, Verwendung von Assist-Systemen, perioperative Transfusionstherapie, sowie lange Operationszeiten und ein verlängerter Aufenthalt auf Intensivstation. Das Überleben bei fulminanter Infektion war mit einer Sterblichkeit von 63,4% bei einer 30-Tages-Mortalität von 21,6% deutlich schlechter als das der Vergleichsgruppen. Die Identifikation der perioperativen Risikofaktoren soll eine individualisierte Stratifizierung und damit die optimale Überwachung von Hochrisikopatienten für einen frühen Therapiebeginn und im besten Falle eine Prävention möglich machen.

Clostridium difficile est un pathogène entérique pouvant causer des diarrhées allant de modérées à sévères, des colites pseudomembraneuses et même la mort. Les traitements actuels contre la bactérie ont des taux de rechutes élevés. De plus, il n'existe pas à ce jour de vaccin permettant de prévenir l'infection. Cette étude épidémiologique porte sur la protection contre la colonisation et/ou la maladie conférée par la présence d'anticorps sériques naturels spécifiques aux antigènes de la bactérie. Nous avons développé un test ELISA (Enzyme-Linked ImmunoSorbent Assay) pour la détection des anticorps contre les toxines A et B de C. difficile et contre les protéines du flagelle (flagellines) dans des échantillons de sérum. Notre test ELISA servant à détecter les anticorps dirigés contre la toxine B a été calibré de façon à obtenir la meilleure corrélation possible avec le test de neutralisation de la cytotoxicité de la toxine B. Les paramètres du test ELISA ainsi mis au point ont été appliqués aux autres antigènes (toxine A et flagellines), pour lesquels un test de référence n'existe pas. Par la suite, nous avons tenté de définir le rôle de la réponse immunitaire humorale de l'hôte en corrélant les résultats de l'analyse des sérums de deux groupes de patients hospitalisés avec les informations sur le suivi des symptômes et la recherche de la présence de la bactérie dans les selles. Le premier groupe de patients nous a permis d'étudier la relation entre la survenue de la colonisation ou de l'infection par C. difficile et la production d'anticorps. Nos résultats montrent que les anticorps sériques ne semblent pas protéger le patient de l'implantation de la bactérie au tube digestif mais que suite à l'infection, une réponse humorale est mise en place contre les toxines du pathogène. Les patients du deuxième groupe, des patients hospitalisés infectés par C. difficile, ont été surveillés pour la survenue de symptômes sévères, du décès ou de rechutes suite à un épisode de maladie. Nous avons observé une plus grande prévalence d'anticorps sériques dirigés contre la toxine B et contre certaines flagellines chez les patients ayant eu une infection simple, sans complications ni rechutes. Les résultats de nos travaux indiquent donc que certains patients développent une réponse humorale contre les antigènes de C. difficile et que les anticorps produits, particulièrement ceux dirigés contre la toxine B, semblent impliqués dans la défense du patient contre la survenue de complications et de rechutes. Nos données laissent toutefois sous-entendre que d'autres caractéristiques de l'hôte contribuent de façon importante à la défense contre la colonisation et l'infection par C. difficile. Des travaux supplémentaires sont nécessaires afin de définir les paramètres qui permettront d'élaborer un protocole de vaccination optimal contre C. difficile.